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European Journal of Medicinal Chemistry 46 (2011) 4769e4807

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European Journal of Medicinal Chemistry

journal homepage: http: / /www.elsevier .com/locate/ejmech

Mini-review

Natural products: An evolving role in future drug discovery

Bhuwan B. Mishra, Vinod K. Tiwari*

Department of Chemistry, Centre of Advanced Study, Banaras Hindu University, Varanasi 221005, India

a r t i c l e i n f o

Article history:Received 7 June 2011Received in revised form29 July 2011Accepted 30 July 2011Available online 16 August 2011

This manuscript is dedicated toProf. Goverdhan Mehta, Indian Institute ofScience, Bangalore.

Keywords:Natural productsClinical developmentDrug discoveryApproved drugs

* Corresponding author. Fax: þ91 542 2368174.E-mail addresses: [email protected], vtiwa

0223-5234/$ e see front matter � 2011 Elsevier Masdoi:10.1016/j.ejmech.2011.07.057

a b s t r a c t

The therapeutic areas of infectious diseases and oncology have benefited from abundant scaffold diversityin natural products, able to interact with many specific targets within the cell and indeed for many yearshave been source or inspiration for the majority of FDA approved drugs. The present review describesnatural products (NPs), semi-synthetic NPs and NP-derived compounds that have undergone clinicalevaluation or registration from 2005 to 2010 by disease area i.e. infectious (bacterial, fungal, parasitic andviral), immunological, cardiovascular, neurological, inflammatory and related diseases and oncology.

� 2011 Elsevier Masson SAS. All rights reserved.

1. Introduction

Natural productshavebeen themajor sourcesof chemicaldiversityfor startingmaterialswhile driving pharmaceutical discoveryover thepast century. Historically pharmaceutical companies have utilizedplant extracts to produce relatively crude therapeutic formulations,butwith the advancementof antibiotics in themid-twentieth century,drug formulations of fairly purified compounds have become moretypical [1]. The interesting chemicals identified as NPs are derivedfromthephenomenonofbiodiversity inwhich the interactionsamongorganisms and their environment formulate the diverse complexchemicalentitieswithin theorganisms thatenhance their survival andcompetitiveness [2]. The therapeutic areas of infectious diseases andoncology have benefited from these numerous drug classes, able tointeract with many specific targets within the cell, and indeed formany years have been central in the drug discovery anddevelopment.Today, NPs are finding increasing use as probes to interrogate bio-logical systems as part of chemical genomics and related researches.

The review summarizes the 3 groups of compounds classified asNPs, semi-synthetic NPs and NP-derived compounds that haveundergone clinical evaluation or registration form 2005 to June 2010by disease area i.e. infectious (bacterial, fungal, parasitic and viral),immunological, cardiovascular, neurological, inflammatory andrelated diseases and oncology. The compoundswhich have biological

[email protected] (V.K. Tiwari).

son SAS. All rights reserved.

activities and are derived from natural sources, e.g., plants, animalsandmicroorganisms, have been grouped asNPs. The compounds thatare derived from a NP template using semi-synthesis have beengrouped in semi-synthetic NPs while the compounds that weresynthetically derived or in some cases inspired from a NP templatehave been classified as NP-derived compounds [3e5]. Previousreviews in this general area come from the 2005 reviews by Kingstonand Newman [6,7], Koehn and Carter [8], Paterson and Anderson [9];the 2006 reviews by Jones et al. [10], Gullo et al. [11], Wilson andDanishefsky [12]; the 2007 reviews by Lam [13], Baker et al. [14],Harvey [15]; the 2008 review by Butler [16]. This review representsa thorough evaluation of publicly available data on NP-derived drugsand templates. Compounds derived from primary metabolites (e.g.steroids, nucleosides, prostaglandins, sialic acid and tyrosine), vita-mins (e.g. vitaminD and retinoids), hormones and protein fragments,herbalmixtures, polyaminesandporphyrinderivativeshavenot beenlisted exhaustively in this review.

2. Drug approval processes

An Investigational New Drug (IND) application is submitted tothe FDA or EMA before commencement of clinical trials. Onceclinical trials are successfully completed, the applicant files a NewDrug Application (NDA) in the US or a Marketing AuthorizationApplication (MAA) in Europe to seek approval for marketing thedrug. The agency then responds in the form of an ‘approval letter’,a ‘non-approval letter’ or an ‘approvable letter’. An “approval letter”

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B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e48074770

allows the applicant to begin marketing the product, while a “non-approval letter” rejects the application. An ‘approvable letter’informs the applicants that the agency have completed theirscientific review and determined that the application can beapproved pending resolution of minor deficiencies identified in theletter or during an inspection of the manufacturing facilities.

3. Natural products based drugs approved during 2005e2010

A total of 19 NP based drugs were approved for marketingworldwide in between the year 2005 to 2010 (Scheme 1), amongwhich 7 are classified as NPs, 10 as semi-synthetic NPs, and 2 as NP-derived drugs (Table 1).

Veregen� (Polyphenon� E ointment), a defined mixture ofcatechins obtained from green tea, is the first ever herbal medicineto receive FDA approval in 2006. Veregen� was developed byMediGene AG and launched in the US by Bradley Pharmaceuticalsin December 2007 for topical use against genital warts. MediGenesigned an agreement with Solvay in 2009 for the licensing andsupply of Veregen� in Germany, Austria, and Switzerland. InMarch2010, Solvay launched Veregen� (10% ointment) in Germany [17].

Sativex� (GWPharmaceuticals) is theworld’sfirst pharmaceuticalprescriptionmedicine derived from the cannabis plant [18]. Sativex�,a mixture of dronabinol 1 and cannabidol 2, was launched in CanadainApril 2005 for neuropathic pain relief inmultiple sclerosis [19], andit was also approved by Health Canada in August 2007 as anadjunctive analgesic for severe pain in advanced cancer patients,

Scheme 1. Drugs approve

reducing the need for the opioidmedications. Otsuka Pharmaceuticalin February 2007 signed an agreement with GW for further devel-opment and marketing of Sativex� in the USA. Sativex� efficientlyreduces pain in patients with advance cancer [20] and has been rec-ommended by the FDA for direct entry into Phase III trials. InNovember 2009, GW Pharmaceuticals disclosed that recruitment fora Phase II/III cancer pain trial of Sativex� had been completed. InMarch2010,GWPharmaceuticals providedanupdateon theprogressof regulatory submission for Sativex� oromucosal spray for thetreatmentof the symptomsof spasticitydue tomultiple sclerosis [21].

Fumagillin (Flisint�, Sanofi-Aventis, 3), an antimicrobial leadcapable of inhibiting the proliferation of endothelial cells, wasisolated from Aspergillus fumigatus [22]. In September 2005, Franceapproved 3 against intestinal microsporidiosis, a disease caused bythe sporeforming unicellular parasite Enterocytozoon bieneusi,causing chronic diarrhea in immunocompromised patients [23].

There are presently nine b-lactams (two cephalosporins, sixcarbapenems and one penem) in clinical trials or undergoing drugregistration. Among carbapenem-type b-lactams, doripenem 4 andthienamycin 5 are the ultra-broad spectrum injectable antibiotics.Doripenem (Finibax�, Doribax�) 4, exhibiting a broad antibacterialspectrum [24a] was launched in Japan by Shionogi & Co. in 2005. InOctober 2007, Johnson& Johnson (J&J) obtained formal FDAapprovalfor use of 4 in intra-abdominal and urinary tract infections [24b].

Tigecycline (Tygacil�, 6) is among a newgeneration of antibioticscalled glycylcyclines, and is structurally similar to tetracycline 7. Itcontains a centralized four-ring carbocyclic skeleton substituted at

d during 2005e2010.

Table 1NP-derived drugs launched since 2005; lead compounds, classification and therapeutic area [17e117].

Year Generic name (trade name) Lead compound Classification Disease area

2005 Dronabinol 1/Cannabidol 2 (Sativex�) Dronabinol 1/cannabidol 2 NPs Pain2005 Fumagillin 3 (Flisint�) Fumagillin 3 NPs Antiparasitic2005 Doripenem 4 (Finibax�/Doribax�) Thienamycin 5 NP-derived Antibacterial2005 Tigecycline 6 (Tygacil�) Tetracycline 7 Semi-synthetic NP Antibacterial2005 Ziconotide 8 (Prialt�) Ziconotide 8 NP Pain2005 Zotarolimus 9 (Endeavor� stent) Sirolimus 10 Semi-synthetic NP Cardiovascular surgery2006 Anidulafungin 11 (Eraxis�/Ecalta�) Echinocandin B 12 Semi-synthetic NP Antifungal2006 Exenatide 13 (Byetta�) Exenatide-4 13 NP Diabetes2007 Lisdexamfetamine 14 (Vyvanse�) Amphetamine 15 NP-derived ADHD2007 Retapamulin 16 (Altabax�/Altargo�) Pleuromutilin 17 Semi-synthetic NP Antibacterial2007 Temsirolimus 18 (Torisel�) Sirolimus 10 Semi-synthetic NP Oncology2007 Trabectedin 19 (Yondelis�) Trabectedin 19 NP Oncology2007 Ixabepilone 20 (Ixempra�) Epothilone B 21 Semi-synthetic NP Oncology2008 Methylnaltrexone 22 (Relistor�) Naltrexone 23 Semi-synthetic NP Pain2009 Everolimus 24 (Afinitor�) Sirolimus 10 Semi-synthetic NP Oncology2009 Telavancin 25 (Vibativ�) Vancomycin 26 Semi-synthetic NP Antibacterial2009 Romidepsin 27 (Istodax�) Romidepsin 27 NP Oncology2009 Capsaicin 28 (Qutenza�) Capsaicin 28 NP Pain2010 Monobactam aztreonam 29 (Cayston�) Aztreonam 29 Semi-synthetic NP Antibacterial

B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807 4771

the D-9 position conferring broad spectrum activity. Tigecyclineeffectively binds to the 30S subunit of bacterial ribosome and blocksthe entry of amino-acyl tRNA molecules into the A site of the ribo-some, thus inhibits protein translation [25]. Tigecycline was devel-oped by Wyeth [26a] and in June 2005 the FDA approved it fortreatment of complicated skin and skin structure infections(cSSSIs) and intra-abdominal infections. Tigecycline was approvedin Europe in May 2006, and a supplemental NDA for community-acquired pneumonia (CAP) was submitted to the FDA in October2007 [26b].

Ziconotide (Prialt�, 8) is a synthetic form of the peptide u-con-otoxin,whichwas isolated fromthe toxinofConusmagus, is anN-typevoltage sensitive calcium channel blocker and is proposed to regulateneurotransmission by inhibiting pro-nociceptive neurochemicalreleases in the brain and spinal cord, thus causing pain relief [27]. InDecember 2004, the FDA approved 8when given as an infusion usingan intrathecal pump into the cerebrospinal fluid. In 2005, Elanlaunched Ziconotide 8 in the US and Europe for the treatment ofpatients suffering from chronic pain. Rights for marketing Ziconotide(Prialt�) in Europe was obtained by Eisai in March 2006 [28].

Zotarolimus 9, a derivative of sirolimus 10, is the active principleof the Endeavor� stent that inhibits cell proliferation, preventingscar tissue formation and minimizeing restenosis in angioplastypatients [29]. Sirolimus 10 (Rapamune�, Wyeth) was originallydiscovered from the bacterium Steptomyces hygroscopicus asa promiscing antifungal agent [30] and is being used along withother coronary stents against restenosis of coronary arteries due toballoon angioplasty. In July 2005, Medtronic received Europeanapproval for the sale of the Endeavor� drug-eluting coronary stentthat consists of a cobalt-based alloy integrated with a biomimeticphosphorylcholine polymer [31]. In February 2008, Medtronicreceived FDA approval for the Endeavor� in the treatment of coro-naryarterydisease [32a]while Cypher� (sirolimus-eluting coronarystent) is being marketed by Cordis (Johnson & Johnson) [32b].

Anidulafungin11 (Eraxis� in theUS,Ecalta� inEurope), is a semi-synthetic derivative of the fungal metabolite echinocandin B 12.Anidulafunginwas originally developed for use against invasive andoesophageal candidiasis and candidemia by Eli Lilly andwas licensedto Vicuron Pharmaceuticals, which was purchased by Pfizer in June2005. Pfizer gained the FDA approval in February 2006 (Eraxis� inthe US) and EMEA approval in July 2007 [33].

Exenatide 13 (Byetta�), is a 39 amino acid peptide, structurallysimilar to glucagon-like peptide-1 (GLP-1) and was isolated from

the oral secretions of the poisonous lizard Heloderma suspectum(Gila monster) [34,35]. Among the incretin (human hormone)mimetics, 13 can mimic the antidiabetic or glucose-loweringproperties of incretins. Eli Lilly obtained the FDA approval in April2005 while Amylin Pharmaceuticals gained the EMEA approval inNovember 2006 for the use of 13 as an adjunctive therapy in type 2diabetes mellitus [36]. Amylin Pharmaceuticals, Eli Lilly andAlkermes in May 2009 submitted a NDA for subcutaneous dosing of13 once weekly to the FDA, which was approved in July 2009.

Attention-Deficit Hyperactivity Disorder (ADHD), a neuro-developmental disorder in which dopaminergic and noradrenergicneurotransmission are supposed to be dysregulated, is primarilycharacterized by the co-existence of attentional problems andhyperactivity. Methylphenidate and amphetamines have been usedfor ADHD management for many years but due to abuse potentialsthese drugs are controlled substances [37]. Lisdexamfetamine(Vyvanse�, NRP104) 14 consisting of dextroamphetamine coupledwith the essential amino acid L-lysine was designed by New RiverPharmaceuticals to help ADHD. Intravenous administration 14produces effects similar to placebo and therefore is completelyineffective, however on oral administration it gets converted toD-amphetamine 15 in the gastrointestinal (GI) tract [38]. InFebruary 2007, New River Pharmaceuticals and Shire Pharmaceu-ticals obtained the FDA approval for use of 14 to help ADHD, and inApril 2007 Shire bought New River Pharmaceuticals.

Pleuromutilin 16 is ametabolite of fungal origin that binds to thepeptidyltransferase and exhibits antibacterial activity by inhibitingprotein synthesis in bacteria [39]. Retapamulin (SB-275833) 17,a semi-synthetic derivative of 16, is the first among pleuromutilinantibiotics developed by GlaxoSmithKline for topical use in impe-tigo caused byGram-positive Staphylococcus aureus or Streptococcuspyogenes [40]. GlaxoSmithKline gained FDA approval for 17 in April2007 [68] and the EMEA approval in June 2007 for a 1% retapamulinointment (called Altabax� in the US and Altargo� in Europe).Temsirolimus (Torisel�, CCI-779,18) is a sirolimus 10 derivative andis an intravenous drug developed byWyeth [41]. It was approved bythe FDA in lateMay2007andby the EMEA inNovember 2007 for useagainst renal cell carcinoma (RCC) [42]. Temsirolimus 18 is a semi-synthetic derivative of sirolimus 10 and is the first mTOR inhibitordeveloped by Wyeth Pharmaceuticals [43].

Trabectedin (Yondelis�, ecteinascidin-743, ET-743, 19), a tetra-hydroisoquinoline alkaloid produced by Ecteinascidia turbinate [44]is sold by Zeltia and Johnson & Johnson for use in the treatment of

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advanced soft tissue sarcoma [45]. Trabectedin binds to the minorgroove of DNA and inhibits cell proliferation by disrupting the cellcycle. It was approved by the EMEA in September 2007 for useagainst soft tissue sarcomas and ovarian cancer. In November 2009,it received its second marketing authorization from the EuropeanCommission for the treatment of relapsed platinum-sensitiveovarian cancer in combination with DOXIL�/Caelyx�. Presently,trabectedin is in Phase II trials against pediatric sarcomas, breastand prostate cancers [46].

Ixabepilone (Ixempra�, BMS-247550, 20) is a semi-syntheticderivative of epothilone B 21 produced by Sorangium cellulosum[47]. Bristol-Myers Squibb (BMS) developed 20 as an anticancerdrug that binds directly to b-tubulin subunits on microtubules,leading to the suppression of microtubule dynamics, blocking ofcells in the mitotic phase, ultimately leading to cell death. InOctober 2007, the FDA approved ixabepilone 20 (Ixempra�) asmonotherapy and in combination with capecitabine (Xeloda�)against metastatic or locally advanced breast cancer patientsresistant or refractory to anthracyclines, taxanes, and capecitabine[48].

Methylnaltrexone (MOA-728, Relistor� by Wyeth, 22), an N-methyl derivative of naltrexone 23, contains a charged tetravalentnitrogen atom and is unable to cross the bloodebrain barrier, andso has antagonist effects throughout the body [49]. Methylnal-trexone blocks peripheral opioid receptors activated by opioidsadministered for pain relief and thus useful in management ofalcohol and opioid dependence [50]. In May 2007, Wyeth andProgenics filed a NDA for subcutaneous doses of 22 for the treat-ment of opioid induced constipation and other pain indications. InMarch 2008, Wyeth and Progenics reported that 22 failed in twoPhase III trials for intravenous use in treatment of post-operativeileus. In April 2008, Progenics and Wyeth announced that HealthCanada and the FDA have approved 22 for the treatment of opioidinduced constipation [51]. As of May 2009 an oral formulation of 22is under Phase II trials against opioid induced constipation inchronic pain. After acquisition of Wyeth by Pfizer in October 2009,the collaboration is continued by Progenics and Pfizer.

Everolimus (Luveniq� or LX211, 24), a mTOR inhibiting deriv-ative of 10, is marketed as an immunosuppressant by Novartisunder the trade Afinitor� for use in advanced renal carcinoma. In


March 2009 the FDA has approved 24 against advanced renal cellcarcinoma after failure of Sutent� (sunitinib) or Nexavar� (sor-afenib) [52].

Telavancin (Vibativ�, TD-6424, 25), a semi-synthetic analog ofvancomycin 26, inhibits bacterial growth through binding to the D-Ala-D-Ala terminus of the bacterial peptidoglycan precursors [53].Telavancin was discovered by Theravance, and is being developedin partnership with Astellas [54]. Theravance submitted a NDA inDecember 2006 and an MAA in May 2007 for use of 25 againstGram-positive cSSSIs, and MRSA, and this was approved inSeptember 2009 by the FDA. Theravance has also submitted 25 tothe FDA for a second indication for the treatment of nosocomialpneumonia or hospital aquired pneumonia (HAP). In November2009, the FDA released a complete response letter toTheravance fortelavancin NDA against nosocomial pneumonia.

Romidepsin (depsipeptide, FK228, FR901228, Istodax�, 27),a naturally occurring histone deacetylase inhibitor obtained fromthe bacteria Chromobacterium violaceum [55], was developed andevaluated by Gloucester Pharmaceuticals in various Phase I/II trialssponsored by the National Cancer Institute (NCI) for use againstcutaneous and peripheral T-cell lymphoma (TCL) [56]. In November2009, Istodax� 27 was approved by the FDA against selective

cutaneous in TCL patients that have received a minimum of oneprior systemic therapy [57], while three Phase II trials for multiplemyeloma and peripheral TCL are still recruiting patients. In January2010, Celgene completed the acquisition of GloucesterPharmaceuticals.

Capsaicin 28, an active component of chili peppers belonging tothe genus Capsicum, was first isolated in pure and crystalline formby John Clough Thresh in 1876 [58a]. Capsaicin 28 producesa burning sensation when it comes in contact with tissues thoughbinding to the ion channel receptor vanilloid receptor subtype 1(VR 1) [58b,c]. In November 2009, NeurogesX gained FDA approvalfor Qutenza� (a transdermal 8% patch of 28) against neuropathicpain combined with post-therapeutic neuralgia. In April 2010,NeurogesX launched Qutenza� in US and is planning to market it inEurope by Astellas Pharma Europe Ltd. [59].

Aztreonam lysine (Cayston�, 29), an inhaled lysine saltformulation [60], wherein the b-lactam ring is alone and not fusedto another ring, has been evaluated by Gilead in various Phase IIItrials against cystic fibrosis (CF) patients having a pulmonaryinfection of the Gram-negative bacteria Pseudomonas aeruginosa[61]. In February 2010, Cayston�was approved by FDA for use in CFpatients, however its safety and efficacy is yet to be established in

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pediatric patients or Burkholderia cepacia colonized patients [62].The drug is a proprietary formulation of aztreonam, an antibioticfirst launched in 1984 for intravenous use.

4. Infectious diseases

4.1. Antimicrobials

4.1.1. Antibacterial agentsNP-derived drugs have been crucial for anti-infective drug

discovery, and the many of antibacterial drugs currently in clinicaluse are NPs or were designed using NP templates. Several antibi-otics have been discovered simply bymeasuring zones of inhibitionof bacterial strains on agar plates by applying whole broth orextracts obtained from microbial ferments. Mining of the bacterialgenome is providing new avenues for recognition of crucial targetsfor the discovery of antibacterial agents with reduced sideeffects [63]. Despite having complex structures the development ofa NP to an antibacterial drug mainly depends on its ability topenetrate bacterial cell membranes [64]. The success of penicillin

led to unparalleled efforts by government, academia and thepharmaceutical industry to discover other compounds from naturalsources for the treatment of bacterial infections, resulting in nearlyall novel classes of antibiotics being from NP sourced scaffoldsthrough 1962. Since the commercialization of penicillins in the1940s, b-lactams that inhibit the formation of peptidoglycan crosslinks in the bacterial cell wall leading to bacterial death, have beenthe mainstay for treating community-acquired infections [65].

Ceftobiprole medocaril (BAL-5788, 30) is a cephalosporin anti-biotic with excellent activity against P. aeruginosa, MRSA andpenicillin-resistant Streptococcus pneumoniae [66]. Ceftobiprole 30is given intravenously [67] and was filed for regulatory approval inthe US and Europe in July 2007, after the successful completion ofpivotal Phase III registration trials by Basilea Pharmaceutica and J&Jaffiliated Cilag GmbH International for the treatment of cSSSIs. InNovember 2008, the FDA declined to approve 30 and recom-mended completion of two new and well-controlled studies forsafety and efficacy accessment against cSSSIs. In addition, variousPhase III trials are underway for HAP/CAP. Ceftaroline acetate (PPI-0903, TAK-599, 31), originally discovered by Takeda is known to

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exhibit efficient antibacterial activity against penicillin-resistantS. pneumoniae. Cerexa licensed 31 from Takeda and the drug iscurrently in Phase II clinical trials by Forest Laboratories to useagainst cSSSIs and CAP [68].

Tebipenem pivoxil (ME-1211, L-084, 32) is an advanced carba-penem being evaluated as a broad-spectrum antibiotic under PhaseIII trials in Japan by Meiji Seika for otolaryngological/respiratoryinfections [69]. Tomopenem (CS-023, RO4908463, R1558, DaiichiSankyo, 33) for use against common nosocomial infections [70],and PZ601 (SM-216601, Protez, licensed from Dainippon Sumi-tomo, 34) for use against MRSA and Pseudomonas aeruginosaare,both are in Phase II trials [71]. ME1036 (CP5609) 35, a DHP-1-stableparenteral carbapenem in which a 7-acylated imidazo[5,1-b]thia-zole-2-yl group is substituted at carbapenem moiety, was licensedby Cerexa and Forest Laboratories fromMeiji Seika Kaisha. ME1036has excellent in vitro activity against multidrug-resistant (MDR)Staphylococci and Enterococcus faecalis. ME1036 exhibits a broadGram-negative activity of the carbapenems (activity against ESBL-producing Escherichia coli and Klebsiella pneumoniae), except forP. aeruginosa and is under Phase I evaluation [72]. Pfizer is evalu-ating sulopenem (CP-70429) 36, and a prodrug, PF-3709270, inPhase I trial [73].

Faropenem daloxate (SUN-208, BAY-56-6824) 37 is a penem-type b-lactam licensed to Replidyne by Daiichi Suntory Pharma tomarket it in conjunction with Forest Pharmaceuticals [74]. InDecember 2005, Replidyne submitted a NDA to the FDA for use of37 against acute bacterial sinusitis (ABS), acute exacerbation ofchronic bronchitis (AECB), CAP and uncomplicated skin and skinstructure infections (uSSSIs). In March 2007, the FDA agreed forPhase III development of 37 with placebo-controlled trials, oneeach in ABS and AECB along with two non-inferiority CAP trials.These additional trials have delayed the launch of drug.

Dalbavancin (Zeven�, BI-397, 38) is a second-generation lip-oglycopeptide antibiotic and semi-synthetic derivative of the tei-coplanin analog A40926 39. It was discovered by Biosearch Italiaand is being developed by Pfizer to use against cSSSIs [75]. VicuronPharamaceutical (now part of Pfizer) in February 2005 filed a NDAto use 38 for the treatment of cSSSIs. In December 2007, the FDAreleased an approval letter to Pfizer for use of 38 against cSSSIsadult patients, including MRSA [76]. However, based on feedbackfrom regulatory authorities, Pfizer has withdrawn the marketingapplications for running another Phase III trial for 38.

Oritavancin (Nuvocid�, LY-333328, 40), a chloroeremomycin 41derivative obtained through semi-synthesis was discovered and

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developed by Eli Lilly and acquired by InterMune in 2001 andtransferred to Targanta Therapeutics in 2005. Oritavancin has theability to attach with two types of peptidoglycans and exertsantibacterial activity through inhibition of cell wall synthesis. Tar-ganta submitted a NDA for approval of 40 to the FDA in February2008 [77], which was accepted for standard review with anestablished action date in December 2008. In December 2008, theFDA stated that there was insufficient data to approve 40. Addi-tionally, Targanta submitted a MAA for 40 to the EMEA that wasaccepted for review in June 2008.

The vancomycin-cephalosporin heterodimer TD-1792 42,combining the antibacterial activities of a glycopeptide anda b-lactam in one molecule, has been designed to target 2 keybacterial cell wall synthesis targets. TD-1792 42 is in clinicaldevelopment by Theravance, who has successfully conducted PhaseII trials for safety and efficacy accessments against cSSSIs, includingMRSA. In July 2007, Theravance disclosed that 42 met primary andsecondary endpoints in a non-inferiority trial compared to vanco-mycin 26 [78].

Ramoplanin factor A2 (ramoplanin, 43), is the major componentof the lipopeptide antibiotic drugs derived from strain ATCC 33076of Actinoplanes [79] which exerts antibacterial activity by inhibitingbacterial cell wall synthesis. Ramoplanin factor A2 43 can form U-shaped structures with the ability to bind and capture Lipid II (C35-MurNAc-peptide-GlcNAc), a specific intermediate in membraneformation [80]. Oscient Pharmaceuticals licensed the North Amer-ican rights for orally active ramoplanin 43 from Vicuron and eval-uated it in Phase II trials for GI tract infections caused by Clostridiumdifficile [81,82].

The NXL-103 (XRP2868), discovered by Sanofi-Aventis, is anorally available mixture (70:30) of two semi-synthetic streptogra-mins, flopristin (RPR132552A, streptogramin A-type, 44) and

linopristin (RPR202698, streptogramin B-type, 45) [83]. Streptog-ramins inhibit bacterial protein synthesis through the synergisticbinding of streptogramin A & B components to different sites on thepeptidyltransferase domain of the 50S ribosomal subunit [84]. InOctober 2008 Novexel announced for positive Phase II trials of NXL-103 against CAP and cSSSIs, including MRSA [85].

MerLion Pharmaceuticals in July 2007 initiated Phase I trials offriulimicin B 46, a lipopeptide antibiotic having activity againstGram-positive bacteria through complex formation withbactoprenol-phosphate, leading to the inhibition of peptidoglycan,and teichoic acid biosynthesis [86]. Friulimicin B is produced byActinoplanes friuliensisHAG 010964 and its structurewas confirmedafter the crystal structure of amphomycin tsushimycin (A-1437B,47), an aspartic acid analog of 46 published in late 2005 [87].

Moli1901 (duramycin, 2262U90, 48), a polycyclic peptideproduced by Streptomyces cinnamoneum [88], is under clinicaldevelopment by AOP Orphan in collaboration with Lantibio inEurope. Moli1901 enhances chloride transport and increases fluidsecretion in vitro, thus has clinical indication against CF [89]. Aftersuccessful Phase I trials [90], aerosolized 48 was evaluated underPhase II clinical development in Europe with positive resultsannounced in adolescents and adults with CF in March 2007. Lan-tibio is also investigating an ophthalmic solution of 48 in Phase IIclinical trials for the treatment of dry eye syndrome. Omiganan 49,an analog of antibacterial peptide indolicidin 50 which was origi-nally purified from neutrophils of bovines [91], has significantactivity against infections caused by antibiotic-resistant andsensitive bacteria. Indolicidin consists of 13 amino acids and has thehighest tryptophan content among the known proteins with ami-dation at the carboxyl terminus [92]. Like other cationic peptides,omiganan exerts antibacterial activity through interaction with thebacterial cytoplasmic membrane, and was developed by MIGENIX


and licensed to Cadence Pharmaceuticals for catheter-relatedinfections (coded Omigard�, CPI-226, MBI-226), and Cutanea LifeSciences for dermatological diseases (coded as CLS001, MX-594AN).A Primary end point was not achieved in a Phase III trial by CadencePharmaceuticals, and additional Phase III trials using a gel-basedformulation are underway. Cutanea Life Sciences have success-fully evaluated 49 in Phase II trials (2007) while the Phase III trialsfor treatment of rosacea, a chronic inflammatory skin disorder, areunderway.

Among the group of macrolide antibiotics, erythromycin 51,obtained from actinomycetes, has ability to bind with the pepti-dyltransferase site of 50S ribosomal subunit, and can exert anti-bacterial activity by the inhibition of protein synthesis [93].Cethromycin (ABT-773, Restanza�, 52), EP-420 53 (by EnantaPharmaceuticals), and BAL-19403 54 (by Basilea), are three semi-synthetic ketolide derivatives of 51 that are in clinical development.Cethromycin was developed originally by Abbott Laboratories [94],and later acquired by Advanced Life Sciences to use against CAP[95], and post-exposure to anthrax inhalation. A NDA by AdvancedLife Sciences for the use of 52 against mild-to-moderate CAP was

accepted by FDA in December 2008 [96]. In placebo-controllednon-human primate studies by Advance Life Sciences, Restanza�has demonstrated a clinically and statistically significant survivalrate in anthrax, plague and tularemia. In September 2009, orphandrug designationwas granted to 52 by the FDA for use in plague andtularemia. A bridged bicyclic derivative, EP-420 (EP-013420, 53) isunder Phase II clinical trials by both Enanta and Shionogi fortreatment of CAP [97]. BAL19403 is a macrolide antibiotic whoseantibacterial spectrum covers clinical isolates of Propionibacteriumacnes with mutations in the 2057 to 2059 region of 23S rRNAconferring resistance to erythromycin and clindamycin [98]. Basileahas reported the first clinical data for 54 in the treatment of acne[99].

The first approved ketolide, telithromycin (Ketek�, 55) wasevaluated in Phase II/III clinical trials by French pharmaceuticalcompany Hoechst Marion Roussel (later Sanofi-Aventis) in 1998.Latter on, telithromycin was approved by the European Commis-sion in July 2001 and subsequently went on sale in October 2001. Inthe US, 55 had received the FDA approval in April 2004 against therespiratory infections. Telithromycin displays bactericidal activity

O O

HN

NH

HN OO

HN

NH

OO

OHOHO

HO

O

O

NH2

O

NH

O

OHOH

O

Cl

HO

NH

CH3

CH3

HN

O

CH3

OH

OH3C

OHNH2

CH3

OH

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N

S

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N42


by blocking the progression of the growing polypeptide chainthrough binding with the 50S subunit of ribosome [100].

Tiacumicin B (OPT-80, PAR-101, 56), an actinomycete-derivedmacrolactone, isolated by Abbott [101a], is in Phase III trialsagainst C. difficile-associated diarrhea (CDAD) by Optimer Phar-maceuticals [101b]. Tiacumicin B exerts antibacterial activity byinhibition of RNA synthesis in bacteria [101c]. The PTK-0796 (MK-2764, 57), an aminomethylcycline with excellent activity againstboth Gram-positive and Gram-negative strains, was discovered andevaluated by Paratek in various Phase II trials against commonhospital infections. The PTK-0796 is a bacterial protein synthesisinhibitor that was in-licensed by Novartis form Paratek for collab-orative Phase III clinical development. In October 2009, Novartisgained exclusive rights for marketing 57 as oral broad-spectrumantibiotic against MRSA, MDR S. pneumoniae and vancomycin-resistant enterococci [102].

Eisai has designed the second-generation lipid A antagonisteritoran (E5564, 58) [103a] from Rs-DPLA 59, a non-toxic lipidA analog originally isolated from Rhodopseudomonas sphaeroides[103b]. Eritoran inhibits the endotoxin response through antago-nism of the Toll-like receptor 4 (TLR4) [104a], and is currently inPhase III development by Eisai against sepsis caused by Gram-negative bacteria [104b].

CBR-2092 60, a hybrid antibiotic combining rifamycin SV and4H-4-oxo-quinolizine, is being developed by Cumbre Pharmaceu-ticals. The studies with S. aureus have shown that CBR-2092 bringsrifampin-like effects to RNA synthesis and quinolone-like effects toDNA synthesis in rifampin-susceptible and resistant strains,respectively [105]. CBR-2092 is supposed to exert antimicrobialactivity through combined effects on RNA polymerase, DNA top-oisomerase IV, and DNA gyrase. Currently, CBR-2092 is in Phase IIa

trial by Cumbre for the treatment of infections caused by gram-positive cocci [106].

4.1.2. Antifungal agentsFungal infections of the bloodstream and organs, e.g., perito-

nitis, meningitis and pneumonia, are among the important causesof morbidity and mortality in organ transplant recipients [107].Despite major advances in drug chemotherapy, fungal infectionsare still a challenge, particularly in the growing number of immu-nosuppressed patients seen in modern medical facilities. Despitehaving a cell wall, fungi are more similar to mammalian cells thanto bacteria at the cellular level; therefore treatment of mycoticinfections is very difficult [108].

Fewer antifungal candidates are undergoing clinical evaluationin which only 2 are NP-derived (aminocandin, 61 and SPK-843, 62).Echinocandins that inhibit the synthesis of glucan in cell wall areknown to exert limited toxicity in human due to lack of biologicaltarget, 1,3-b-D-glucan synthesis, and thus, are significant againstinvasive infections by Candida species [109]. Among semi-syntheticechinocandins, caspofungin (first launch 2001, Cancidas�, Merck),micafungin (first launch 2002, Mycamine�/Funguard�, Astellas)and and anidulafungin 11 (first launch 2006, Eraxis�/Ecalta�,Pfizer) have been approved since 2001.

Deoxymulundocandin 63, originally isolated from the fungusAspergillus sydowii [110], is the lead compound of aminocandin(NXL-201, IP960, HMR-3270, 61), an investigational drug withexcellent activity against Candida albicans and C. tropicalis [111]. InDecember 2006, Novexel and Indevus signed an agreement overthe out-licensing of 61. The Dutch company APARTS BV hassuccessfully completed Phase I trials for SPK-843 62, obtainedthrough semi-synthesis of patrician-A 64 produced by Streptomyces


aureofaciens. SPK-843 can destabilize the cell membrane of fungilike other polyenes [112]. Kaken Pharmaceuticals has restartedPhase II trials of 62 for treatment of systemic mycosis. APARTS BVhas acquired world wide rights for the development of 62 anda license for Japan has been signed while contracts are still pendingwith US and European companies [113].

4.1.3. Antiparasitic agentsDespite the fact that several NPs have been tested against

protozoans followed by the implementation of heroic vector-control measures, the incidence of parasitic infections hasincreased globally [114]. The use of medicinal plants against para-sitic diseases has been traced from ancient records i.e. Cinchonacalisaya (bark), Strychnos pseudoquina (bark), Deianira erubescens(roots and leaves) and Remijia ferruginea (bark) [115].

In the 1970s, artemisinin 65, an important antimalarial drugwasidentified from traditional Chinese medicine Artemisia annua.Arterolane (RBx11160, OZ-277, 66), a synthetic trioxolane modeledon artemisinin 65 pharmacophore, is being evaluated in combina-tion with piperaquine (a synthetic bisquinoline antimalarial drug)to fight against malaria by Ranbaxy [116]. In May 2009, Ranbaxyannounced for commencement of Phase III clinical trials of 66 incombination with piperaquine phosphate in India, Bangladesh andThailand to treat Plasmodium falciparum malaria [117].

Paromomycin 67 (Humatin�, King Pharmaceuticals), an ami-noglycoside antibiotic first isolated from Streptomyces krestomuce-ticus [118a], was developed as therapeutic agent against visceralleishmaniasis by the Institute for OneWorld Health [118b]. Paro-momycin has orphan drug status and was approved by the Drug-Controller General of India in September 2006 against visceral

ILRWPWWPWRRK-NH2

49

ILPWKWPWWPWRR-NH2

50

H-Ala-Lys-Gln-Ala-Ala-Ala-Phe-Gly-Pro-Phe-Abu-Phe-Val-Ala-HOAsp-Gly-Asn-Abu-LysOHNH

48

SS

S

O

H3C

HO

H3C

H3C

O

CH3

CH3

OH

O

O

CH3

O

OH

H3CO

N

H3C

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CH3HO

O

OCH3

CH3OH

CH351

O

H3C

H3C

O

CH3

CH3

O

O

CH3

O

H3CO

N

H3C

CH3

CH3HO

O

N

52

O

HNO

CH3

O

H3C

H3C

N

CH3

CH3

O

O

CH3

O

O

N

H3C

CH3

CH3HO

O

53

HO O

H3C

N

H3C

O

NNN

CH3

O

H

O

O

O

CH3

H3CCH3

CH3

OCH3

CH3

O

H3CO O

O

OCH3

CH3OHCH3

N CH3H3C

CH3

O

N N

N

S

HO

O

H3C

54


leishmaniasis (VL) [119]. Paromomycin 67 is an off-patent antibioticmarketed in the US to treat intestinal parasites. In February 2008,King Pharmaceuticals discontinued the sale of Humatin� but thesubstance is continually available in the US from anothermanufacturer.

4.1.4. Antiviral agentsThe single celled viruses represent the smallest existing life-

form causing most common (i.e. cold, influenza, chickenpox andcold sores) to greatest human health risk (i.e. ebola, AIDS, avianinfluenza and SARS). Significant research and development over thelast 25 years into antiviral drug discovery has resulted in theidentification of important antiviral drugs like betulinic acid 68,a triterpenoid obtained from bark of Betula pubescens [120a].Betulinic acid was originally identified as a weak inhibitor of HIVreplication by Lee and co-workers at the University of North Car-olina [120b]. Betulinic acid can inhibit topoisomerase I [121a], andis being evaluated in Phase I trials as a cancer chemo-preventiveagent. Bevirimat (PA-457, 69), extracted from a Chinese herbSyzygium claviflorum is under Phase IIb trial in combination therapyby Panacos [121b]. Bevirimat is believed to inhibit HIV throughmaturation inhibition and blocks HIV maturation by inhibiting thefinal step of the HIV Gag protein processing. In December 2007,Panacos announced the results of Phase IIb trial while in January

2009, Myriad Genetics announced for the acquisition of all rightsfrom Panacos for 69 [122].

Ribavarin 70 is a NP-derived compound having structure basedupon the Streptomyces-derived nucleoside antibiotics pyrazomycinand showdomycin, isolated in the 1960s, was marketed as ‘Rebetol’in the US by Schering Plough with Valeant Pharmaceuticals until2005. Taribavirin (Viramidine�, ribamidine, 71), a liver-targetingprodrug of ribavirin 70 [123], is under Phase II/III development byValeant Pharmaceuticals against chronic hepatitis C virus (HCV) intreatment-naive patients. Taribavirin is the standard treatmentwith interferon a-2b for HCV, and gets converted inside the liver byadenosine deaminase to 70. In 2006, Valeant had announced theresults of Phase III trials, in which 71 failed to meet the non-inferiority efficacy endpoints. In 2007, Valeant initiated a PhaseIIb trial for 71 at higher doses, and reported the final results in June2009 against HCV [123].

MBI-3253 (celgosivir, 6-O-butanoylcastanospermine, 72), a semi-synthetic analog of castanospermine 73, was first isolated from theseeds of Castanospermum australe [124a]. Castanospermine is aninhibitor of some glucosidase enzymes, and has excellent antiviralactivity [258]. In January 2009, MIGENIX disclosed the completion ofPhase II clinical studies [124b] of 72 as a ‘triple combination’ (withpeginterferona-2bandribavirin70) anda ‘doublecombination’ (withpeginterferon a-2b) in HCV patients. An exclusive option agreement

O

OH

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CH3

O

HO

HN

H3C

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CH3

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OHO HN

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59

O

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58

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55

CH3

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OH

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OH3C

H3C H3C CH3

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OH

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56

CH3 HN

OH

CONH2

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NCH3H3C

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OH

57

CH3OH

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NH

O

H3C OCH3 CH3 CH3

H3CO OH

CH3OHOHH3C

O

CH3O

OH

NN

N NCH3

ON

CH3

FO

CO2H

60


with United Therapeutics Corporation (UTC) was signed byMIGENIXfor further development of 72whichwas discontinued in April 2009.MIGENIX are currently seeking other strategic options for their drugdevelopment programe [125].

Cyclosporin74, a fungal cyclic peptide consistingof 11 amino acidsobtained from Beauveria nivea, is an immunosuppressant that exertsantiviral activity through inhibition of cyclophilin. However, devel-opment of 74 as antiviral drug is not possible due to calcineurin-related and immunosuppressive side effects [126]. NIM 811 (SDZ

NIM 811, cyclosporin 29, MeIle4-cyclosporin, 75), a NP discovered bySandoz (now Novartis) with comparatively less immunosuppressiveactivity (1700 times less than cyclosporin 74) with favorable saftyprofile [127], is in Phase I trials for anti-HIV and HCV activity. Debio-025 (UNIL025, MeAla3EtVal4-cyclosporin, 76) is a cyclophilin inhib-itor that displays 7000 times less immunosuppressive activity than74, and is in various Phase IIb trials by Debiopharm for the treatmentof HCV [128]. Debio-025 acts with a novel mechanism of action bybinding to cyclophilin A (CypA) [129a]. In February 2010, Novartis in-


licensed the exclusive rights to develop and market 76, as potentialfirst-in-class antiviral agent except in Japan [129b].

4-Methylumbelliferone 77, an active ingredient of nutraceuticalproduct Heparvit� byMTmedical Institute of Health and BioMonde,is currently in Phase II development against HBV and HCV [130a].The chinese academy of military medical sciences have started theclinical evaluation of HIV-1 integrase inhibitor [130b], 1,5-DCQA(1,5-di-O-caffeoylquinic acid, 78), extracted from Inula Britannic,for the treatment of HIV. In 2006, Chinese scientists have initiatedthe human trials of 78 to treat HIV/AIDS and hepatitis B [131].

WAP-8294A2 (JA-002, 79), a major component of the antibac-terial complex produced by Gram-negative Lysobacter species, ispotentially effective against the treatment of MRSA, cSSSIs, pneu-monia and septicemia [132]. WAP-8294A2 exerts antibacterialactivity by selective interaction to membrane phospholipids,

causing sever damage to membrane while remains inactive againstGram-negative bacteria, yeasts and fungi. The aRigen Pharmaceu-ticals are developing injectible, gel, and cream of 79 in variousPhase I/II trials against MRSA and acne. In August 2009, New Energyand Industrial Technology Development Organization (NEDO) inJapan had selected the aRigen Pharmaceuticals for funding two-thirds of the R&D costs for the development of 79 as first-lineanti-MRSA product candidate under the Innovation PromotionProgram (IPP) until February 2011 [133].

4.2. Halted or discontinued compounds in infectious diseases

Rifalazil (ABI-1648, KRM-1648, 80) is a new generation semi-synthetic rifamycin B 81 derivative, that was evaluated by Activ-Biotics, and failed in a Phase III trial for the treatment of the


intermittent claudication, associated with peripheral arterialdisease [134]. In December 2007, ActivBiotics went on sale for allthe proprietary assets that opened a new hope for 80 to re-enterclinical evaluation with a different company.

Incyclinide (Col-3, 82), is a chemically modified tetracyclinewhich was evaluated by NCI and CollaGenex for the treatment ofvarious cancers (including a Phase II trial against Kaposi’s sarcoma),and rosacea. In July 2007, CollaGenex discontinued their acneprogramme with 82 due to disappointing results in Phase II trial[135].

The two orally bio-available pleuromutilin derivatives, 565154and 742510, being evaluated in Phase I trial, were dropped by GSKin September 2007 pipeline products. Artemisone (BAY 44-9585)83, a semi-synthetic derivative of artemisinin 63 having low lip-ophilicity and negligible neuro- and cytotoxicity in vitro and in vivo,was first synthesized at Hong Kong University [136]. BAY 44-958583 exhibits efficient activity against malarial parasite compared tocurrent artemisinin. Bayer was evaluating 83 as a potential anti-malarial [137] in various Phase II trials but in last few years, there isno information available about the further development of 83.


Calanolide A 84, a coumarin inhibiting non-nucleoside reversetranscriptase [138] was first obtained from Calophyllum lanigerumtrees in Malaysia with potent activity against HIV-1 [139], waslicensed and evaluated to Phase II clinical trials by Sarawak Medi-chem Pharmaceuticals. After purchase of the remaining 50% ofSarawak Medichem and full rights from Advanced Life Sciences bySarawak Government in late 2006, no subsequent announcementfor further drug development has been made.

5. Neurological diseases

Neurological diseases involve the disease of central, peripheral,and autonomic nervous systems. Historically, the plant alkaloidssuch as morphine 85 (from Papaver somniferum), cocaine (fromErythroxylon coca) and physostigmine 86 (from Physostigma ven-enosum) have been used to treat sever pain and central nervoussystem (CNS) diseases. A sesquiterpene alkaloid, huperzine-A 87, anacetylcholinesterase (AChE) inhibitor [140a] isolated from firmossHuperzia serrata [140b], is under clinical development by Chinesescientists for treatment Alzheimer’s disease. NIA, a division NIH isevaluating 87 when administered orally in Phase II trials againstAlzheimer’s disease [141]. Morphine-6-glucuronide (M6G) 88,a glucuronide derivative produced by metabolism of 85 in humanbody, was evaluated as analgesic by CeNeS Pharmaceuticals underPhase II and III trials in Europe [142a]. In 2007, a successful Phase IIIstudydemonstrated that88effectively reducespainequivalent to85with significant reduction in vomiting, post-operative nausea,sedation and other common side effects. In June 2008, a bio-pharmaceutical company PAION acquired the CeNeS Pharmaceuti-cals and announced for completion of two Phase III trials byNovember 2008 [142b]. KRN-5500 89, a spicamycin derivativeproduced by Streptomyces alanosinicus [143a], was evaluated forsafety and efficacy in Phase I trial by DARA BioSciences againstneuropathic pain. Currently,DARABioSciences are conductingPhaseIIa trials of 89 as an intravenously (IV) administred medicine for the

CH3OH OH

OO

NH

O

O

H3C OCH3 CH3

CH3OH

H3C

ON

H3CO

OCH3

CH3

80

N

NHO

O

CH

OH O OH O

CONH2

OHHH

OH

82

O

OO

H3CH

CH3

H

treatment of neuropathic pain in cancer patients [143b]. ShanghaiInstitute of Material Medica has synthesized Debio 9902 (ZT-1, 90)[144], a prodrug of 87, and licensed it to Debiopharm. In June 2007,Debiopharm announced the positive results of a Phase IIa trial forsafty and efficacy of 90 in treatment of mild Alzheimer’s disease. AnIndependent Data Safety Monitoring Board (IDSMB) inMarch 2008,recommendedDebiopharm to continue Phase II study of 90withoutmodification in Alzheimer’s patients. In October 2008, Debiopharmannounced for starting of tablet formulation bridging study underIND for Alzheimer’s patients [145].

Lobeline 91, a piperidine alkaloid found in Lobelia species (suchas Lobelia inflata, Lobelia tupa, Lobelia cardinalis, Lobelia siphilitica)andHippobroma longiflora, has been used traditionally as an emetic,respiratory stimulant and more recently as a tobacco smokingcessation agent [146]. Lobeline acts as a VMAT2 ligand [147a,b] thatreduces the methamphetamine induced dopamine release. YauponTherapeutics and NIH are evaluating 91 in Phase II trials asa dopamine modulating agent for the treatment of methamphet-amine addiction and ADHD [147c].

Anabaseine 92, a neurotoxic principle identified from marineworms of the phylum Rhynchocoela [148a], stimulates a widevariety of nicotinic acetylcholine receptors (AChRs), especially theneuromuscular [e.g. a12b1gd (embryogenic) or a12b1g 3 (adult)]and a7 AChRs [148b]. The 3-(2,4-Dimethoxybenzylidene)-anaba-seine (DMXBA also called GTS-21, 93), a synthetic derivative of 92,was evaluated by Kem’s University of Florida in a sponsoredresearch by Taiho Pharmaceutical against Alzheimer’s disease[149]. In April 2006, CoMentis (previously Athenagen) disclosed foracquiring the assets of Osprey Pharmaceuticals, who had licensedGTS-21 93 from the University of Florida. CoMentis have completeda Phase II trial in Alzheimer’s disease and are assessing 93 in variousPhase I and II trials for assessment of safety and cognitiveimprovement in ADHD patients.

Tetrodotoxin (Tectin�, Wex Pharmaceuticals) 94, a potentneurotoxin extracted and purified from the puffer fish [150a] by

CH3OH OH

OOH

NH

O

O

H3C OCH3 CH3

CH3OH

H3C

OO CO2H

H3CO

OCH3

CH3

81CH3

3

ON S

CH3

O

O

83

O

O

O

H3C CH3

O

H3C OH

CH3

CH3

84


means of a proprietary process developed by Wex Pharmaceuti-cals, is able to block the action potentials in nerves throughbinding to sodium channels in cell membrane [150b]. Wex incolaboratin with Chinese medical institute, are evaluating 94 forthe treatment of cancer pain [151a] and management of opiatewithdrawal symptoms in Phase III and I trials, respectively. WexPharmaceuticals are also conducting Phase IIa clinical study for 94against neuropathic pain caused by chemotherapy in patients withcancer [151b].

Conotoxins, a group of neurotoxic peptides obtained from conesnail of genus Conus, are supposed to modulate the activity of ionchannels [152]. Xen-2174 95, a 13 amino acid peptide with 2cysteine bridges that targets the norepinephrine transporter (NET)[153], was originally discovered by researchers at the University ofQueensland who characterized the various effects of Conus mar-moreus venom. Xenome are evaluating 95 in Phase II trials againstacute post-operative pain and chronic pain in cancer patients whoare no longer responsive, minimally responsive, or intolerant tomorphine and hydromorphone [154]. One of the major cap-saicinods, capsaicin 28, has been found significant in clinicalconditions like osteoarthritis [155a], post-herpetic neuralgias,psoriasis [155b] and diabetic neuropathy [155c]. As discussedearlier that Qutenza� (an 8% trans-dermal patch of capsaicin 28)has been approved in 2009, Anesiva are evaluating differentformulations of capsaicin 28 (coded 4975, ALGRX 4975) for treat-ment of severe post-surgical pain, post-traumatic neuropathic painand musculoskeletal diseases in various clinical trials. In December2008, Anesiva announced to attain primary end point while eval-uating Adlea� (ALGRX 4975) in a Phase III clinical trial againstacute pain following orthopedic surgery [156a]. Winston Labora-tories undertook Phase III trials of civamide (cis-capsaicin, zucap-saicin,WL-1001) for the treatment of episodic cluster headache andknee osteoarthritis. In October 2008, a NDS byWinstonwas filed inCanada for Civanex� (civamide 0.075%) for releving osteoarthritispain. In February 2009, an orphan drug designation to Civanex�

was given by FDAwith NON release to Winston Pharmaceuticals inOctober 2009 [156b].

Phlorizin 96, a polyphenolic glucoside obtained from apple tree,lowers glucose plasma levels and improves insulin resistance byinhibiting sodium glucose co-transporters (SGLTs) [157]. Poorintestinal absorption and inactivation by lactase-phlorizin hydro-lase were serious drawbacks that restricted the development of 96as drug [158]. Dapagliflozin (BMS-512148) 97, an analog of 96 andselective inhibitor of SGLT2 is being evaluated by by Bristol-MyersSquibb in partnership with AstraZeneca as a potential treatmentfor type 2 diabetes [159]. In October 2009, the BMS announced theresults of Phase III trial of 97, a 24-week study showing statisticallygreater mean reductions of body weight compared to individualsreceiving placebo [160]. Among other phlorizin-inspired deriva-tives in development, the Phase II trials for GSK-189075 intreatment-naive type 2 diabetes mellitus have been completed byGlaxoSmithKline in June 2008.

Resveratrol 98, a triphenolic stilbene isolated from a variety ofplants has been reported significant in the treatment of cancer,ischemic injuries and cardiovascular disease [161]. In 2003, Howitzand co-workers reported that resveratrol 98 is an agonist ofSaccharomyces cerevisiae silent information regulator (Sir2) protein,a class III histone deactylase whose presence results in extendedlifespan of S. cerevisiae, Caenorhabditis elegans and Drosophilamelanogaster [162]. In 2006, Italian scientists announced the posi-tive result of 98 supplementation in Nothobranchius furzeri, a fishthat demonstrated an increased median life span by 56% [163].Sirtris proprietary formulation of 98, SRT-501, targets SIRT1 andacts by increasing mitochondrial activity, hence is significantagainst diabetes and obesity. Sirtris have successfully completed

the Phase IIa trial demonstrating oral doses 1.25 or 2.5 g of SRT501are safe and tolerable when administered twice daily for 28 days intype 2 diabetes. Similar Phase IIa cancer trial with SRT501 isunderway [164].

Cannabinoids, a unique group of secondary metabolites found inthe cannabis plant (Cannabis sativa) and others, are responsible forthe plant’s peculiar pharmacological effects [165]. CP 7075 (IP 751,ajulemic acid, CT-3, 99) is a synthetic cannabinoid that suppressinflammatory cytokines, including IL-1b and matrix metal-loproteinases (MMPs) through a peroxisome proliferator-activatedreceptor (PPAR) g-mediated mechanism [166]. Pre-clinical toxi-cology and pharmacology studies of 99 was evaluated by IndevusPharmaceuticals and later in October 2007, the drug was licensed toCervelo Pharmaceuticals for further manufacturing and pre-clinicalstudies in preparation for Phase I trials in neuropathic pain [167].

5.1. Halted or discontinued compounds in neurological diseases

CEP-1347 (KT-8138) 100 is a semi-synthetic derivative of K-252a101 [168a], a CaM kinase and phosphorylase kinase inhibitingalkaloid isolated from Nocardiopisis species [168b,169], was evalu-ated by Cephalon and H Lundbeck AS against Parkinson’s disease.CEP-1347 100was discontinued byMay 2005 due to lack of efficacyin various Phase II/III trials [169].

Devacade 102 is an orally active cholecystokinin A (CCK A)antagonist whose structure was based upon asperlicin 103 [170],a mycotoxin derived from Aspergillus alliaceus. ML Laboratories,who evaluated 102 in Phase II trials for the enhancement of opioidpain relief, has discontined the clinical development in May 2005.

Cognetix were associated with clinical developments of con-otoxins isolated from marine cone snail. Contulakin G (CGX-1160)104 is anorphandrugdesignated leadofCognetix thathascompleteda Phase Ib clinical trial against chronic and intractable pain. Thefurther clinical evaluations of CGX1160104 and conantokin-G (CGX-1007) 105 are on hold until more funding can be obtained.

ACV1 (Vcl.1, 106), a neuronal nicotinic receptor antagonist thatdisplays selectivity for the a9a10 subtype, was identified byscreening some uncharacterized conopeptide sequences from thevenom duct of C. victoriae using PCR [171a]. ACV1106was evaluatedby Metabolic Pharmaceuticals against neuropathic pain in diabetesand post-herpetic neuralgia. In August 2007, Metabolic announcedfor discontinuation of Phase IIa trials of 106 due to less activityagainst the human a9a10 nAChR receptor compared to equivalentrat receptors [171b].

Torrey-Pines Therapeutics (formally Axonyx) evaluated phen-serine 107, an AChE inhibitor showing disease modifying action byreducing plaque through inhibition of APP synthesis as well asprovides symptomatic relief [172]. In November 2008, QR Pharmalicensed 107 from TorreyPines, and evaluated Posiphen� (a (þ)-enantiomer of 107) against Alzheimer’s disease. In May 2009, QRPharma reported the failour of 107 in placebo-controlled Phase IIItrials. In April 2009, QR Pharma received investment from BenFranklin Technology Partners for further clinical development of107. In February 2010, QR Pharma gained US Patent for the use ofPosiphen� against cognitive impairments combined with Downsyndrome [173].

Gantacurium chloride (AV430A, GW280430A, 108), anultrashort-acting, non-depolarizing surgical neuromuscular blocker(NMB), was evaluated by GSK in Phase I trials demonstratingexcellent safety and potent neuromuscular blocking effects [174].Avera in 2002 gained acquisition assets from GSK and completedPhase I and II developments of 108. Currently, Avera are seeking toout-license the development and commercialization rights for 108.

Some phlorizin-inspired derivatives discontinued from devel-opment are KGT-1681 (GSK and Kissei), TS-033 (Taisho) and YM-

O

RO

HO

H HN CH3

OHOHO

HO2C

OH

85 R = H; 88 R=

H3C

O

HN O

N

N

H3C

HCH3

CH386

N O

H3CH2N

H3C H

87

H3C NH

O

OHN O

HO OH

HOOH

NH

NN

NNH

89

N

H3C

CH3

O

H

HO

H3CO Cl

CH3

N

OHO

90

91

N N92

N

N

OCH3

OCH3

93

HNNH

O

OHOH

OHO

O

HO

H2NOH

94

NGVCCGYKLCHOC

95

O

O OH

OH

OHHO

HO

OHO

O

Cl

O

HO

HO

OH

CH3

HO HO

OH

HO

OH

96

97

98

CO2H

OH

CH3

H3C

H3CH3C CH399


543 (Astellas). GlaxoSmithKline by 2009 have discontinued devel-opment of remogliflozin etabonate (KGT-1681, 109), a SGLT-2inhibitor licensed from Kissei Pharmaceutical. Taisho Pharmaceu-tical in October 2008 announced for discontinuation of TS-033, aninvestigational compound for treatment of diabetes [175a]. As onMay 2009, Astellas have discontinued the development of YM-543for the treatment of type 2 diabetes [175b].

6. Cardiovascular and metabolic diseases

NPs have made a major impact in the treatment of cardiovas-cular and metabolic diseases. Simvastatin (Zocor�, Merck & Co),a hypolipidemic drug belonging to the class of statins, is a syntheticderivate of Aspergillus terreus fermentation product and is known toexert the lipid-lowering activity through inhibition of 5-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase. Orlistat, a potentnatural inhibitor of pancreatic lipases, is the saturated derivative of

lipstatin, isolated from bacterium Streptomyces toxytricini, and isused to treat the obesity [176]. The antihypertensive angiotensin-converting enzyme (ACE) inhibitors (e.g. captopril, ramipril andquinapril) are derived from the snake venom peptide teprotide.Ilepatril (AVE-7688, 110), is an endopeptidase inhibitor (NEP)currently in Phase IIb/III trials by sanofi-aventis against hyperten-sion while in Phase II development for diabetic nephropathy [177].

Migalastat (Amigal�, AT1001, 1-deoxygalactonojirimycin,1-deoxygalactostatin, 111) was first reported by semi-synthesisfrom galactonojirimycin (galactostatin) 112 isolated from Strepto-myces species. Migalastat is a pharmacological chaperone thatenables the restoration of correct folding by stabilizing the proteinstructures through binding with them. In May 2006, orphandesignation was granted by the European Commission to AmicusTherapeutics for use of 111 against Fabry disease, which wastransferred to Shire Pharmaceutical in June 2008. As of January2010, Amigal� is in Phase III trials as monotherapy by Amicus


Therapeutics in conjunction with Shire Pharmaceuticals for thetreatment of Fabry disease [178].

Isofagomine (Plicera�, AT2101, 113), a synthetic aza-sugardesigned to mimic the carbocation transition state used by glyco-sidases [179], was evaluated by Amicus Pharmaceuticals in Phase IItrials against Gaucher’s disease, a lysosomal storage disordercaused by b-glucocerebrosidase deficiency [180a]. In October 2009,Amicus disclosed the positive results of Phase II randomized andopen-label clinical trial for two dose regimens (225 mg three dayson/four days off and seven days on/seven days off) [180b].

Ruboxistaurin (LY333531, 114), a protein kinase C (PKC) inhib-itor, was evaluated by Eli Lilly against microvascular complicationsin diabetes mellitus [181]. In February, 2006, Lilly submitted a NDAfor 114 in diabetic peripheral retinopathy. In August 2006, Lillyreceived an “approvable” letter from the FDA with a request ofanother Phase III trial for additional efficacy data but no new clin-ical trials are running.

SCH 530348 (TRA, 115), an oral thrombin receptor (PAR-1)antagonist [182a] based on himbacine 116, isolated from the plantGalbulimima baccata, is under clinical development by Schering-Plough to prevent atherothrombotic events in patients with ACS,MI, stroke, or disease of peripheral arteries [182b,c]. SCH 530348 isin Phase III clinical development against cardiovascular diseasessuch as atherosclerosis, ischemia, myocardial infarction and stroke.

Trodusquemine (MSI-1436, 117), a sulfated aminosterol isolatedfrom Squalus acanthias (dogfish shark) along with squalamine 118and other steroids [183a], is in clinical development by GenaeraCorporation for the treatment of type 2 Diabetes. MSI-1436 isa potent appetite suppressant (protein tyrosine phosphatase 1Binhibitor) [183b,c] that causes weight loss without metabolicrebound, and normalize fasting blood glucose, blood cholesterol,and triglyceride levels in obese animals. Genaera is currentlyevaluating 117 as an IND in a second Phase I trial against obesityusing an ascending single dose in overweight type 2 diabetes.

Ouabain (g-strophanthin, 119), is among some cardiac glyco-sides found in the ripe seeds of Strophanthus gratus, and the bark ofAcokanthera ouabaio. Ouabain can inhibit the Naþ/Kþ-ATPase ofplasma membrane especially at the higher concentrations attain-able in vitro or with intravenous dosage [184]. Digoxin 120 is

a purified cardiac glycoside isolated from the foxglove plant Digi-talis lanata [185a] and also occurs in the human adrenal gland andhas been considered significant in heart conditions, namely atrialfibrillation, and atrial flutter. Rostafuroxin (PST 2238, 121), anouabain antagonist syntesized by Sigma-Tau, is in Phase II trials forthe treatment of chronic arterial hypertension [185bed].

Mitemcinal (GM-611, 30-N-dimethyl-11-deoxy-30-N-isopropyl-12-O-methyl-11-oxo-8,9-didehydroerythromycin, 122) is an orallyadministered motilin agonist discovered by Chugai Pharma.Mitemcinal lacks the antibiotic properties of erythromycin andincreases the amplitude & frequency of antral contractions, andinitiates gastric contractions. Chugai has completed Phase I trials of122 in Japan while Phase II trials in US are ongoing for the treat-ment of diabetic reflux oesophagitis, and idiopathic gastroparesis[186]. Mitemcinal is also under Phase II trials by Chugai for treat-ment of the irritable bowel syndrome (IBS).

Pyridoxamine (Pyridorin�, 123) is a vitamin B6 analog basedon a pyridine ring bearing hydroxyl, methyl, aminomethyl, andhydroxymethyl substituents [187a]. BioStratum have evaluated123 in two Phase II trials, and observed significant retardation inthe progression of diabetic nephropathy. In KK-A(y)/Ta micemodel, 123 improves the urinary albumin/creatinine ratio thoughinhibition of advanced glycation end products (AGEs) and anti-oxidant effects in the kidneys. In October 2006, BioStratumlicensed the programme to NephroGenex. Currently, Neph-roGenex has initiated a new Phase IIb clinical trial (PYR-210) forsafety and efficacy assessments of 123 in slowing the progressionof nephropathy in patients with type 2 diabetes [187b]. TaishoPharmaceutical is evaluating 123 (coded as K-163) in Phase IItrials against diabetic nephropathy. In January 2009, the FDA ruledfor regulation of 123 as a pharmaceutical drug, and awarded itwith a fast track drug designation.

6.1. Halted or discontinued compounds in cardiovascular andmetabolic diseases

1-Deoxynojirimycin (AT2220, moranoline, 124) is obtained bycatalytic hydrogenation or borohydride reduction of antibioticnojirimycin 125 (isolated from Streptomyces species) [188]. Later,

N

O

H

CO2H

NH

H3C

O

SAc

H3C

110

HN

HOOH

R

OH

HO

111 R = H112 R = OH

HN

HOOH

OH

113

HN

NN

ON

CH3

CH3

OO

O

O

H3C

H H

H

NH3C

H3C

H

114 116

O

O

H3C

H H

H

N

H

HN O

O

CH3

F115

RHN

NH

NH

H3CCH3

H3C

H

OH

H

H

CH3 H

CH3H

OSO3H

NH

NH2

117 R =

118 R = H

O

HO

OH

H

OH

CH3

O

O

HHO

H

HO

OHOH3C

OHOH

119

O O

CH3

H

H

OH

OH

CH3H

HOO O O

HO

OH

H3CO

OH

H3CO

OH

H3C

120

O

CH3

H

H

OH

CH3

H

HO121

OH3C

O O

H3C

O

H3CH3C

CH3

CH3

O

O

CH3

O

CH3

O

O

OCH3

CH3OH

CH3

HOCH3

NH3C

CH3

CH3

122

N

OHHO

H3C

NH2

123

OH



Yagi and co-workers isolated 124, which they called moranoline,a NP occurring in the root bark of various Morus species andmicroorganisms [189]. Amicus launched the Phase II trials for 124in June 2008 against Pompe disease [190a,b]. In February 2009,Amicus put the development on hold by suspending enrollment forthe Phase II trials [190c]. In September 2009, Amicus Therapeuticsannounced that they are planning to initiate a Phase I trial forpharmacokinetic studies of 124 in muscle tissues of healthy adults.The FDA has agreed for proposed Phase I study by Amicus and kept124 on a partial hold [190d].

MC-1 (pyridoxal 5-phosphate, 126), a naturally occurringvitamin B6 metabolite and P2X receptor antagonist, was success-fully evaluated in Phase II trials as monotherapy as well as incombination with angiotensin blocker lisinopril (coded MC-4232)by Medicure for the treatment of chronic cardiovascular, andmetabolic diseases [191]. InMarch 2008, Medicure couldn’t met theend point in a Phase III trial of 126 to acertain the effects oncardiovascular death combined with nonfatal myocardial infarc-tion. Currently, Phase II trials of 126 for the treatment of chroniccardiovascular disease, and Phase III trials for Coronary ArteryBypass Graft Surgery (CABG) by Medicure are on clinical hold.Medicure is now planning for a Phase II trial of 126 in lipid loweringduring metabolic syndrome, a group of symptoms that promotecoronary artery disease, stroke, and type 2 diabetes [192].

7. Immunological, inflammatory and related diseases

Autoimmune diseases are the results of overactive immuneresponse of the body against substances and tissues. This may belocalized to certain organs or particular tissue affecting the base-ment membrane of lung and kidney. Aspirin, a NPs derivedcompound discovered in the late 1890s is still being used as ananalgesic and anti-inflammatory drug. Salbutamol is a short-actingb2-adrenergic receptor agonist marketed by GlaxoSmithKlinen forrelief of asthma and chronic obstructive pulmonary disease.

The launch of NPs, e.g., cyclosporin 74 (1983), tacrolimus (1993),sirolimus 10 (1999) and mycophenolate sodium (2003), and thesemi-synthetic NPs mycophenolate mofetil (1995) are surving assignificant immunosuppressive drugs. Everolimus (Luveniq� orLX211, 127), an mTOR inhibitor and derivative of 10 is marketed asimmunosuppressant by Novartis under the trade names Certican�

in organ transplantation.Voclosporin (ISA-247, R1524) 128, a calcineurin inhibitor [193a]

and semi-synthetic derivative of cyclosporine-A 74, is in a Phase IIbtrial to prevent the rejection of kidney graft while in Phase IIIdevelopment against psoriasis. Isotechnika has licensed 128 to LuxBiosciences for ophthalmic indications. In March 2009, the threePhase III trials for 128 (coded LX211) oral capsules against uveitiswere completed successfully by Lux Biosciences. In February 2010,Lux Biosciences filed a NDAwith the FDA and a MAAwith the EMAfor 128, under Luveniq� to use in the treatment of non-infectiousuveitis involving the posterior eye segment, which were acceptedby respective agencies in March 2010 [193b]. TAFA-93, a prodrug of

HN

HO

OH

R

OH

HO

124 R = H125 R = OH

N

O

H3C

HO

CHO

P

O

OH

OH

126

the mTOR inhibitor sirolimus 10 was developed and successfullyevaluated by Isotechnika in Phase I trials against transplant rejec-tion [193c].

Eupatilin 129 is a pharmacologically active flavone derivedfrom Artemisia argyi, a Korean traditional medicine significant forchronic diarrhea [194a]. Dong-A Pharmaceutical are evaluatingDA-6034 130, a synthesized analog of eupatilin 129, in variousPhase I and Phase II trials to use in the treatment of dry eye andgastritis, respectively [194b]. The synthetic isoflavone derivativeNV-52, a thromboxane synthase (TXS) inhibitor is being developedas a treatment for inflammatory bowel diseases by Novogen.Novogen have completed Phase IIa and IIb trials and found thatonce-daily dosaging of NV-52 has demonstrated no detectableside effects. Novogen also have NV-07a in Phase II trials for anti-aging as well as for protection of human skin from sunlight-induced damage [194c].

7.1. Halted or discontinued compounds in immunological andinflammatory diseases

Fingolimod (FTY720, 131) is an immunosuppressant agentderived from fungal metabolite myriocin 132 isolated from fungusIsaria sinclairii [195]. Fingolimod 131 produces immunosuppressantactivity after phosphorylation in vivo by sphingosine kinase to yieldan active metabolite that is a potent agonist of sphingosine-1-phosphate (S1 P) receptors 1, 3, 4 and 5 [196]. Novartis and Mit-subishi Tanabe were evaluating 131 for the treatment of multiplesclerosis in US & European Phase III and Japanese Phase II trials. Ina Phase III clinical trial in kidney transplantation, the drug 131 wasfound to be no better than the existing standard of care. BothNovartis and Mitsubishi Tanabe have discontinued clinical devel-opment of 131 for transplantation.

Ancrod (Viprinex�), a defibrinogenating agent which bindswith high specificity to fibrinogn [197a], was extracted fromMalayan pit viper venom. In January 2005, fast-track status wasgiven to Viprinex� by the FDA for treatment of acute ischemicstroke, a condition that arises due to blockage of blood vesselssupplying brain. Neurobiological Technologies have evaluatedViprinex� in various Phase III trials, which failed to show benefitsin patients suffering from acute ischemic stroke [197b]. In January2009, Neurobiological Technologies have suspended the Viprinex�development program and have decided not to develop it furtherfor the treatment of acute ischemic stroke [197c].

8. Oncological diseases

8.1. Small-molecule anticancer agents

8.1.1. Plant-derived compoundsCamptothecin 133, a quinoline based cytotoxic alkaloid isolated

from the bark and stem of Camptotheca acuminata [198], showssignificant anticancer activity through inhibition of topoisomeraseI. BioNumerik are developing Karenitecin� (BNP-1350, 134) as aninvestigational anti-tumor agent among camptothecin class ofchemotherapy drugs [199]. In February 2008, BioNumerik Phar-maceuticals have initiated the Phase III clinical trial of 134 inadvanced ovarian cancer patients [200]. Diflomotecan (BN80915)135, an analog of 134, is currently under Phase II clinical develop-ment by Ipsen against advance metastatic cancers [201]. InNovember 2003, Novartis gained rights to develop and commer-cialize (ST-1481, 136) from Sigma-Tau as an oral topoisomerase Iinhibitor. Gimatecan is currently in Phase II development to use intreatment of solid tumors [202]. Elomotecan (BN-80927, LBQ707,R-1559, 137), a cytotoxic agent inhibiting topoisomerase I and II, isbeing evaluated by Ipsen against certain advanced metastatic


cancers (e.g. colon, breast and prostate) [203]. As of April 2009, 137is a promising Phase I pipeline by Ipsen in oncology. DRF 1042 138,is an orally active camptothecin derivative that was evaluated by Dr.Reddy’s Laboratories in Phase I trials for the treatment of variouscancers [204]. In September 2006, Dr. Reddy’s Laboratoriescollaborated with ClinTec International for development of 138 inPhase II/III trials. SN2310 139, an injectable prodrug of SN-38 140, iscurrently in Phase I clinical trial for safety, pharmacokinetics andtolerance accessment in cancer patients. In September 2006, Sonusinitiated a Phase I study of 139which is presently ongoing, and aftermerger of Sonus Pharmaceuticals with OncoGenex Technologies inMay 2008, the new company, OncoGenex Pharmaceuticals havelisted 139 in oncology pipeline to address cancer [205].

CH3

HO

HONH2

HONH2 OH

CH3

OH

HO2C O

131

132

Combretastatin A-4 phosphate (Zybrestat�, CA4P, 140) isa prodrug of combretastatin A-4 141, a most potent among thecombretastatin class of natural stilbenoid phenols obtained fromCombretum caffrum, South African Bush Willow [206]. Com-bretastatin A-4 141 acts as a reversible tubulin depolymerizingagent and causes tumor-associated endothelial cells to change froma flat to a round shape, thus plugging the blood vessels, anddeprives the tumor from oxygen and nutrients [207]. Oxigene areevaluating 140 as a vascular disrupting agent (VDA) in variousPhase I/II/III trials [208]. As on September 2008, 140 is under PhaseIII trial against anaplastic thyroid cancer (ATC). In November 2009,Oxigene announced for positive results from Phase II trial of 140 innon-small cell lung cancer (NSCLC) [209a]. Ombrabulin (AVE8062)142, another water soluble derivative of 141was licensed to Sanofi-Aventis from Ajinomoto, is under Phase III trials in advanced softtissue sarcoma (STS) patients [209b].

Combretastatin A-1 diphosphate (OXi4503, 143), a pro-drug ofcombretastatin A-1 144, is metabolized by oxidative enzymes thatare present in various solid and liquid tumors and tumor infiltratesresulting in the creation of reactive oxygen species (ROS) and anorthoquinone metabolite which covalently binds to proteins andnucleic acids (DNA), causing direct cytotoxic effects on tumor cells[210]. OXGENE are evaluating 144 in various Phase I trials againstadvanced-stage solid tumors. Noscapine (CB3304, noscapine, 145),a microtubule targeting antitussive benzylisoquinoline alkaloidisolated from plants of the Papaveraceae family, is currently under


Phase I/II trials by Cougar Biotechnology against multiple myeloma,a cancer of plasma cells [211].

Vinblastine (Alkaban-AQ�, Velban�, 146), a vinca alkaloid firstisolated from Catharanthus roseus [212], inhibits the assembly ofmicrotubules by binding to tubulin. An intravenous injection of 146is significant against non-Hodgkin’s lymphoma, Hodgkin’s disease,Kaposi’s sarcoma, TCL, breast, testicular, lung, neck and headcancers and choriocarcinoma [213]. The fluorinated vinca alkaloid,vinflunine (Javlor�, 147) [214a] was licensed by Bristol-MyersSquibb from Laboratoires Pierre Fabre that was terminated inNovember 2007. In June 2008, after positive Phase III trial in themetastatic treatment of bladder cancer, 147 was submitted forregistration with the EMEA by Laboratoires Pierre Fabre. In June2009, Laboratoires Pierre Fabre announced for receiving a positive

N

N

O

R

O

OHO

H3C

Si(CH3)3N

O C(CH3)3

133 R = H

134 R =

136 R =

N

N

F

F

HO

H3C

135

N

NO

O

HO

H3C

OOH

O138

OH3C

CH3

CH3

H3C

CH3 CH3 CH3

R

OCH3

OCH3

OCH3

H3CO

141 R = OH140 R = OPO3Na2

142

OCH3

OCH3

H3CO

O

O N

OH3C O

OH3C O CH3

O

CH3

H

145

N

N

NH

N CH3

CH3

OH

H

H3CO2C

H3CO H

O

C146

opinion with recommendation for marketing authorization of 147in the metastatic treatment of bladder cancer [214b].

Paclitaxel (Taxol�, Abraxane�, 148) [215a], a mitotic inhibitorused to treat patients with lung, ovarian, breast cancer, head andneck cancer, and advanced forms of Kaposi’s sarcoma, was isolatedoriginally from Taxus brevifolia. Paclitaxel 148 stabilizes microtu-bules and interferes with the normal breakdown of microtubulesduring cell division [215b]. Bristol-Myers Squibb (BMS) are associ-ated with commercial development of 148.

Sanofi-Aventis have designed cabazitaxel (XRP6258) 149 andlarotaxel (XRP9881) 150 as poor substrates for membrane-associated P-glycoprotein (P-gp), since overexpression of P-gp iscrucial in taxane resistance [216]. Cabazitaxel 149 and larotaxel 150are currently in a Phase III trials to use in the treatment of patients

O

O

O N

N

O

H3C

Cl

O

OHO

H3C

N

H3C

137

N

NO O

O

HOH3C O

CH3OO

OCH3

139

HN

NH2

OHOOCH3 OR

OCH3

OCH3

OCH3

H3CO

OR

143 R = PO3Na2144 R = H

N

N

NH

N CH3

CH3

H

H

H3CO2C

H3CO H

OH

OAc

CH3

CO2CH3

FF

147

H

OAc

CH3

O2CH3


with pancreatic and hormone-refractory prostate cancers [217].DHA-paclitaxel (Taxoprexin�) 151, a fatty acid conjugate of pacli-taxel 148, is currently under pivotal Phase III trial by LuitpoldPharmaceuticals against metastatic melanoma [218]. Spectrum isevaluating a third generation intravenously as well as orally avail-able taxane, ortataxel (IDN-5109, BAY-59-8862, 152) [219] havingsimilar toxicity/tolerance profile to paclitaxel 148 in Phase I/II trials.Ortataxel 152 displays activity in tumors resistant to Taxol� and asof June 2009, the drug is in Phase II trials in taxane-refractory solidtumors [220]. Milataxel (MAC-321, TL-00139) 153, an orallybioavailable taxane and poor substrate for P-gp is under Phase IIclinical development by Wyeth Pharmaceuticals to use in thetreatment of colorectal neoplasms [221].

Tesetaxel (DJ-927, 154), an orally bioavailable semi-synthetictaxane that was evlaulated by Genta in various Phase I/II trials inpatients with advanced gastric and breast cancer [222]. A Phase IIclinical trial of 154 is undergoing in advanced melanoma patientswith a normal serum lactate dehydrogenase (LDH) and have pro-gressed after one chemotherapy regimen. Genta are also planningto explore the activity of 154 in advanced castrate-resistant pros-tate cancer (CRPC). Other taxanes, i.e. TPI-287 155 by TapestryPharmaceuticals for the treatment of advanced pancreatic cancer[223], BMS-188797 156 by Bristol-Myers Squibb for treatment of

NHO

OH

O

OO

H3COH3C

O

OCH3

OH

HO

H

O

H3C

O

CH3

CH3

O

O

148

NHO

OH

O

OO

H3COH3C

O

O

HO

H

O

H3C

O

CH3

CH3

O

O

CH3O

CH3CH3

150

H3C

NHO

OH

O

OO

H3COH3C

O

OCH3

O

H

O

H3C

O

CH3

CH3

O

O

CH3O

CH3CH3

152

CH3

OH

O

O

patients with advanced malignancies are currently in Phase IIclinical development [224].

Acronycine 157, an alkaloid isolated in 1948 from the stem barkof a Australian Rutaceous tree, Acronychia baueri, displays activityagainst a panel of murine solid tumor models, including S-180 andAKR sarcomas, X-5563 myeloma, S-115 carcinoma and S-91 mela-noma [225]. A benzoacronycine derivative S23906-1 158 showsantineoplastic activity by inhibition of DNA synthesis and alsocauses an irreversible S-phase blockage in the cell cycle and effi-ciently triggeres apoptosis in several cancer cell types. Currently,Laboratories Servier are evaluating 158 in various Phase I trialsagainst solid tumors [226].

Homoharringtonine (omacetaxine mepesuccinate, Ceflatonin�,159), a myelosuppressive alkaloid originally isolated from theevergreen tree Cephalotuxus fortuneii, inhibits synthesis of Mcl-1protein and induces apoptosis [227a]. In October 2004, the Euro-pean Commission granted orphan designation to Stragen FranceSAS for 159 against acute myeloid leukemia (AML). In January 2009,sponsorship was transferred to ChemGenex Europe SAS, France. InJanuary 2009, an Orphan Drug designation was given to 159 by theFDA to use in the treatment of myelodysplastic syndromes (MDS).In September 2009, ChemGenex submitted a NDA for 159 underOmapro� (omacetaxine mepesuccinate) to the FDA for the

OH

O

NH

CH3O

O

CH3CH3

O

O

H

OOHO

H3CO OCH3 O

H3C

CH3

CH3

H3C

OO

149

CH3

NHO

OR

O

OO

H3COH3C

O

OCH3 OH

HO

H

O

H3C

O

CH3

CH3

O

O

151

NHO

OH

O

OO

H3C

OHO

CH3

HO

H

O

H3C

O

CH3

CH3

O

O

CH3O

CH3CH3

153

O

O

H3C O

CH3

O

6R =


treatment of chronic myelogeneous leukemia (CML) patients whohave a particular gene mutation (T315I mutation) or failed inimatinib therapy. In March 2010, Oncologic Drugs AdvisoryCommittee of the FDA recommended for validated test to identifythe T315I mutation prior to approval of Omapro� [227b]. Chem-Genex are also evaluating 159 in Phase II clinical trial to use in thetreatment of patients with refractory or relapse AML who havefailed intensive chemotherapy.

30-O-methyl-nordihydroguaiaretic acid (NDGA) 160, a lignanoriginally isolated from the creosote bush Larrea divaricatta isknown to exhibit significant antipromoter, anti-inflammatory, andantineoplastic activities. NDGA 160 probably inhibits activation ofinsulin-like growth factor receptor (IGF-1R) and the c-erbB2/HER2/neu receptor, causing retardation in tumor cell proliferation [228].Terameprocol 161, a transcription inhibitor and synthetic derivativeof 160, was licensed to Erimos by The Johns Hopkins University touse in oncology. Terameprocol 161 induces apoptosis in cancer cellsby inactivation of maturation promoting factor (CDC2/cyclin Bcomplex) and survivin production and phosphorylation [229]. Eri-mos are evaluating 161 in various Phase I/II trials against solidtumors, glioma and leukemia [230].

CH3H3C

OR OR

ORH3CO

160 R = H

161 R = CH3

NHO

OH

O

OO

H3CO

CH3

HO

H

O

H3CO

CH3CH3

O

O

CH3O

CH3CH3

154

N

F

O

NCH3

CH3

N O

O

CH3

OCH3

CH3

CH3

157 R = H158 R = OAc

NHO

OH

O

H3CH3C

H

O

156

RR

O

O

O OO

O

O

O

O

OF

F

F F

F

H3C

H3CO

OP

O

O

163

O

OO

OH

H O

OCH3

OCH3H3CO

162

Epipodophyllotoxin (F11782, 162), a naturally occurring non-alkaloid extracted from root of Podophyllum peltatum [231a], isa non-intercalating dual inhibitor of both topoisomerases I and IIthat impairs the binding of the enzyme to DNA, but does notstabilize the cleavage complex [231b]. Tafluposide 163 is a deriva-tive of 162 and is currently in Phase I clinical development for anti-tumor activity by Pierre Fabre [232].

Ingenol 164, extracted from the sap of Euphorbia peplus is underclinical development by Peplin Biotech for topical treatment ofcertain skin cancers, such as basal cell carcinomas and squamouscell carcinomas [233]. In November 2009, Peplin merged with LEOPharma. Peplin’s oncology lead, ingenol mebutate (PEP005, 165),a PKC activator and derivative of 164, is currently in Phase III clinicaldevelopment against actinic keratosis (AK). In December 2009, LEOPharma announced the positive results of 165 in two Phase III trialsfor the treatment of AK lesions on head, including the face andscalp. In February 2010, LEO Pharma disclosed to meet the primaryend point with disappearance of AK lesions in non-head locationsduring a Phase III study [234].

Daidzein 166, an isoflavone occurring in a number of plants andherbs including Pueraria Mirifica, soybeans and soy products,

N

OO

H3C CH3OH

OHO

OH3C

OCH3

HO

O

159

NHO

OH

O

OO

H3COH3C

O

CH3

HO

H

O

H3C

O

CH3CH3

O

O

CH3O

CH3CH3

155

H3C CH3

OO

CH2

OO

O

O

OCH3 OH

O

H

O

H3CO

O

CH3

CH3

O

H3C

H3C

RO HOHO

HO

O

CH3CH3

O CH3

CH3

164 R = H

165 R =

O

F

O

H

F

F F

F

OCH3OHOH

O


exhibits clinical indication against tumors [235]. Novogen areevaluating a series of synthetic analogs of 166 in various preclinicaland clinical trials to use in the treatment of caners. Phenoxodiol 167[236], a synthetic analog of 166, was licensed by Marshall Edwardsfrom Novogen for development as a chemosensitizing agent incombination therapy with platinum drugs against chemoresistantovarian cancer and also as amonotherapy to use in the treatment ofprostate and cervical cancers. Phenoxodiol 167 is supposed toinhibit selectively S-1-P (sphingosine-1-phosphate), the overex-pressed pro-survival regulator and makes cancer cells more sensi-tive to chemotherapy. Phenoxodiol 167 is under Phase IIIinvestigations by Marshall Edwards to restore chemosensitivity inpatients with ovarian cancer resisting platinum drugs. A Phase IItrial of 167 in patients with castrate and noncastrate prostatecancer is also underway [237]. Triphendiol (NV-196), an orally-delivered chemosensitizing derivative of 167 that was licensed toMarshall Edwards by Novogen, is under Phase I trials for use incombination therapy against cholangiocarcinoma, advanced pros-tate cancer and melanoma. An orphan drug status was granted to167 by the FDA for cholangiocarcinoma, prostate cancer and stageIIb-IV malignant melanoma. In January 2009, FDA granted INDapproval to 167. Genistein 168, a soy-derived antineoplastic phy-toestrogen, inhibits protein-tyrosine kinase and induces celldifferentiation, is under Phase I/II trials by Astellas, Bausch & Lombfor treatment of tumors. Genistein 168 is also supposed to inhibittopoisomerase II, resulting in DNA fragmentation and apoptosis.

Gossypol 169, a polypenolic aldehyde extracted from cottonseedplant of genus Gossypium, family Malvaceae, acts as an inhibitor forseveral dehydrogenase enzymes [237]. Ascenta Therapeutics aredeveloping (�)-gossypol (AT-101,169) as an orally-active, pan-Bcl-2inhibitor that causes apoptosis in cancer cells through working asBH3 mimetic. In June 2009, Ascenta Therapeutics announced thepromising results of Phase I/II study of 169 in prostate, brain andlung cancers. In October 2009, Ascenta Therapeutics announced theresults of a Phase I trial for two combination regeims containing 73in patients with malignant brain tumor [238].

ASA 404 (vadimezan, AS1404 and DMXAA, 170), a derivative offlavone-8-acetic acid 171, was discovered originally at AucklandCancer Society Research Centre. The flavonoid 171 works asa tumor-VDA that was in-licensed by Antisoma in 2001 [239]. InApril 2007, Novartis AG signed an agreement with Antisoma forworldwide rights and co-selling of 170 in the US. As on April 2008,after a positive Phase II trial, 170 is currently in Phase III clinicaldevelopment by Novartis as a second line treatment for NSCLC.A second Phase III trial for 170 as a first line treatment for NSCLChas been discontinued in March 2010 [240]. b-Lapachone (ARQ-501, 172), a naphthoquinone derived from Tabebuia avellanedae,exerts anti-tumor effect by a rapid and sustained increase of thepro-apoptotic protein E2F-1, as well as induces expression ofcyclin dependent kinase inhibitor 1A (CDKN1A or p21) [241a].ArQule are currently evaluating 172 as a combination therapy inPhase II trials to treat pancreatic and ovarian cancer [241b,c].Alvocidib (Flavopiridol, HMR 1275, 173) a synthetic derivative ofrohitukine 174, isolated from Dysoxylum binectariferum [242a], isbeing developed by Sanofi-Aventis as their oncology pipeline incollaboration with NCI. Alvocidib 173 is a CDK inhibitor [242b] thatprevents phosphorylation of CDKs and by down-regulating cyclinD1 and D3 expression results in G1 cell cycle arrest and apoptosis.As on May 2009, 173 is under late Phase III oncology pipeline bySanofi-Aventis to use in the treatment of NSCLC patients while inPhase IIb for patients with chronic lymphocytic leukemia [242c].

Curcumin 175, a polyphenol extracted from roots of Curcumalonga (a popular Indian spice of family Zingiberaceae), has beenconsidered significant against metastatic colon cancer due to itsability to interfer with the p53 tumor suppressor pathway [243].

Curcumin 175 is under various world wide Phase I/II trials whilea Phase III trial in patients with MCC is underway.

RTA 402 (CDDO-Me, Bardoxolone methyl, 176) a synthetic tri-terpenoid analog of oleanolic acid 177, occurring naturally in variousfood and medicinal plants [244a], is being evaluated by ReataPharmaceuticals in under Phase I/II clinical development againstprostate cancer and Phase II trials in type 2 diabetes with chronickidney disease (CKD). RTA 402176 potently inhibits the activation ofIkB alpha kinase (IKK) associated with suppression of nuclear factorkappa-B (NF-kB) dependent genes that prevent apoptosis, promoteproliferation and angiogenesis [244b]. In October 2008, an orphandrug designation by the FDA was granted to 176 against prostatecancer. In January 2010, Reata Pharmaceuticals have given exclusiverights to Kyowa Hakko Kirin for development and commercializa-tion of 176 in Japan and other selectedAsian regions for treatment oftype 2 diabetes suffering from CKD [244c].

Betulinic acid (ALS-357) 68, a pentacyclic triterpenoid isolatedfromwhite birch (B. pubescens), was evaluated in preclinical studiesby Advanced Life Sciences where it demonstrated specific anti-tumor activity against malignant melanoma (MM). ALS-357 68has a unique mechanism of action that disrupts mitochondrialmembrane function and is associated with the intrinsic,mitochondria-mediated pathway of apoptosis [245]. ALS-357 68has orphan drug designation by the FDA for topical treatment ofMM and is currently in Phase I clinical development by AdvancedLife Sciences. Silybin 178, a flavonolignan extracted from blessedmilk thistle (Silybum marianum) and the active constituent of IdB1060 (silybin-phosphatidylcholine complex, Siliphos�), is currentlyin Phase II clinical development by American College of Gastroen-terology for cancer chemoprevention [246].

8.1.2. Microorganism-derived compounds8.1.2.1. Actinomycetes. Pladienolide D 179, discovered as bioactivecompounds in Streptomyces platensis Mer-11107 fermentationbroth, exerts potent antiproliferative activities against a widevariety of cancer cell lines [247a,b]. E7107 180 is a syntheticurethane derivative of 179 that binds with spliceosome-associatedprotein 130 (SAP130) and inhibits the splicing of pre-mRNAresulting in cell cycle arrest [247c]. Eisai are evaluating 180 inPhase I trials against solid tumors.

Chartreusin (U-7257, 181) and elsamicin A (BMY-28090, elsa-mitrucin,182) are the antibiotics having similar structures and bothinhibit RNA synthesis and result in single-strand scission of DNA.Chartreusin 181 was originally isolated from the culture broth andmycelial cake of Streptomyces chartreuses. Elsamicin A 182 thatbears chartarin chromophore but differ in sugar moieties i.e. bearsan amino sugar, was isolated from actinomycete strain J907-21 in1986 [248]. Elsamicin A 182 is also a potent inhibitor of top-oisomerase I and II, enzymes that play an important role in DNAreplication. Elsamicin A 182 is under Phase II clinical trials bySpectrum Pharmaceuticals for treatment of patients with advancesolid tumors.

Doxorubicin (Adriamycin�) 183, an anthracycline antibioticoriginally isolated from bacteria found in soil samples taken fromCastel del Monte, an Italian castle, is a DNA intercalating drugcommonly used against a wide range of cancers, including hema-tological malignancies, many types of carcinoma, and soft tissuesarcomas [249a]. L-annamycin 184 was originally developed at theM D Anderson Cancer Center while studies on clinical limitationswith anthracycline drugs. Doxorubicin 183 has orphan drug statusby the FDA to use in the treatment of acute lymphocytic leukemia(ALL) and AML. L-annamycin 184 inhibits topoisomerase II and iscurrently in Phase I/IIa trials by Callisto Pharmaceuticals in adultswith ALL as well as younger adults with refractory or relapsed ALLor AML [249b]. Berubicin (RTA744, WP744, 185) is an anthracycline


that intercalates with DNA and inhibits DNA replication by bindingwith topoisomerase II, is able to cross the blood brain barrier, hencefinds significance in the treatment of primary brain tumor. InOctober 2006, orphan drug designation to 185 was granted by theFDA against malignant gliomas. Reata Pharmaceuticals arecurrently conducting Phase II clinical trials of 185 for treatment ofmalignant gliomas. Sabarubicin (MEN-10755,186), a topoisomeraseII inhibitor [250a] and disaccharide analog of 183, is currently inPhase II clinical trial by Menarini Pharmaceuticals against solidtumors [250b,c]. Sabarubicin 186 is also being evaluated ascombination therapy with cisplatin against small-cell lung cancer(SCLC). Nemorubicin (MMDX, PNU-152243A, 187) a 30-deamino-30

[2-(S)-methoxy-4-morpholinyl] derivative of 183, is a DNA-intercalator and potent inhibitor of topoisomerase I, showsactivity on selected tumors resistant to current treatment. Nem-orubicin 187 is currently in Phase I/II trials by Nerviano MedicalSciences [251].

Distamycin A 188 is the lead compound of brostallicin (PNU-166196) 189 that was originally developed by Nerviano as a DNAminor grove binder (MGB) which retains sensitivity in DNAmismatch repair-deficient tumor cells [252]. The a-bromoacrylicmoiety of 189 appears to reacts with GSH, in a reaction catalyzed byGST, with the possible formation of a highly reactive GSH-complexable to bind covalently to DNA [253]. Nerviano had transferred theexclusive world right of 189 to Systems Medicine Inc. that has nowbeen taken over by the Cell Therapeutics. Cell Therapeutics arecurrently evaluating189 in a Phase II trial asmonotherapy inpatientswith advanced or metastatic soft tissue sarcoma (MSTS), and ina context of vulnerability trial in several patient populations [254].

Geldanamycin 190, a benzoquinone ansamycin antibiotic origi-nally discovered in the broth and the mycelium of Streptomyces

species [255a], can bindwith heat shock protein 90 (HSP90) playingcrucial role in apoptosis, angiogenesis and oncogenesis [255b,c].Tanespimycin (17-AAG, KOS-953, NSC-330507, 191) is a compara-tively less toxic derivative of190 and exerts anti-melanomaeffect bybinding to HSP90 and interrupts the MAPK pathway [256]. As onNovember 2009, a Phase II/III randomized open-label trial of 191 incombination with Velcade� in relapsed-refractory multiplemyeloma patients has been completed by Kosan. Alvespimycin (17-DMAG,KOS-1022,NSC-707545,192) developedbyKosanasa secondgeneration HSP90 inhibitor [257] is under clinical development fortreatment of solid tumors. As of January 2008,192 is being evaluatedas combination therapy in a Phase I trial with trastuzumab & pacli-taxel (Taxol�) against solid tumors, Phase II trial as monotherapyagainst HER2-positive metastatic breast cancer and Phase I trialagainst solid tumors. Retaspimycin (IPI-504, 17-AAG hdroquinonesalt, 193) is a HSP90 inhibitor that is under Phase I/II clinical devel-opment by Infinity Pharmaceuticals as a single agent and incombination with existing drugs against certain cancers [258].Infinity is currentlyconductingaPhase II clinical trial of193 inNSCLCpatients, while also enrolling patients for another Phase II trial toevaluate 193 in combinationwith Herceptin� in patients with HER2positive metastatic breast cancer [259].

The mTOR inhibitor, deforolimus (AP23573, MK-8669, 194) isbeing co-developed by Merck and ARIAD Pharmaceuticals for thetreatment of several tumor types including sarcoma [260]. In May2009, ARIAD have changed the name of 194 form ‘deforolimus’ to‘ridaforolimus’, and the same was adopted by the United StatesAdopted Name (USAN) Council. Ridaforolimus 194 has fast-trackand orphan drug designation by the FDA and orphan drug statusby the EMEA against soft tissue and bone sarcomas. In December2009, ARIAD Pharmaceuticals completed the enrollment for


a Phase III study of oral 194 in patients with metastatic soft tissueand bone sarcomas. Besides, ARIAD are also running several PhaseI/II trials to evaluate 194 as a single agent and in combinationtherapies [261].

Salinosporamide A (NPI-0052, 195), possessing a g-lactam-b-lactone bicycle is produced by a marine bacterium Salinisporatropica [262a]. Salinosporamide A 195 is a proteasome inhibitorthat exerts activity by modifying the threonine residues of the 20Sproteasome [262b]. In May 2006, 195 entered Phase I clinical trialsby Nereus against solid tumors and lymphomas. As on April 2008,Nereus Pharmaceuticals are enrolling patients for a Phase Ib trial of195 in combination with vorinostat (Zolinza�) for selected solidtumor malignancies [262c].

Staurosporine 196, an alkaloid originally isolated from bacte-rium Streptomyces staurosporeus [263a], is the precursor of proteinkinase inhibitors [263b], enzastaurin (LY317615) 196 and mid-ostaurin (PKC-412, CGP 41251, 40-N-Benzoyl-staurosporine) 198.Enzastaurin (LY317615, 197) is a serine/threonine kinase inhibitorand is under clinical development by Eli Lilly for treatment ofvariety of tumor types [264]. In June 2007, Eli Lilly announced theresults of a Phase II clinical trial of 197 in patients with late-stageNSCLC. As of April 2010, 197 is under Phase III trials againstdiffuse large B-cell lymphoma (DLBCL) [265]. Midostaurin 198 wasdemonstrated safe in Phase I pharmacokinetic study by Novartis

[266]. PKC-412 198 inhibits several protein kinases including FLT3and is highly anticipated as a potent therapeutic agent for Phase IItrials in AML patients carrying FLT3 mutations.

K252a 199, an alkaloid isolated from soil fungi of Nocardiopisisspecies, is a staurosporine analog and the lead compound of les-taurtinib (CEP-701, KT-5555, 200) that inhibits FLT3 [267a] andtyrosine phosphorylation of Trk A. As of 2008, lestaurtinib 200 is inPhase III clinical trials for AML and Phase II trials for myeloprolif-erative disorders. In June 2009, Cephalon disclosed the results froma pivotal trial of 200 in patients with relapsed AML expressing FLT3mutations [267b]. Another staurosporine analog, KRX-0601 (UCN-01, KW-2401, 201) inhibiting CDKs, is currently in Phase II clinicaltrials by Keryx (Kyowa Hakko) under sponsorship of NCI for treat-ment of melanoma, TCL and SCLC [268].

Diazepinomicin (ECO-4601, TLN-4601, 202) is a dibenzodiaze-pine alkaloid originally isolated from the culture of a marine acti-nomycete of the genusMicromonospora [269] that binds selectivelyto peripheral benzodiazepine receptor (PBR), resulting in tumorapoptosis, and inhibits the Ras/MAP kinase signaling pathwayinvolved in cellular proliferation and migration [269c]. ECO-4601202 was found safe and well-tolerated in Phase I/II trial con-ducted by the NCI and Thallion. In November 2007, Thalliondemonstrated that 202 can cross the blood brain barrier and targetsglioblastoma multiforme (GBM). As on September 2008, Thallion


are enrolling patients for Phase II trial of 202 as a second linetreatment for GBM [269d].

8.1.2.2. Eubacteria. Prodigiosin (Streptorubin B, 203), a redpigment produced by many strains of the bacterium Serratia mar-cescens [270] and is the lead compound of obatoclax (GX15-070,204), a Bcl-2 inhibitor that is under clinical development by GeminX for treatment of tumors. Gemin X are developing intravenousinfusion of 204 in multiple Phase I/II trials as a monotherapy inhematological and solid tumor cancer indications while as combi-nation therapy with carboplatin & etoposide in SCLC and withbortezomib (Velcade�) in mantle cell lymphoma (MCL). In March2009, Gemin X launched a Phase II study of 204 in combinationwith carboplatin & etoposide as first-line treatment SCLC whileresults of a Phase Ib trial of 204 as first line treatment for extensive-stage SCLC was release in May 2009 [271].

8.1.2.3. Myxobacteria. Patupilone (epothilone B, EPO-906, 21),microtubule-stabilizing NP produced by the myxobacteriumS. cellulosum, is currently under Phase III trials by Novartis againstovarian cancer while Phase II clinical development for the treat-ment of other tumor types [272]. Sagopilone (ZK-EPO, ZK-219477,205) is a synthetic derivative of 21 that binds to tubulin andinduces microtubule polymerization [273a] causing inhibition ofcell division, induction of G2/M arrest, and apoptosis [273b]. Unliketaxanes, 205 is able to retain activity in MDR cancer cells over-expressing the P-gp. As of February 2010, ZK-EPO 205 is in Phase IIclinical development by Schering AG against lung, ovarian andprostate cancers [273c].

Epothilone D (desoxyepothilone B) 206 is a natural polyketidethat inhibits the disassembly of microtubules by binding totubulin. The 9,10-didehydroepothilone D (KOS-1584, 207) [274],a second-generation epothilone derivative of 206 being evaluatedby Kosan Pharmaceuticals in multiple solid tumor types. In Phase Idose escalation trials by Kosan, 207 has defined efficacy andtolerability against patients with ovarian cancer and NSCLC. As of

February 2007, Kosan were planning to initiate Phase II clinicaldevelopment of 207 against multiple solid tumors in collaborationwith Roche.

8.1.2.4. Fungi. NPI-2350 (halimide, phenylahistin, 208), a diketopi-perazine metabolite consisting of L-phenylalanine and iso-prenylated dehydrohistidine, was originally isolated from a marinefungi aspergillus ustus. Plinabulin (NPI-2358, 209), a tubulin-depolymerizing synthetic analog of 208 [275a], is under clinicaldevelopment by Nereus. In November 2009, Nereus announced thepositive results of a Phase II trial of 209 as combination therapywith docetaxel in NSCLC patients [275b]. Irofulven (MGI-114,HMAF, 210), an analog of illudin S 211, a sesquiterpene toxin foundinmushrooms of the genus Omphalotus [276]. Irofulven 210 inhibitsDNA synthesis and is currently in Phase II/III development by Eisai(MGI Pharma) in patients with advanced-stage prostate cancer andadvanced GI solid tumors.

8.1.3. Marine-derived compoundsPlitidepsin (Aplidin�, 212), a cyclic depsipeptide extracted from

Aplidium albicans, is being evaluated in Phase II clinical trials byPharmaMar in hematological and solid tumors. Plitidepsin 212inhibits the vascular endothelial growth factor (VEGF) protein thatcauses vascularization and growth of tumors. After getting prom-icing results from a multicenter Phase Ib study, PharmaMar arecurrently evaluating 212 under Phase II trials as a first-line mono-therapy treatment and in combination with dacarbazine foradvanced unresectable melanoma [277].

Halichondrin B 213, isolated from Halichondria okadai sponge[278a], has been considered significant by NCI as a novel anticanceragent. Eribulin mesylate (E7389, ER-086526, NSC-707389) 214,a structurally-simplified and pharmaceutically-optimized analog of213, is being developed by Eisai as a third-line treatment againstadvanced breast cancer patients, previously treated with standardcancer chemotheraputics. Eribulin 214 is a microtubule dynamicsinhibitor that prevents various cellular processes [278bed]. In

NH

N

OCH3

HN

H3C

203

NH

N

OCH3

HN

H3C

CH3204

S

N H3C

O

OCH3

OH

OHO O

CH2

H3C

CH3H3C

205

O

CH3S

NH3C

H3C

O

CH3

CH3

O

H3C

CH3

OH

OH

206

O

CH3S

NH3C

H3C

O

CH3

CH3

O

H3C

CH3

OH

OH

207

HN

NH NNH CH2

O

O H3CCH3

208

HN

NH NNH

CH3

O

O H3C CH3

209

HOH3C

OH

CH3OH

CH3

O

HOH3C

CH3

O

CH3

OH

211210


March 2010, Eisai submitted regulatory applications to agencies inJapan, US and EU for approval of 214 against locally advanced ormetastatic breast cancer. Hemiasterlin 215, a NP-derived frommarine sponges [279], inhibits tubulin assembly and disruptsnormal microtubule dynamics and depolymerizes the microtu-bules. E7974 216, a synthetic analog of 215 that can bind to a andb tubulin, is under Phase I clinical development by Eisai againsta variety of human tumor xenografts.

Psammaplin A 217, isolated from the marine sponge Psamma-plinaplysilla, inhibits the key enzymes that control gene expression,DNA replication and angiogenesis. Panobinostat (LBH-589, 218)a synthetic analog of 217 is being evaluated by Novartis in Phase I asa single agent therapy in several tumor types [280a]. Panobinostat218 is a pan-deacetylase inhibitor and induces death of tumor celllines but not thenormal cells [280b]. Panobinostat218 is currently inPhase Ib/II clinical trils as monotherapy and in combination withchemotherapy and/or targeted therapy against Hodgkinslymphoma, MM, AML/MDS and other hematological malignancieswhile global enrollment for Phase III trial in relapsed MM isunderway.

Bryostatin 1 219, a macrolide lactone first isolated from extractsof a species of bryozoan, Bugula neritina collected in the Gulf ofCalifornia and Mexico, exerts antineoplastic activity by inhibitingPKC [281a]. Bryostatin 1 219 has orphan drug status granted by the

FDA (2001) and a similar designation by the EU (2002) for use incombination with Taxol� against esophageal cancer. In 2001, the219was licensed by GPC Biotech from Arizona State University andis currently in various Phase I/II trials under guidance of the NCI[281b,c].

Jorumycin 220, first isolated from the nudibranch Jorunnafunebris [282a], is the lead compound of Zalypsis� (PM00104/50)221 that was evaluated in Phase I clinical trials by PharmaMaragainst solid tumors or lymphoma. Zalypsis� 221 exerts cytotoxiceffects dependent on DNA binding that are not associatedwith DNAdamage. As on November 2009, 221 is in Phase II clinical trial fortreating cervical cancer as well as endometrial cancer patientspreviously with standard chemotherapy [282b].

Dolastatin 15 222, a seven-subunit depsipeptide derived fromDolabella auricularia, is a potent antimitotic agent structurallyrelated to the antitubulin agent dolastatin 10 224, a five-subunitpeptide obtained from the same organism [283]. Although firstisolated from a sea hare D. auricularia, the dolastatins (222 & 224)have cynobacteria origin. Tasidotin (synthadotin, ILX-651, 223),a third-generation analog of 222 that induces G2/M phase cell cyclearrest by inhibiting tubulin polymerization in vitro similar to thevinca alkaloids [284a], was evaluated by Genzyme in Phase I/II trialsagainst solid tumors [284b]. In May 2009, Genzyme signed anagreement with Ergomed for the co-development of 223 as an


antineoplastic agent. Soblidotin (YHI-501, TZT-1027, auristatin PE,225), a derivative of 224 that inhibits tubulin polymerization,resulting in G2/M phase cell cycle arrest and apoptosis, [284c] isunder Phase II clinical development by Yakult Honsha for treatmentof solid tumors.

Kahalalide F 226, a depsipeptide that alters lysosomalmembrane functionwas originally extracted from the Hawaiian seaslug Elysia rufescens [285a]. Kahalalide F 226 alters lysosomalmembrane function, and as of October 2008 it is in Phase II trials

O

NH

H3CH3C

O

O OHNH

ONH

O

NCH3

CH3

O

H3CCH3

O

H3C

NH3C

O

CH

O

H3C

212

O

O

O

OO

O

OHHO

HO

CH3

CH3 H

H

H

H

H

H

H

213

O

O

OO

OO

O

H H

H

H

H2C

OO

CH2

CH3

HO

OH3C

NH2

HO

214

H

NH3C

CH3CH3

N

OH3C

NH

N CO2HCH3O

CH3H3CCH3H3C

216

O

NHO

OHBr

HN

HN

NH

O

CH3 218

CH3

against severe psoriasis. Various other Phase II clinical trials for 226in melanoma, NSCLC and hepatocarcinoma are still running. In June2009, PharmaMar licensed 226 toMedimetriks Pharmaceuticals foruses other than oncology and neurology [285b]. PM02734 (Irvalec�,227) is another derivative of 226 being evaluated in Phase IIdevelopment by PharmaMar against solid tumors. As on February2010, PharmaMar are recruiting for a Phase I study of 226 ascombination therapy with erlotinib against advanced malignantsolid tumors.

O

N

3

OCH3

O CH3

CH3

N

CH3

O

O

OO

O

OO

OO

O

H

HCH3

H H

H

H

H2C

OO

CH2

CH3

H

CH3CH3

N

OH3C

NH

HNCH3

CO2HCH3O

CH3H3CCH3

3C CH3

215

NH

SS

HN

O

OH

Br

NOH

217

OH

OCH3

OO

O

H3CO

OCH3CH3

H3C

O

H3CH3CHO

OAc

O

O

HOHO

O

OH3C

OH

219


8.2. NPeantibody anticancer conjugates

During the last few decades, conjugation of potent anticanceragents to various supports such as antibodies, polymers, liposomesand nanoparticles for anticancer drug delivery has been extensivelyexplored, hoping to improve the efficacy and to reduce side effectsof chemotherapy. Certain kind of anticancer drug nanovectors havebeen developed to target tumors [286a]. Zinostatin stimalamer(ZSS), synthesized by conjugation of one molecule of neo-carzinostatin (NCS) chromoprotein and two molecules ofpoly(styrene-co-maleic acid), was first polymer-based anticanceragent launched by Yamanouchi (now Astellas) in Japan for thetreatment of hepatocellular carcinoma. Gemtuzumab ozogamicin

(Mylotarg�) 228, a humanized anti-CD33 antibody linked to cal-icheamicin 229 [286b,c], a cytotoxin enediyne antibiotic derivedfrom the bacteria Micromonospora echinospora, was the first andonly approved antibody-anticancer conjugate co-developed byWyeth and UCB Pharma.

Another calicheamicin-antibody conjugate, inotuzumab ozoga-micin (CMC-544) having the same CalichDMH and hydrazonelinker attached to humanized IgG4 anti-CD22 [287], is beingdeveloped by Wyeth and UCB Pharma. CD22 is a B-lymphoidlineage-specific differentiation antigen that undergoes rapidinternalization upon binding and delivers the conjugated Cal-ichDMH inside the cancer cells. Inotuzumab ozogamicin is underPhase II/III trials against non-Hodgkin’s lymphoma as combination


therapy with rituximab, a chimeric human IgG1 antibody thattargets another B-lymphoid lineage-specific molecule, CD20.

Maytansine 230, a macrolide isolated from plants of the genusMaytenus, inhibits the assembly of microtubules by binding totubulin at the rhizoxin binding site. Maytansine 230 despite

Table 2Halted or discontinued NP’s in oncology [16].

Lead and source Name (synonym)

PlantCamptothecin 133 Rubitecan (Orathecin�, 9-NC)Paclitaxel 148 BMS-184476

BMS-275183TL-310Simotaxel(MST-997, TL-909)

Vinblastine 146 (Hydravin�, KRX-0403)MicroorganismDoxorubicin 183 Galarubicin (DA-125)Spicamycin KRN-5500 89Rebeccamycin (staurosporine 196) Edotecarin (J-107088)

XL-119, NSC 655649, BMY-27557Epothilone D 206 KOS-862 207Patupilone 21 ABJ879

BMS-310705Fumagillin 3 CKD-732

PPI-2458MarineHemiasterlin 215 HTI-286 (SPA-110)Squalamine 118 Squalamine 118Dolastatin 10 224 Dolastatin-10 224

positive Phase I/II trials in the 1970s, failed to show significantefficacy at non-toxic concentrations.

To exploit the anticancer potential of these compounds Immu-noGen introduced new maytansinoid-antibody conjugates [288],e.g., IMGN-242 (HuC242-DM4, 231), a conjugate of the cytotoxic

Mechanism of action Comment

Topoisomerase I SuperGen discontinued developmentTubulin stabilization No update by BMSTubulin stabilization Phase II trials halted by BMSTubulin stabilization Not on clinicaltrials.govTubulin stabilization Phase I trials terminated (Wyeth/Taxolog)Tubulin binding Keryx discontinued

Topoisomerase II inhibition Not listed on Dong A pipelineDNA synthesis inhibitor Discontinued by Kirin BreweryTopoisomerase I Discontinued in 2005 by PfizerTopoisomerase II Helsinn Healthcare discontinuedTubulin stabilization Discontinued by Kosan and RocheTubulin stabilization Not in Novartis’s pipelineTubulin stabilization Not listed in BMS’s pipelineMetAP2 inhibition No update by Chong Kun DangMetAP2 inhibition GSK terminated the trial

Tubulin assembly inhibition Discontinued by Wyeth in 2005NHE-5 inhibition Trials discontinued by GenaeraTubulin assembly inhibition Discontinued by NIH


maytansinoid DM4 and the monoclonal antibody huC242 througha disulfide linker, was developed and evaluated by ImmunoGen asa targeted therapy in Phase II trials for CanAg-expressing cancers,including gastric cancer. In June 2009, ImmunoGen discontinuedfurther internal development of 231 and shifted it to out-licensingportfolio. ImmunoGen are also evaluating IMGN-901 (HuN901-DM1, 232), a conjugate of maytansinoid DM1 and huN901 thattarget CD56 expressing tumors is in a Phase II trial against SCLC anda Phase I trial for multiple myeloma. An orphan drug designationwas given to 232 by FDA in March 2010 for the treatment of merkelcell carcinoma (MCC).

8.3. Halted or discontinued compounds in oncological diseases

Compounds for which clinical trials in oncology have beenhalted or discontinued since 2005 are listed in Table 2.

9. Conclusion

NP scaffolds are infact key in drug discovery and in optimizingchemical diversity for human use. The abundant scaffold diversityin NPs is coupled with ‘purposeful design’ e usually to afford anadvantage for survival in environments threatening growth and/orsurvival of producer orgainsm. It is reasoned that these ecologicaldefense systems, produced to combat competing life forms, wouldhave some biological activity that gives the producer organism anadvantage. The quality of leads arising from NP discovery is betterand often more biologically friendly, due to their co-evolution withthe target sites in biological systems.

The large number of NP-derived compounds in various stages ofclinical development indicates that the use of NP templates is stilla viable source of new drug candidates. The traditional strengths ofNPs in oncological and infectious diseases are still ahead from thecompounds under clinical trials against metabolic and otherdiseases.

Acknowledgments

Financial assistance from Department of Science & Technology,India has gratefully been acknowledged.

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