combinatorial synthesis of natural products

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Combinatorial syntheses allow production of compound librariesin an expeditious and organized manner immediately applicablefor high-throughput screening. Natural products possess apedigree to justify quality and appreciation in drug discoveryand development. Currently, we are seeing a rapid increase inapplication of natural products in combinatorial chemistry andvice versa. The therapeutic areas of infectious disease andoncology still dominate but many new areas are emerging.Several complex natural products have now been synthesisedby solid-phase methods and have created the foundation forpreparation of combinatorial libraries. In other examples, naturalproducts or intermediates have served as building blocks orscaffolds in the synthesis of complex natural products, bioactiveanalogues or designed hybrid molecules. Finally, structural motifsfrom the biologically active parent molecule have been identifiedand have served for design of natural product mimicry, whichfacilitates the creation of combinatorial libraries.

AddressesDepartment of Chemistry, Building 207, Kemitorvet, TechnicalUniversity of Denmark, DK-2800 Kgs. Lyngby, Denmark; e-mail: [email protected]

Current Opinion in Chemical Biology 2002, 6:297–305

0959-440X/02/$ — see front matter© 2002 Elsevier Science Ltd. All rights reserved.

Published online 15 April 2002

AbbreviationsAHL acylated homoserine lactoneBCRP breast cancer resistance proteinHDAC histone deacetylaseHTS high-throughput screeningHWE Horner–Wadsworth–EmmonsMRSA methicilin-resistant Staphylococcus aureusSPPS solid-phase peptide synthesis

IntroductionMother Nature has always provided fascination andchallenges for mankind. Steep and inaccessible mountains,extreme living conditions in deserts, arctic tundra andsubmarine volcanic valves or the beauty and diversity ofthe tropical rainforest are such examples. Likewise, themolecules provided by nature have always represented theultimate challenge for the synthetic chemist [1]. Examplesof biologically active structures from nature span all theway from small molecules such as the toxin responsible forDogger Bank itch [2] 11 (Figure 1) to complex, polycycliccompounds such as paclitaxel 22 [3]. It is a well-acceptedfact that natural products, especially those originating fromplant extracts and fermentation broths from soil bacteria,can provide compounds directly useful as drugs or asinspiration for the synthesis of medicinal drugs.

Some years ago, Newman and co-workers [4] providedan excellent overview illustrating the prevalence of

natural product structures in drugs. According to theiranalysis, 42% of all drugs approved from 1983 to 1994originated from natural products and, moreover, morethan 60% of all approved anti-infective and anticancerdrugs in the same period were derived from natural prod-ucts. For a more thorough review on how natural productshave impacted the different therapeutic classes, see therecent and excellent review by the Newman group [5]. Onecould speculate that this abundance of natural productstructures in drugs is diminishing due to the efforts insynthetic and rational approaches. However, when analyzingthe 35 therapeutic chemical and biological entitieslaunched in 2000 as reported in the ‘To Market, to Market— 2000’ chapter of the most recent Annual Reports inMedicinal Chemistry [6], it is still clear that around a third ofall new market entries originate from natural products.Thus, it is obvious that we should continue to exploit thediversity and quality provided by natural products andextracts to facilitate and optimize the drug-discoveryprocess and improve the pipeline. However, traditionalnatural product chemistry is sluggish, time-consuming,expensive and requires extensive resources. Especiallyimportant, natural products will have to meet the require-ments of high-throughput screening (HTS) and thereforesome pharmaceutical companies and research groups arecurrently addressing high-throughput natural productchemistry to meet these requirements [7,8].

As a complement to natural product extracts, I find it anattractive approach to combine the quality of naturalproduct drug discovery with the efficiency of combinatorialchemistry and high-throughput synthesis. The great interestin combinatorial synthesis of natural products and librariesthereof is shown by an increasing number of original papers

Combinatorial synthesis of natural productsJohn Nielsen

Figure 1

Examples of nature’s diversity. (a) The Dogger Bank itch toxin from amarine bryozoan and (b) the anticancer drug paclitaxel isolated fromPacific yew trees.

OHS

1

O

OHO

NHO HO

O

Current Opinion in Chemical Biology

OH

OO

OO

O

O

2

and reviews. These include reviews on natural productscaffolds [9] and templates [10•], natural-product-basedcompound libraries [11•,12], antibiotics [13], anticancercompounds [14], lead candidates [15•], stereoselectivereactions by solid-phase synthesis [16••], and carbohydrates[17,18]. Another interesting but very different perspectiveon a chemist’s interpretation of nature’s preferred methodsof synthesis, termed ‘Click Chemistry’, has recentlybeen put forward by Sharpless and co-workers [19••].‘Click Chemistry’ is the chemist’s adaptation of nature’smodular approach to synthesis pinpointed towards for-mation of carbon–heteroatom–carbon bonds rather thancarbon–carbon bonds.

An alternative approach toward combinatorial libraries ofnatural products is combinatorial biosynthesis. However,these methodologies have recently been reviewed [20] andwill not be commented on further here.

The generation of combinatorial libraries of natural productstructures can be approached in several different ways. Oneapproach is total synthesis, either in solution or on solidsupport, to enable expeditious automated library generation.Alternatively, a natural product can be used as a template orscaffold in the synthesis of natural-product-like structures.Likewise, libraries of natural product ‘look-alikes’ or mimeticscan present a way to generate biologically active compounds.

298 Combinatorial chemistry

Figure 2

An 11-hydroxy analogue of calcitriol

SiEt

Et

OH

TsO O

HO

H

HO

OH

OH1) HWE reaction2) Cu(I)-mediated Grignard reaction3) Cleavage from resin (HF-Py)

BrMgOTMS

(2)

Ph2OP

OTBSTBSO

(3)

(1)

Side chain

CD-rings

A-ring

LSO

O

OH

O

POPh2

BrMgOTMS

n

R1 R2

R3

R4

4 Different A-rings

6 Different side chains

3 Different CD-rings

SiEt

EtO(CH2)9OL =

(a)

(b)

–

–


Solid-phase synthesis of vitamin D analogs. (a) Synthesis of11-hydroxylated vitamin D3 analogs by an HWE-installation of theA-ring and Cu(I)-catalyzed Grignard reaction for introduction of theside chain. (b) The synthetic scheme for library production of

vitamin D3 analogs using a side-chain-immobilized CD-ring systemallowing for installation of the A-ring by the HWE-reaction andattachment of the side chain and synchronous cleavage from the resin.TBS, tert-butyldimethylsilyl; TMS, trimethylsilane; Ts, p-tosyl.

Solution- and solid-phase synthesis of naturalproducts and analogsVitamin D represents a large class of biologically activecompounds with therapeutic interest. Two differentsolid-phase approaches have been developed for theirsynthesis, one solely for 11-hydroxy analogs of calcitrioland one more general for vitamin D3 derivatives [21••].The 11-hydroxy analogs were synthesized by attaching the11-hydroxy function of the CD-ring system to diethylsilylpolystyrene followed by installation of the A-ring by aHorner–Wadsworth–Emmons (HWE) reaction and the sidechain by a Cu(I)-mediated Grignard reaction (Figure 2a).For a more general methodology facilitating library pro-duction, the CD-ring system was immobilized to the resinby a side chain sulfonate linker, which allowed installationof different side chains by Grignard following the HWEreaction (Figure 2b). Using three different CD-rings, fourdifferent A-rings and six different side chains, a library of72 discrete compounds was produced using a radiofrequency-encoded synthesis strategy. A solution- and solid-phaseapproach exploiting the Suzuki–Mayaura coupling towardsvitamin D3 derivatives has also been reported [22].

Psammaplin A is a marine metabolite consisting of asymmetrical bromotyrosine-derived disulfide and hasshown activity towards methicilin-resistant Staphylococcusaureus (MRSA). To explore this natural product lead, amethodology for solution-phase combinatorial scramblingof homodimeric disulfides was developed and applied tothe synthesis of a 3828-member library of homodimericand heterodimeric psammaplin A analogs [23]. The scramblingwas mediated by the catalytic action of dithiothreitoland led to the theoretically expected 50% of heterodimeror better in 95% of the reactions analyzed. The librarywas screened directly as the approximate 1:2:1-ratio of

homo-hetero-homo dimers and several compoundsshowed high potency in a series of therapeutically relevantbacterial strains.

Fumitremorgin C is a fungal metabolite with specific rever-sal activity against breast cancer resistance protein (BCRP).A Pictet–Spengler-mediated solid-phase synthesis commencingwith an L-tryptophan charged hydroxyethyl polystyrenehas been developed and led to a 42-member fumitremorgin-type compound library as well as demethoxyfumitre-morgin C [24]. Several selective and potent BCRP-inhibitorswere identified.

The marine natural product hapalosin, which is a cyclicdepsipeptide capable of reversing the effect of multidrugresistance in tumor cells, has been approached by a solid-phase-based synthesis of mimetics using β-hydroxy acidsand a γ-amino-β-hydroxy acid together with a range ofα-amino acids. The trimeric unit was synthesized on aWang resin, released from the support and then cyclized bya macrolactamization in solution to yield analogs possessingtwo amides and one ester as opposed to the two esters andone amide of native hapalosin [25]. In another report, anefficient macrolactamization exploiting the N-bromosuc-cinimide-mediated intramolecular oxidative cleavage froman aryl hydrazide handle has been implemented for thesynthesis of cyclic peptides including the marine naturalproduct stylostatin [26].

Solution- and solid-phase synthesis usingnatural product templatesMacrolides such as erythromycin A (33, Figure 3) areimmensely important antibiotic drugs. However, the searchfor candidates with improved bioavailability (absorption,distribution, metabolism and excretion; ADME) and activity

Combinatorial synthesis of natural products Nielsen 299

Figure 3

Erythromycin A

O

HO OOH

O

O

HO

O

O

NMe2

OMeOH

HO

O

O

O

OO

O

O

NMe2

HO

OH

N

OO

FmocHN

O

O

O

OO

O

O

NMe2

HO

OH

N

OO

HN

N COOH

R1

R3

R2

3 4'Erythromycin' aldehyde

5Erythromycin-likelibrary members


Erythromycin A (3) and a strategy towards an erythromycin-likecompound library. Erythromycin aldehyde 4 was synthesized from6-allyl-erythromycin and coupled to a Wang-type amino-acid-chargedresin defining R1. Two successive reductive aminations defined R2 and

R3 followed by acidic release from the resin to yield 5. Please note that I have kept the 6R-configuration of erythromycin A andderivatives although [27] consistently shows the 6S-isomer.Fmoc, 9-fluorenylmethoxycarbonyl.

towards resistant bacterial strains continues. Starting from6-O-allyl-erythromycin A, which is available as a syntheticintermediate in the production of an Abbott clinicalcandidate, aldehyde 44 was obtained in seven steps [27].Diversity was introduced at three different sites by amino acidacylation followed by two successive reductive aminationsto yield target library compounds 55. Crude purities rangedfrom 54–100% and yields from 9–33% after high-throughputHPLC. A scope-and-limitation study was reported, enablinga future split-and-mix synthesis of about 70 000 members.Unfortunately, there was no report of biological data or thesplit-and-mix combinatorial library generation.

AP1867 is a synthetic analog of the natural productmacrolides FK506 and rapamycin [28]. Using solid-phase

synthesis, 320 resin-bound tetrahydrooxazepines were conjugated to AP1867 to form an array of heterodimers.These compounds were used in the search for cell-permeableprotein–protein heterodimerization.

The glycopeptide vancomycin (66, Figure 4) is often thelast resort for treatment of infections by MRSA, a resistantstain of Staphylococcus aureus and several other serious andpotentially life-threatening infections. However, becauseof an emerging resistance even towards vancomycin,combinatorial libraries of vancomycin analogs could provideleads for the development of new, effective antibiotics.Nicolaou et al. [29••] have investigated several approachesleading to derivatives diversified at the carbohydratemoieties, at the C- and N-termini (Figure 4a). While


Figure 4

6Vancomycin

OO O

NH

O

HN

O

O

O

NH2

OH

HOHO

Cl

Cl

HO

OHHO

HN

O

HOOC

H

HN

O

H

OHOH

HO

O HN

ONH

OHN

C-terminus N-terminus

Carbohydrate moieties

NH2

O

SeI

O

OHVancomycin

Se

O

OVancomycin


Se

O

OVancomycin

OH

H2O2

O

OVancomycinPh(PPh3)4 (cat.)

SnHn-Bu

n-Bu

CsHCO3

(a)

(b)

Combinatorial and solid-phase synthesis of vancomycin.(a) Vancomycin and the sites chosen for diversification. (b) A schemefor the attachment and release of vancomycin or analogs. The selenyl

handle functions as a safety-catch pro-allyl linker, which is stabletowards the synthesis conditions but cleaved under mild conditionsafter oxidation.

photo-labile and allyl-based linkers proved insufficient,the phenylselenyl resin, which acts as a pro-allyl safety-catch linker, proved successful for selective chemicalmanipulations and high-yielding attach-and-release ofappropriately protected vancomycin (Figure 4b). Thecarbohydrate moieties were diversified through a seriesof manipulations including selective deglycosidation followed by reglycosidation using trichloroacetamidates andazido sugars. A solution-phase methodology was developedfor the synthesis of olefinic- and thioacetate-modifiedvancomycin analogs. This methodology, when combinedwith solid-phase peptide synthesis (SPPS) on a super-acid-labile Wang-type resin, allowed the synthesis of asmall library of C-, N- and carbohydrate-modified van-comycin analogs. Several compounds with activity againstvancomycin-resistant bacteria were identified.

Steroids and terpenoids represent other classes of thera-peutically relevant natural products, which, as yet, arenot easily synthesized by solid-phase synthesis. Therefore,in order to generate a library of potential inhibitors oftype 3 17β-hydroxysteroid dehydrogenase, which is aninteresting target for anticancer and anti-fertility agents,

the relevant 3-azidomethylandrostan-17-one steroidscaffold was coupled to the glycerol-linked solid-supportvia an efficient transketalisation [30]. After reduction ofthe azide to an amine, SPPS introduced three sites ofdiversity from two sets of lipophilic amino acids and oneset of termination by N-acylating agents. A compoundwith high nanomolar activity was identified. Along theselines, this research group has developed four alternativeprocedures for immobilizing hydroxysteroids for solid-phase synthesis [31]. Using a similar approach, the labdanediterpenoid scaffold of 14-deoxyandrographolide wasattached to a chlorotrityl polystyrene and modified andfunctionalized by reactions at the free hydroxy functionand double bond, respectively [32]. In an alternativeapproach towards analogs of the antibiotic and anti-angiogenic squalamine, a new safety-catch linker utilizingthe 1,6-elimination scheme of 4-hydroxymethylphenolswas developed [33].

Anticancer natural products possessing the characteristiclabile nine-membered enediyne structure, such ascalicheamicin, esperamicin, dynemicin A and neocarzinos-tatin, have long been true synthetic challenges for


Figure 5

7

Neocarzinostatin-like chromophore

O

O

HO

O

Br

O

OH

O

HN

O

Si

O

O

BzOBzO

NHFmoc

O

Br

Et Et HN

O

Si

O

O

BzOBzO

NHFmoc

O

SH

Et Et

HN

O

Si

O

O

BzOBzO

NHFmoc

O

S

Et Et

O

O

HO

OO

5 Steps 3 Steps

DIEA24 h


The solid-phase synthesis of a neocarzinostatin-type compound library.Using a 5-silanylpentanoic-acid-based handle, 14 differentlyfunctionalized mono- di- and trisaccharides were coupled to anaminopolystyrene commericially available crown pin-polymer (for

simplicity, only one exemplary monosaccharide is shown here). After asimple functional group transformation, the neocarzinostatin-likechromophore was introduced by alkylation. Bz, benzoyl group; DIEA,N,N′-diisopropylethylamine; Fmoc, 9-fluorenylmethoxycarbonyl.

chemists. In order to access combinatorial libraries of suchcompounds by solid-phase synthesis, a new silyl linkerwas elaborated from 4-pentenoic acid [34•]. Rhodium-catalyzed dehydrogenative silylation installed the linker atthe free 6-hydroxy of an array of oligosaccharides allowingsubsequent immobilization to polystyrene in the form of so-called crown pins (Figure 5). Following a simplefunctional group transformation, a neocarzinostatin-likechromophore (77) was attached to the resin-bound carbohy-drate by alkylation. Mild, acidic hydrolysis allowed releasefrom the support in 50–80% yield in the initial libraryconsisting of 14 individually purified and characterizedenediyne-hybrid molecules.

The natural product saphenic acid, which is a hydroxyacid, has been synthesized in large scale and coupled tochlorotrityl polystyrene [35]. Acylation of the benzylichydroxy function with a variety of different acids generatedan array of saphenyl benzoates analogous to the potentantibiotic saphenamycin. Eight of these analogs showedantimicrobial activity.

Solid-phase synthesis of naturalproduct mimeticsAround a decade ago, Hirschmann, Smith and co-workerspresented their pioneering and groundbreaking applicationof the β-D-glucose scaffold to mimic the action of L-363,301,a cyclic hexapeptide somatostatin agonist [36]. To apply thistechnology in a combinatorial scheme, a solid-phase versionhas been developed [37]. Installation of a thioglycosidehandle allows simultaneous introduction of diversity atC1 and detachment from the support. Regioselective andstereoselective transformations have been elaborated andopen synthesis of carbohydrate libraries around the centralglucose core or alternatively for combinatorial display fordiverse or pharmacophoric elements.

In an approach termed ‘biomimetic diversity-orientedsynthesis’, the natural product galanthamine (88, Figure 6) isused as a rigid diversity-generating scaffold to generatemore than 2500 individual compounds [38••]. Takingadvantage of the insight of the chemical transformationsoutlined in the biosynthetic pathway towards galanthamine,these steps were paralleled chemically by a short, efficientsequence comprising reductive amination, oxidation andpalladium-catalyzed cyclization to provide 99. This immo-bilized scaffold 99 allowed efficient decoration of the centralcore by utilizing four high-yielding transformations comprisingMitsunobu alkylation, Michael-type addition, N-acylationor N-alkylation and hydrazone or oxime formations. Macrobeads were used for the synthesis and a high-nanomolarinhibitor of the secretory pathway was identified.

The two natural products trichostatin A and trapoxin areinhibitors of histone deacetylase (HDAC) and are thereforeinteresting as potential immunosupressive agents [39•].Structural motifs from these natural products and the X-raystructure of trichostatin-bound HDAC-like protein wereused to design a solid-phase based synthetic approachtowards a library of 7200 potential HDAC modulators. Usinga silane-linked resin, nucleophilic ring opening of a γ,δ-epoxyalcohol produced a 1,3-diol, which subsequently wasketalized stereoselectively to the corresponding rigidamino-protected aryl-1,3-dioxane (Figure 7). N-deprotection,followed by chemoselective monoacylation by a diacylatingagent led to the immobilized carboxy-functionalized carboxyamides. Using a ‘global approach’ (the ‘globalapproach’ or ‘library from a library’ has been put forward byseveral different research groups. See, for example, [40] andreferences therein) the resin was split into three parts and onethird were cleaved leading to 2400 carboxy-functionalizedcarboxyamides 1100. The remaining two thirds were elaboratedfurther by reaction with o-phenylenediamine to yield 2400


Figure 6

Pri

PriN

O

MeO

OH

NH

O

Br

O

HO

HO Si

N

O

Br

N

OOH

SR2

R4

R1

R3

(1) Mitsunobu alkylation

(2) Michael-type addition

(3) N-acylation or N-alkylation

(4) Hydrazone or oxime formation

8Galanthamine

9Immobilized galanthamine-scaffold Library members indicating the

four elements of diversity


Galanthamine (8) and the scaffold synthesized by chemicalinterpretation of the galanthamine biosynthesis. Four high-yieldingreactions comprising Mitsunobu alkylation, Michael-type addition,

N-acylation or N-alkylation and hydrazone or oxime formations wereapplied to generate a library of 2946 potential compounds of which2527 were confirmed. Pri, isopropyl group.

o-aminoanilides 1111 or with methoxypropanehydroxylamineto yield 2400 hydroxamic acids 1122 after deprotection. Fullbiological data were not reported, but several potent inhibitorswere identified, which validates the 1,3-dioxane mimicry.

A solid-phase approach towards mureidomycins, a class ofantibiotic nucleopeptides, has been developed [41]. Thesynthetically difficult and unusual enamide moiety ofmureidomycin was exchanged with a synthetically more


Figure 7

10Carboxy-functionalized carboxyamides

O NH

O

Sii-Pr i-Pr

O

OHO

=X

OHOH

R1

MeO OMe

NHFmocn

R1XH

XR1

NH2n

OO

R2

R2

(1) Nucleophilic epoxide opening

(2) 1,3-Dioxane formation

i)

ii) Deprotection (piperidine)

XR1

NHn

OO

R2

O

HOO

m

XR1

NHn

OO

R2

O

HNO

m

OH

OH

(3) Monoacylation by diacid

(3′) hydroxamic acid formation

(3′′ ) o-Aminoanilide formation

XR1

NHn

OO

R2

O

NHO

m

NH2

XR1

NHn

OO

R2

O

NHO

m

NH2

OH

Deprotection/cleavage

Cleavage

O

OR

O

mRO

XR1

NHn

OO

R2

O

HOO

m

OH

Cleavage


11o-Aminoanilides

12

Hydroxamic acids

MeO ONH2

A ‘global approach’ for the synthesis of libraries based on naturalproducts trichostatin A and trapoxin. The first step of diversificationincludes a nucleophilic opening of the immobilized epoxide. Thesecond diversification includes a stereoselective 1,3-dioxane formation.

The third step is defined by reaction with glutaric anhydride or amonoprotected diacid. Finally, the acid intermediates can be convertedto hydroxamic acids or o-aminoanilides by reaction withmethoxypropanehydroxylamine or o-phenylenediamine, respectively.

straight-forward SPPS-type amide linkage through a2′,3′-acetal-linked 5′-aminouridine. Four sites of diversitywere introduced to provide a mimetic library of 80 discretecompounds but no activity was detected against therelevant pathogens.

Acylated homoserine lactones (AHLs) are naturally occurringautoinducers for inter-bacterial communication, oftentermed quorum sensing. Several halofuranones fromred-green algae, which mimic the AHL structure, have beenshown to be potent inhibitors of quorum sensing and thuspotential lead compounds for the design of medicinal drugsacting against biofilm formation coursed by the opportunisticpathogen Pseudomonas aeruginosa. Synthetic solution-phasemethodologies were developed to install and further func-tionalize the lactone scaffold in a combinatorial fashion at the3- and 4-positions, respectively [42]. Only the 4-substitutedN2-acylated lactones showed some ability to antagonizequorum sensing in the test system. A solid-phase-basedmethodology for the synthesis of 4-functionalized3-methyllactones from crotylstannanes has been reported, buthas not yet been applied for the generation of libraries [43].

ConclusionsNatural products have long proven valuable and useful inassisting drug discovery. Many drugs used today have theirorigin in natural products and many more are derived fromnatural product lead structures. However, natural productchemistry is resource-intensive and sluggish and sufferssome difficulties in meeting the demand from HTS.Combinatorial chemistry, on the other hand, was created tomeet this demand by HTS playing ‘the numbers game’,but has yet to prove valuable when it comes to puttingdrugs on the market. Therefore, we are currently seeing arapidly growing field combining the best of these twoworlds. Using natural product structures as inspiration forsynthesis, as structural scaffolds or simply as buildingblocks provides combinatorial libraries with an increasedchance of finding potent biological activity. Until now,most activity has been focused around antimicrobialresearch and anticancer compounds, probably because ofthe already established value of natural products in thesefields. However, new areas are opening up and it must beexpected that scientists in the future will broaden thescope of natural product combinatorial chemistry to enterother fields such as protein kinases, phosphordiesterases,immunosupressive agents and evolving targets such asprotein–protein interactions and drug–DNA interactions.

References and recommended readingPapers of particular interest, published within the annual period of review,have been highlighted as:

• of special interest•• of outstanding interest

1. Nicolaou KC, Sorensen EJ: Classics in Total Synthesis. Weinheim:VCH; 1996.

2. Carle JS, Christophersen C: Dogger Bank itch. The allergen is(2-hydroxyethyl)dimethylsulfonium ion. J Am Chem Soc1980,102:5108-5109.

3. Nicolaou KC, Yang Z, Liu JJ, Ueno H, Nantermet PG, Guy RK,Claiborne CF, Renaud J, Couladouros EA, Paulvannan K, Sorensen EJ:Total synthesis of taxol. Nature 1994, 367:630-634.

4. Cragg GM, Newman DJ, Snader KM: Natural products in drugdiscovery and development. J Nat Prod 1997, 60:52-60.

5. Newman DJ, Cragg GM, Snader KM: The influence of naturalproducts upon drug discovery. Natural Product Reports2000,17:215-234.

6. Gaudilliere B, Bernardelli P, Barna P: To market, to market — 2000.In Ann Rev Med Chem. Doherty AM (Ed.) Academic Press; 2001,36:293-318.

7. Quinn RJ: High-throughput screening in natural product drugdiscovery in Australia utilising Australia’s biodiversity. DrugDevelopment Res 1999, 46:250-254.

8. Zeng L, Cremin P, Lee C, O’Neil-Johnson M, Caporale L:High-throughput natural product chemistry for drug discovery.In Abstracts of Papers of the American Chemical Society, Division ofMedicinal Chemistry, Abstract 193, 221st ACS National Meeting:2001 April 1–5; San Diego, California.

9. Lee ML, Schneider G: Scaffold architecture and pharmacophoricproperties of natural products and trade drugs: application in thedesign of natural product-based combinatorial libraries. J CombChem 2001, 3:284-289.

10. Hall DG, Manku S, Wang F: Solution- and solid-phase strategies • for the design, synthesis, and screening of libraries based on

natural product templates: a comprehensive survey. J CombChem 2001, 3:125-150.

A thorough review on the impact of natural products in combinatorial chemistry.The review is divided into different structural classes and goes back to thebeginning of the field.

11. Wessjohann LA: Synthesis of natural-product-based compound • libraries. Curr Opin Chem Biol 2000, 4:303-309.A review on natural products in combinatorial chemistry preceding this review.

12. Kulkarni BA, Roth GP, Lobkovsky E, Porco JA: Combinatorialsynthesis of natural product-like molecules using afirst-generation spiroketal scaffold. J Comb Chem 2002, 4:56-72.

13. Trias J: The role of combichem in antibiotic discovery. Curr OpinMicrobiol 2001, 4:520-525.

14. Bhattacharyya S: Combinatorial approaches in anticancer drugdiscovery: recent advances in design and synthesis. Curr MedChem 2001, 8:1383-1404.

15. Golebiowski A, Klopfenstein SR, Portlock DE: Lead compounds • discovered from libraries. Curr Opin Chem Biol 2001, 5:273-284.A review on the drug development perspectives of combinatorial chemistry.A list of thematic libraries is provided.

16. Arya P, Baek M-G: Natural product-like chiral derivatives by •• solid-phase synthesis. Curr Opin Chem Biol 2001, 5:292-301.A review on stereoselective synthesis of natural products for combinatorialchemistry.

17. Seeberger PH, Haase WC: Solid-phase oligosaccharide synthesisand combinatorial carbohydrate libraries. Chem Rev 2000,100:4349-4393.

18. Barkley A, Arya P: Combinatorial chemistry toward understandingthe function(s) of carbohydrates and carbohydrate conjugates.Chem Eur J 2001, 7:555-563.

19. Kolb HC, Finn MG, Sharpless KB: Click chemistry: diverse •• chemical function from a few good reactions. Angew Chem Ed Int

Engl 2001, 40:2004-2021.A seminal review on ‘Click Chemistry’. The strategy focuses on nature’smodular approach to synthesis rather than its structures.

20. Rodriguez E, McDaniel R: Combinatorial biosynthesis ofantimicrobials and other natural products. Curr Opin Microbiol2001, 4:526-534.

21. Hijikuro I, Doi T, Takahashi T: Parallel synthesis of a vitamin D-3 •• library in the solid-phase. J Am Chem Soc 2001, 123:3716-3722.An interesting report on the application of solid-phase combinatorial synthesisof vitamin D derivatives.

22. Hanazawa T, Wada T, Masuda T, Okamoto S, Sato F: Novel syntheticapproach to 19-nor-1 alpha,25-dihydroxyvitamin D-3 and itsderivatives by Suzuki–Miyaura coupling in solution and on solidsupport. Org Lett 2001, 3:3975-3977.


23. Nicolaou KC, Hughes R, Pfefferkorn JA, Barluenga S, Roecker AJ:Combinatorial synthesis through disulfide exchange: discovery ofpotent psammaplin A type antibacterial agents active againstmethicillin-resistant Staphylococcus aureus (MRSA). Chem Eur J2001, 7:4280-4295.

24. van Loevezijn A, Allen JD, Schinkel AH, Koomen GJ: Inhibition ofBCRP-mediated drug efflux by fumitremorgin-type indolyldiketopiperazines. Bioorg Med Chem Lett 2001, 11:29-32.

25. Hermann C, Giammasi C, Geyer A, Maier ME: Syntheses ofhapalosin analogs by solid-phase assembly of acyclic precursors.Tetrahedron 2001, 57:8999-9010.

26. Rosenbaum C, Waldmann H: Solid phase synthesis of cyclicpeptides by oxidative cyclative cleavage of an aryl hydrazide linker— synthesis of stylostatin 1. Tetrahedron Lett 2001, 42:5677-5680.

27. Akritopoulou-Zanze I, Sowin TJ: Solid-phase synthesis of macrolideanalogs. J Comb Chem 2001, 3:301-311.

28. Koide K, Finkelstein JM, Ball Z, Verdine GL: A synthetic library ofcell-permeable molecules. J Am Chem Soc 2001, 123:398-408.

29. Nicolaou KC, Cho SY, Hughes R, Winssinger N, Smethurst C, •• Labischinski H, Endermann R: Solid- and solution-phase synthesis

of vancomycin and vancomycin analogs with activity againstvancomycin-resistant bacteria. Chem Eur J 2001, 7:3798-3823.

An interesting and thorough report on the application of both solution-phaseand solid-phase combinatorial synthesis of vancomycin and derivatives.

30. Maltais R, Luu-The V, Poirier D: Parallel solid-phase synthesis of3 beta-peptido-3 alpha-hydroxy-5 alpha androstan-17-onederivatives for inhibition of type 3 17 beta-hydroxysteroiddehydrogenase. Bioorg Med Chem 2001, 9:3101-3111.

31. Maltais R, Tremblay MR, Poirier D: Solid-phase synthesis ofhydroxysteroid derivatives using the diethylsilyloxy linker. J CombChem 2000, 2:604-614.

32. Biabani MAF, Grover RK, Singh SK, Kumar S, Raj K, Roy R, Kundu B:A novel diterpenoid lactone-based scaffold for the generation ofcombinatorial libraries. Tetrahedron Lett 2001, 42:7119-7121.

33. Chitkul B, Atrash B, Bradley M: A new bio-compatible pH cleavablelinker for solid-phase synthesis of a squalamine analog.Tetrahedron Lett 2001, 42:6211-6214.

34. Matsuda A, Doi T, Tanaka H, Takahashi T: Parallel synthesis of • oligosaccharide conjugated enediynes onto silyl-linked

solid-support. Synlett 2001:1101-1104.A report on the application of solid-phase synthesis towards complexendiyne conjugates.

35. Laursen JB, de Visser PC, Nielsen HK, Jensen KJ, Nielsen J:Solid-phase synthesis of new saphenamycin analogs withantimicrobial activity. Bioorg Med Chem Lett 2002, 12:171-175.

36. Hirschmann R, Nicolaou KC, Pietranico S, Salvino J, Leahy EM,Sprengeler PA, Furst G, Smith AB, Strader CD, Cascieri MA et al.:Nonpeptidal peptidomimetics with a ββ-D-glucose scaffolding.A partial somatostatin agonist bearing a close structuralrelationship to a potent, selective substance P antagonist. J AmChem Soc 1992, 114, 9217-9218.

37. Hirschmann R, Ducry L, Smith AB: Development of an efficient,regio- and stereoselective route to libraries based on the beta-D-glucose scaffold. J Org Chem 2000, 65:8307-8316.

38. Pelish HE, Westwood NJ, Feng Y, Kirchhausen T, Shair MD: Use of •• biomimetic diversity-oriented synthesis to discover

galanthamine-like molecules with biological properties beyondthose of the natural product. J Am Chem Soc 2001,123:6740-6741.

This report shows that natural product structures can serve as appropriatescaffolds for diversity generation towards therapeutic indication unrelated tothe activity of the parent molecule. More, insight into the biosynthesis isapplied in the synthetic transformation.

39. Sternson SM, Wong JC, Grozinger CM, Schreiber SL: Synthesis of • 7200 small molecules based on a substructural analysis of the

histone deacetylase inhibitors trichostatin and trapoxin. Org Lett2001, 3:4239-4242.

Solid-phase combinatorial synthesis introducing the 1,3-dioxane as a rigidnatural product mimetic.

40. Nuss JM, Desai MC, Zuckermann RN, Singh R, Renhowe PA, GoffDA, Chinn JP, Wang L, Dorr H, Brown EG, Subramamian S:Development of general strategy for the solid supportedsynthesis of heterocycles: application to the generation ofmolecular diversity and drug discovery. Pure Appl Chem 1997,69:447-452.

41. Bozzoli A, Kazmierski W, Kennedy G, Pasquarello A, Pecunioso A:A solid-phase approach to analogs of the antibioticmureidomycin. Bioorg Med Chem Lett 2000, 10, 2759-2763.

42. Olsen JA, Severinsen R, Rasmussen TB, Hentzer M, Givskov M,Nielsen J: Synthesis of new 3- and 4-substituted analogs of acylhomoserine lactone quorum sensing autoinducers. Bioorg MedChem Lett 2002, 12:325-328.

43. Cossy J, Rasamison C, Pardo DG: Reactivity of alpha-(benzoyloxy)crotylstannane with aldehydes in liquid phase and on solidsupport. Synthesis of substituted lactones. J Org Chem 2001,66:7195-7198.


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