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Sachan Dinesh et al: Biological activities of purine analogues JPSI 1 (2), MARCH – APRIL 2012, 29-34 Journal of Pharmaceutical and Scientific Innovation www.jpsionline.com Review Article BIOLOGICAL ACTIVITIES OF PURINE ANALOGUES: A REVIEW Sachan Dinesh 1* , Gangwar Shikha 2 , Gangwar Bhavana 3 , Sharma Nidhi 4 , Sharma Dileep 5 1 Department of Pharmacy, Sri Rawatpura Sarkar Institute of Pharmacy, Datia-475661). M.P., India 2 Project Directorate for Farming Systems Research (PDFSR) Meerut-250110. U. P., India 3 Central Drug Research Institute, Lucknow-226001.U.P., India 4 Smt. Vidyawati College of Pharmacy, Jhansi- 284121. U.P. India 5 Sri Rawatpura Sarkar Institute of Technology and Science, Datia-475661. M.P.,India *Email: [email protected] Received on: 12/03/12 Revised on: 13/04/12 Accepted on: 17/04/12 ABSTRACT The purine analogues are a new class of nonclassical antimicrobial agents that bind with riboswitches. Purine (adenine) analogues are having antimicrobial, antifungal, antitumour, antiproliferative, antiviral and activity against HSV-1. Riboswitches are structured RNA domains that can bind directly to specific ligands and regulate gene expression. These RNA elements are located most commonly within the non-coding regions of bacterial mRNAs, because these genes were involved in fundamental metabolic pathways in certain bacterial pathogens. Purine-binding riboswitches may be targets for the development of novel antimicrobial agents. In vitro the designed compounds can be bound by purine riboswitches aptamer with affinities comparable to that of the natural ligand and many of these compounds also inhibit microbial growth. KEY WORDS: Purine analogues, Introduction, Biological activities. INTRODUCTION Purine is a heterocyclic, aromatic, organic compound, consisting of a pyrimidine ring fused to an imidazole ring. Purines, including substituted purines and their tautomers, are the most widely distributed kind of nitrogen-containing heterocyclic compounds present in nature 1 . Heterocyclic compounds are organic compounds (containing carbon) that have a ring structure containing atoms in addition to carbon, such as sulfur, oxygen, or nitrogen, as part of the ring. Aromaticity is a chemical property in which a conjugated ring of unsaturated bonds, lone pairs, or empty orbitals exhibit stabilization stronger than would be expected by the stabilization of conjugation alone. Imidazole refers to the parent compound C 3 H 4 N 2 , while imidazoles are a class of heterocycles with similar ring structure but varying substituent’s. Purines and pyrimidines make up the two groups of nitrogenous bases, including the two groups of nucleotide bases. Two of the four deoxyribonucleotides and two of the four ribonucleotides, the respective building blocks of DNA and RNA, are purines 2 . More broadly, the general term purine also is used in reference to derived, substituted purines and their structurally related tautomers (organic compounds that are inter-convertible by a chemical reaction). Prominent purines (derivatives) include caffeine, and two of the bases in nucleic acids are adenine and guanine. In DNA, adenine and guanine form hydrogen bonds with their complementary pyrimidines, thymine and cytosine. In RNA, the complement of adenine is uracil instead of thymine. Purine is also a component in Adenosine triphosphate (ATP), which stores and transports chemical energy within cells. Purine was named by the German chemist Emil Fischer in 1884. He synthesized it in 1898. Fischer showed that the purines were part of a single chemical family 3 . The structure of adenine and guanine, two of the four bases in the DNA molecule, are given in (figure 1). N N N H N NH 2 HN N N H N O H 2 N Adenine Guanine Figure 1: Structures of purine bases In addition to being biochemically significant as components of DNA and RNA, purines are also found in a number of other important biomolecules, such as ATP, GTP, cyclic AMP, NADH, and coenzyme A. The quantity of naturally occurring purines produced on earth is huge. Fifty percent (50%) of the bases in nucleic acids, adenine and guanine , are purines. In DNA, these bases form hydrogen bonds with their complementary pyrimidines thymine and cytosine, respectively. This is called complementary base pairing. In RNA, the complement of adenine is uracil (U) instead of thymine 1 . Other notable purines are hypoxanthine, xanthine, theobromine , caffeine , uric acid, and isoguanine (Figure 2). N N N H N HN N H N H N O O HN N N H N O Pur i ne Xanth i ne Hypoxanth i ne N N N O HN O theobromine N N N O N O caffi ne H N N H N H O HN O O uri c aci d HN N N H N NH 2 O i soguani ne Figure 2: Some notable purines The name 'purine' (purum uricum) was coined by the German chemist Emil Fischer in 1884. He synthesized it for the first time in 1899 1 . The starting material for the reaction sequence was uric acid, which had been isolated from kidney stones by Scheele in 1776 1 . Uric acid was reacted with PCl 5 to give 2,6,8-trichloropurine, which was converted with HI and PH 4 I to give 2,6 diiodopurine. This latter product was reduced to purine using zinc-dust (Scheme 1).

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Page 1: Sachan Dineshet al: Biological activities of purine analogues · Sachan Dineshet al: Biological activities of purine ... BIOLOGICAL ACTIVITIES OF PURINE ANALOGUES: ... Riboswitches

Sachan Dinesh et al: Biological activities of purine analogues

JPSI 1 (2), MARCH – APRIL 2012, 29-34

Journal of Pharmaceutical and Scientific Innovation www.jpsionline.com Review Article

BIOLOGICAL ACTIVITIES OF PURINE ANALOGUES: A REVIEW Sachan Dinesh1*, Gangwar Shikha2, Gangwar Bhavana3, Sharma Nidhi4, Sharma Dileep5 1Department of Pharmacy, Sri Rawatpura Sarkar Institute of Pharmacy, Datia-475661). M.P., India 2Project Directorate for Farming Systems Research (PDFSR) Meerut-250110. U. P., India 3Central Drug Research Institute, Lucknow-226001.U.P., India 4Smt. Vidyawati College of Pharmacy, Jhansi- 284121. U.P. India 5Sri Rawatpura Sarkar Institute of Technology and Science, Datia-475661. M.P.,India *Email: [email protected] Received on: 12/03/12 Revised on: 13/04/12 Accepted on: 17/04/12 ABSTRACT The purine analogues are a new class of nonclassical antimicrobial agents that bind with riboswitches. Purine (adenine) analogues are having antimicrobial, antifungal, antitumour, antiproliferative, antiviral and activity against HSV-1. Riboswitches are structured RNA domains that can bind directly to specific ligands and regulate gene expression. These RNA elements are located most commonly within the non-coding regions of bacterial mRNAs, because these genes were involved in fundamental metabolic pathways in certain bacterial pathogens. Purine-binding riboswitches may be targets for the development of novel antimicrobial agents. In vitro the designed compounds can be bound by purine riboswitches aptamer with affinities comparable to that of the natural ligand and many of these compounds also inhibit microbial growth. KEY WORDS: Purine analogues, Introduction, Biological activities. INTRODUCTION Purine is a heterocyclic, aromatic, organic compound, consisting of a pyrimidine ring fused to an imidazole ring. Purines, including substituted purines and their tautomers, are the most widely distributed kind of nitrogen-containing heterocyclic compounds present in nature1. Heterocyclic compounds are organic compounds (containing carbon) that have a ring structure containing atoms in addition to carbon, such as sulfur, oxygen, or nitrogen, as part of the ring. Aromaticity is a chemical property in which a conjugated ring of unsaturated bonds, lone pairs, or empty orbitals exhibit stabilization stronger than would be expected by the stabilization of conjugation alone. Imidazole refers to the parent compound C3H4N2, while imidazoles are a class of heterocycles with similar ring structure but varying substituent’s. Purines and pyrimidines make up the two groups of nitrogenous bases, including the two groups of nucleotide bases. Two of the four deoxyribonucleotides and two of the four ribonucleotides, the respective building blocks of DNA and RNA, are purines2. More broadly, the general term purine also is used in reference to derived, substituted purines and their structurally related tautomers (organic compounds that are inter-convertible by a chemical reaction). Prominent purines (derivatives) include caffeine, and two of the bases in nucleic acids are adenine and guanine. In DNA, adenine and guanine form hydrogen bonds with their complementary pyrimidines, thymine and cytosine. In RNA, the complement of adenine is uracil instead of thymine. Purine is also a component in Adenosine triphosphate (ATP), which stores and transports chemical energy within cells. Purine was named by the German chemist Emil Fischer in 1884. He synthesized it in 1898. Fischer showed that the purines were part of a single chemical family3. The structure of adenine and guanine, two of the four bases in the DNA molecule, are given in (figure 1).

N

N NH

N

NH2

HN

N NH

N

O

H2N

Adenine Guanine Figure 1: Structures of purine bases

In addition to being biochemically significant as components of DNA and RNA, purines are also found in a number of other important biomolecules, such as ATP, GTP, cyclic AMP, NADH, and coenzyme A. The quantity of naturally occurring purines produced on earth is huge. Fifty percent (50%) of the bases in nucleic acids, adenine and guanine , are purines. In DNA, these bases form hydrogen bonds with their complementary pyrimidines thymine and cytosine, respectively. This is called complementary base pairing. In RNA, the complement of adenine is uracil (U) instead of thymine1. Other notable purines are hypoxanthine, xanthine, theobromine , caffeine , uric acid, and isoguanine (Figure 2).

N

N NH

N H N

NH

NH

N

O

O

H N

N NH

N

O

P urin e X anth ine H y po xan th in e N

NNO

HN

O

theobromine

N

NNO

N

O

caffine

HN

NHN

HO

HN

O

O

uric acid

HN

N NH

N

NH2

O

isoguanine

Figure 2: Some notable purines

The name 'purine' (purum uricum) was coined by the German chemist Emil Fischer in 1884. He synthesized it for the first time in 18991. The starting material for the reaction sequence was uric acid, which had been isolated from kidney stones by Scheele in 17761. Uric acid was reacted with PCl5 to give 2,6,8-trichloropurine, which was converted with HI and PH4I to give 2,6 diiodopurine. This latter product was reduced to purine using zinc-dust (Scheme 1).

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Sachan Dinesh et al: Biological activities of purine analogues

JPSI 1 (2), MARCH – APRIL 2012, 29-34

H NHN

ONHN

H

O

O

uri c aci d

PC L5 N NC l

NHN

C l

C l

HI/ PH4 I N N

NHN

I

I NH

N N

N

puri ne

Zn

Scheme 1: Synthesis of purine from uric acid

Purines are found in high concentration in meat and meat products, especially internal organs such as liver and kidney. Plant based diets are generally low in purines1. Examples of high-purine sources include: sweetbreads, anchovies, sardines, liver, beef kidneys, brains, meat extracts (e.g., Oxo, Bovril), herring, mackerel, scallops, game meats, and gravy. A moderate amount of purine is also contained in beef, pork, poultry, fish and seafood, asparagus, cauliflower, spinach, mushrooms, green peas, lentils, dried peas, beans, oatmeal, wheat bran, wheat germ, and hawthorn. Higher levels of meat and seafood consumption are associated with an increased risk of gout, whereas a higher level of consumption of dairy products is associated with a decreased risk. Moderate intake of purine-rich vegetables or protein is not associated with an increased risk of gout. BIOLOGICAL ACTIVITIES OF PURINE ANALOGUES: Anti-leishmanial avtivity: The purine ring system possesses undisputed biological importance and it is considered to be one of the most important heterocyclic rings in nature. Anti-leishmanial activity of purines and its derivatives has been widely reported. Carmo L et al synthesized new tricyclic purine derivatives with 6 and 7 members and evaluated all these compounds for their cytotoxic activity and anti-leishmanial activity on KB (Human epidermoid carcinoma) and Vero (African green monkey kidney) cells. They have synthesized 7,8-dihydro-[1,4]thiazino[3,2,4-hi]purine (1), 8,9-dihydro-7H-[1,4]thiazepino[3,2,4-hi]purine (2), 7,8-dihydro-[1,4]thiazepino[3,2,4-hi]purine Hydrofluoride (a), 7,8-dihydro-[1,4] thiazepino[3,2,4-hi]purine Hydrochloride (b)7,8-dihydro-[1,4]thiazepino[3,2,4-hi]purine Hydrobromide (c) (figure 3)4.

S

NN

N N

S

NN

N N

.H X

a (X = F )b (X = C l)c (X = B r)S

NN

N N

1

2 Figure 3: New tricyclic purine derivatives with 6 and 7

members Among the tested compounds, only 8,9-dihydro-7H- [1,4] thiazepino [3,2,4-hi] purine hydrofloride (a) showed an activity against two species of Leishmania (L. amazonensis and L. chgasi). Therefore this compound showed antiproliferative activity against these two species (figure 4)4.

S

NN

N N

.H X

a (X = F ) Figure 4: 8,9-dihydro-7H- [1,4] thiazepino [3,2,4-hi]

purine hydrofloride In a similar study, Berman J. D. et al observed and reported antileishmanial activity of some purine analogs against Leishmania donavani In Vivo. The dose of orally administered 9-deazainosine calculated to suppress 50% of Leishmania donovani amastigotes in hamster livers was 19 mg/kg (body weight) per day; 96 to 99% of Leishmania organisms were eliminated from the liver and spleen of squirrel monkeys by 50 mg/kg per day. Because these activities were greater than that of the experimental clinical agent allopurinol and comparable to that of the classical agent parenteral pentavalent antimony, 9-deazainosine should be considered for clinical development for visceral leishmaniasis (figure 5)5.

N

NN

HN

Ribose

NH2

FORMYCIN A

N

NN

HN

Ribose

OH

N

N N

N

Ribose

OH

N

N N

N

Ribose

OH

H2NN

N NN

H

OH

ALLOPURINOL3-DEAZAGUANOSINE

FORM YCI N B 3-DEAZAGUANOSINE

Figure 5: Various purine derivatives

Antiviral activity: Virus-infected cells have an increased demand for purine nucleotides which are needed for viral RNA or DNA synthesis, and this renders the enzyme, IMPDH, as a sensitive target for antiviral chemotherapy. Nair et al synthesized 2-functionalized purine nucleosides and these compounds were tested as antiviral against vaccinia virus (in vitro)6. In line with the above study, it was also known at the time that many adenosine derivatives are biologically active in vitro but are inactive in vivo because of deamination by adenosine deaminase to inactive inosine derivatives. We then made the assumption that a molecule (such as 9-[[2-hydroxy- 1 -(hydroxymethyl)ethoxy]methyl]adenine) which has all of the chemical features of deoxyadenosine, but which lacks a rigid carbohydrate ring structure, would be a poor substrate of adenosine deaminase. We further reasoned that if the above compound were also a poor inhibitor (i.e. had low binding to the enzyme) of adenosine deaminase, then it might serve as an excellent antiviral agent. This reasoning was purely intuitive and was based on the assumption that key viral enzymes would have a less rigorous structural requirement in their substrates than would the equivalent mammalian enzymes. Thus a molecule such as 1 might be exempt from degradation by adenosine deaminase and other mammalian enzymes but might be accepted as a substrate by replicative enzymes in viral systems. Ogilve et al synthesized purine acyclonucleoside series and evaluated these

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Sachan Dinesh et al: Biological activities of purine analogues

JPSI 1 (2), MARCH – APRIL 2012, 29-34

compounds for their pronounced antiviral activity against HSV-17.

N

NHN

N

O

NH2O

OH

HO N

NN

NO

OH

HO

Cl

Y

Y= H

N

NN

N FO

OH

HO

NH2

N

NN

NO

OH

HO

Cl

Y

Y= NH2

a b

c d

Figure 6: Purine acyclonucleoside In a similar study, Holy et al synthesized a series of dialkyl esters of purine N-[2-(phosphonomethoxy) ethyl] derivatives substituted at position 2, 6, or 8 of the purine base and evaluated these compounds for antiviral activity8.

N

N N

N

NH2

RBr

O P(O)(OR')2

R = NH2, R' = H

N

N N

N

SH

O P(O)(OR)2

HN

N N

N

H2NBr

O P(O)(OR)2

O

R = C3H7 R = H Figure 7: dialkyl esters of purine N-[2-(phosphono

methoxy) ethyl] derivatives In a similar study, Yahyazadeh et al synthesized 'carboacyclic' nucleoside analogues such as 1 and purine derivatives with simple 9-hydroxyalkylsubstituents, such as 2 and 3. These compounds were evaluated as potent antiviral activities9. In the same context, Murti et al synthesized N-9 substituted-6-chloropurine derivatives and evaluated these compounds for their antiviral activities against Japanese encephalitis virus (JEV). None of the synthesized compounds have significant antiviral activity10. Antimicrobial Activity: a- Antifungal Activity: The purine derivatives are of great

importance to chemists as well as to biologists as they are found in a large variety of naturally occurring compounds and also in clinically useful molecules having diverse biological activities. Moreover, they are known to possess antitubercular, antiulcer, antimicrobial, antineoplastic, antitumor, antiviral and cardiotonic properties. O6-Alkylguanine derivatives are considered to be of major importance for the induction of cancer, mutation, and cell death. These adducts direct the incorporation of either thymine or cytosine without blocking DNA replication, resulting in GC to AT transition mutations, which provide a mean to effectively inactivate the O6-alkylguanine-DNA alkyltransferase (AGT) protein and increase the chemotherapeutic effectiveness of alkylating agents in

vitro and in human tumorxen ograft models. Hu Lin et al synthesized O6-alkylguanine derivatives (O6-(2-Cyclohexyl)ethoxylguanine and O6-Benzylguanine) and evaluated this for antifungal activity against some species of fungi, namely Aspergillus niger and Candida tropicalis using the disc diffusion method11.

N

N NH

N

O R

H 2 N ONa ONa

R = , Figure 8: O6-alkylguanine derivatives

Purine bases modified in the 6-position and their derivatives and analogues possess a wide range of biological properties such as antitubercular, fungicidal, antiallergic, antimicrobial, antitumor, antihistamic, myocardium inhibiting agent etc. In the same context, Hu Lin et al synthesized 6-substituted purines [N6-cyclopropyl-9H-purine-2,6-diamine, N6-phenyl-9H-purine-2,6-diamine, N6-[3-(trifluoromethyl)phenyl]-9H-purine-2,6-diamine, N6-[4-(2,2,2-trifluoroethoxy)phenyl]-9H-purine-2,6-diamine (1-4)], [2-Amino-6-fluoropurine, 2-Fluoro-6-fluoropurine, 2-Hydroxyl-6-fluoropurine, 2-Amino-6-trifluoromethylpurine, 2-Fluoro-6-trifluoromethylpurine, 2-Hydroxyl-6-trifluoromethylpurine, 2-Amino-6-trifluoroethylpurine, 2-Fluoro-6-trifluoroethylpurine, 2-Hydroxyl-6-trifluoroethylpurine (5-13)] and evaluated for their antifungal activities against some species of fungi, namely Aspergillus niger, and Candida tropicalis using the disc diffusion method, and most of the compounds showed promising activities12.

N

N NH

N

F

R2

N

N NH

N

CF3

R2

N

N NH

N

OCH2CF3

R2

R2 = NH2, F, OH

N

N NH

N

NHR1

H2NR1 =

F3C

F3CH2CO, , ,

1-4

5-13 Figure 9: 6-substituted purine derivatives

In a similar study, Murti et al synthesized N-9 substituted-6-chloropurine derivatives and evaluated these compounds for their antifungal activity against Aspergillus niger and Candida albicans, and none of the synthesized compounds have significant antifungal activity10.

b- Antibacterial Activity: Novel purine derivatives are a privileged structure present in many biological active compounds. The previous research on purine derivatives showed that purine derivatives exerted pronounced activities like antimicrobial, antimycobacterial, anti autoimmune, cytostatic and antiviral activities. In addition some 6-chloropurines constitute an important class of compounds possessing diverse type of biological properties including cytotoxic and antiviral. Keeping in view the diverse therapeutic activities of 6-chloropurine derivatives, Murti et al synthesized N-9 substituted-6-chloropurine derivatives and evaluated these compounds for their antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus subtilis, and reported that

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Sachan Dinesh et al: Biological activities of purine analogues

JPSI 1 (2), MARCH – APRIL 2012, 29-34

none of the synthesized compounds have significant antibacterial activity10. In line with above study, Gordaliza M. et al isolated agelasines, asmarines and related compounds as natural products having a hybrid terpene-purine structure from numerous genera of sponges (Agela sp., Raspailia sp.) and some of these natural products have exhibited broad-spectrum antibacterial activity against a variety of species, including Mycobacterium tuberculosis13. Phosphodiesterase inhibitor: Phosphodiesterases (PDEs) are enzymes which catalyze the hydrolysis of 3’, 5’-cyclic nucleotides cAMP and cGMP to their 5’-monophosphates. PDEs are classified into seven families, five of which, PDE1—PDE5, are characterized. 1) For instance, PDE4 specifically hydrolyzes cAMP and exerts antiinflammatory and tracheal relaxant activity. Recently, it was reported 9-benzyladenines as potent and selective PDE inhibitors, in which 9-(2-fluorobenzyl)-N6-methyladenine (BWA 78U)3) and its 2-trifluoromethyl congener (NCS 613)2) were found to be selective inhibitors of PDE4. However, purines bearing halogen at nucleobase have not been examined for their inhibition of PDEs in the literature. Because biological activities of 6-chloropurine and 2-chloropurine nucleosides4,5) have been reported, we are interested in the activity of purine analogs bearing chlorine at the base moiety. 2,6-Difluorobenzyl group was introduced in the anticonvulsant agent (534U87),6) so this group was chosen as a substituent at N9 of purine. In this paper, synthesis of 9-(2,6-difluorobenzyl)-9H-purine analogs bearing chlorine at the base moiety and their inhibition of PDEs are described. Kozai et al synthesized 9-(2,6difluorobenzyl)- 9H-purines (2,6-dichloro-9-(2,6-difluorobenzyl)-9H-purine, 2,6-Dichloro-7-(2,6-difluorobenzyl)-7H-purine, 2,6-dichloro-9-(2,6-difluorobenzyl)-9H-purine, 2,6-Dichloro-7-(2,6-difluorobenzyl)-7H-purine, 2-chloro-9-(2,6-difluorobenzyl)adenine, 6-Chloro-9-(2,6-difluorobenzyl)-9Hpurine) and evaluated these compounds as inhibitors of phosphodiesterase (PDE, PDE1 to PDE5) isozymes14.

N

N N

N

X

Cl

F

FX = ClX = NH2X = H

N

N

N

N

F

F

X

Cl

X = ClX = NH2

N

N N

N

Cl

NH2

F

F

Figure 10: 9-(2,6difluorobenzyl)- 9H-purines

Antitumour Activity: L-Ascorbic acid and its derivatives have been of multifold biological and pharmacological interest. Thus, some derivatives of L-ascorbic acid, e.g., 6-bromo-, 6-amino-, and N,N-dimethyl-6-amino-6-deoxy-L-ascorbic acid, have been found to inhibit the growth of certain human malignant tumor cells lines: cervical carcinoma (HeLa), laryngeal carcinoma (Hep2), and pancreatic carcinoma (MiaPaCa2). Furthermore, several nucleosides containing a 5-substituted pyrimidine moiety have been shown to inhibit growth of the murine mammary carcinoma (FM3A TK-/HSV 1 TK+) cells transformed with the herpes simplex virus type 1 (HSV-1) TK gene. Searching for compounds related to these classes of biologically and pharmacologically active molecules, we have prepared new types of molecules containing pyrimidine or purine moieties

connected via an acyclic chain to 2,3-dibenzyl-4,5-didehydro-5,6-dideoxy-L-ascorbic acid. Raic-Malic et al synthesized purine derivatives of L-Ascorbic acid [1-(6-Chloropurin-9-yl)-2-(2,3-O,O-dibenzyl-2-buten-4-olidylidene ) ethane, 1-(6-Chloropurin-7-yl)-2-(2,3-O,O-dibenzyl-2-buten -4-olidylidene)ethane,1-[6-(N-Pyrrolyl) purin-9-yl]-2-(2,3-O,O-dibenzyl-2-buten-4-olidylidene)ethane & evaluated these compounds for their antitumour activity against malignant tumor cell lines: pancreatic carcinoma (MiaPaCa2), breast carcinoma (MCF7), cervical carcinoma (HeLa), laryngeal carcinoma (Hep2), murine leukemia (L1210/0), murine mammary carcinoma (FM3A), and human T-lymphocytes (Molt4/C8 and CEM/0)15.

N

N N

N

OO

O BnBnO

R 6

7

9 R 6 = C l,N

B n = benzyl

Figure 11: Purine derivatives of L-Ascorbic acid

The naturally occurring N-(purin-6-yl)amino acids are important intermediates in biochemical processes. Adenylsuccinic acid (9-ribosyl-6-aspartopurine-5'-monophos-phate) is an intermediate product in the amination of inosinic acid (IMP) to adenylic acid (AMP). Also, synthetic 6- and 9-substituted purine derivatives have been previously reported for their antitumour and antiviral activity, as cardiovascular agents and for their use as hepadnaviride-active antiviral agents. Therefore in line with above study, Shalaby et al synthesized new N-(purin-6-yl)-amino acid and -peptide derivatives expected to have antitumour activity. All these compounds were evaluated for Anti-tumour activity against 60 human tumour cell lines derived from nine cancer types (leukaemia, non-small cell lung, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer and breast cancer) according to a well known procedure16.

N

NN

N

NH CH

RCO2Na

ArN

NN

N

NH CH

RCO2H

Ar

R = H, CH(OH)Me, CH2CH2SMe, CH2CO2H, CH2Ph, CH2

N NH Figure 12: New N-(purin-6-yl)-amino acid and -peptide

derivatives In the similar study, Murti et al synthesized N-9 substituted-6-chloropurine derivatives and evaluated these compounds for their cytotoxic activities against HEp-2 cell line by SRBS assay. Some of the tested compounds showed moderate anticancer activity10.

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Sachan Dinesh et al: Biological activities of purine analogues

JPSI 1 (2), MARCH – APRIL 2012, 29-34

N

N N

N

NR2

R1R

Cl

Figure 13: N-9 substituted-6-chloropurine derivatives

Table: showing various substitutions for N-9 substituted-6-

chloropurine derivatives

Compound No. Substitutions R R1 R2 1 4-Cl H H 2 4-Cl 4-Cl H 3 4-Cl 2-NO2 H 4 4-Cl 4F H 5 4-Cl H CH3

6 4-Cl 4-Br H 7 4-Cl 3,5- di Cl H 8 4-NO2 4-F H 9 4-NO2 3,5- di Cl H

10 4-NO2 4-Cl H 11 4-OH 2-NO2 H 12 4-OH 4-Br H

In the above context, Gordaliza M. et al isolated agelasines, asmarines and related compounds as natural products having a hybrid terpene-purine structure from numerous genera of sponges (Agela sp., Raspailia sp.) and some of these natural products have an important cytotoxic activity against several cancer cell lines, including multidrug-resistant ones13. Phadtare S. et al synthesized a series of twenty four acyclic unsaturated 2,6-disubstituted purines using 2,6-dichloropurines and these compounds were evaluated for their cytotoxic activity against NCI-60 DTP human tumor cell line at 10 µM concentration. Out of which N9-[(Z)-4'-chloro-2'-butenyl-1'-yl]-2,6-dichloropurine, N9-[(E)-2',3'-dibromo-4'-chloro-2'-butenyl-1'-yl]-6-methoxypurine and N9-[4'-chloro-2'-butynyl-1'-yl]-6-(4-methoxyphenyl)-purine exhibited highly potent cytotoxic activity with GI50 values in

the 1–5 μM range for most human tumor cell lines. Other compounds exhibited moderate activity17.

N

N N

N

Cl

Cl

Cl

H

H

N

N N

N

OCH3

H

Br

Br

ClN

N N

N

Cl

OCH3

a b c

Figure 14: acyclic unsaturated 2,6-disubstituted purines

Growth Inhibitors: Recent reviews on the chemotherapy of Chagas' disease and American cutaneous leishmaniasis have emphasized the deficiencies of currently available therapeutic agents and the need for new ones. These diseases are still important health problems in the Western Hemisphere, while Trypanosoma rangeli, which is apparently a harmless parasite of humans and a variety of birds and domestic animals, infects about 52% of exposed people in endemic areas. Avila et al reported growth inhibitory effects of six guanine and guanosine analogs, 3-deazaguanine (compound 1); 3-deazaguanosine (compound 2); 6-aminoallopurinol (compound 3); 9-I-xylofuranosyl guanine (compound 4); a ribosylated derivative of compound 3, 6-aminopyrazolo(3,4-d)pyrimidin-4-one (compound 5); and 5-aminoformycin B (compound 6), were tested against some pathogenic members of the family of American Trypanosomatidae. Compounds 1 and 2 were highly active against Trypanosoma cruzi, Trypanosoma rangeli, and American Leishmania spp. in in vitro culture forms. Compound 3 was the most active compound in vitro, inhibiting all of the American Trypanosomatidae culture forms tested. It was also highly inhibitory in mice that were acutely infected with T. cruzi. Ribosylation of compound 3 resulted in a derivative that showed decreased inhibitory activity on Trypanosomatidae multiplication. Compound 6 was highly inhibitory of in vitro multiplication of American Leishmania and T. rangeli but had no effect on T. cruzi epimastigotes and on mice that were acutely infected with T. cruzi. Compound 4 showed only a slight effect on T. cruzi epimastigotes18. Antiprotozoal Activity: Gordaliza M. et al isolated agelasines, asmarines and related compounds as natural products having a hybrid terpene-purine structure from numerous genera of sponges (Agela sp., Raspailia sp.) and some of these natural products have displayed high general toxicity towards protozoa13.

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Sachan Dinesh et al: Biological activities of purine analogues

JPSI 1 (2), MARCH – APRIL 2012, 29-34

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CONCLUSION This review illustrates different types of biological activities revealed by synthetic compounds having purine ring and its analogues. Several novel purines have been evaluated for their biological activities. Biological screening study of purine analogues show that the compounds exhibit different physiological activities and can contribute to further development of medicinal agents. Some natural purine derivatives have a profound impact on human health. The biosynthetic engine of Nature produces innumerable purine derivatives with distinct biological properties that make them valuable as health products or as structural templates for drug discovery. Purines and related structures display cytotoxicity and antiprotozoal, antimicrobial activity. The review demonstrates that purine and its analogs exhibit some potent medicinal properties in vitro and in vivo thus suggesting a new rationale for its use in the management of various diseases and in maintenance therapy. ACKNOWLEDGEMENTS The author would like to express hisr gratitude to the Central Drug Research Institute for providing sufficient research papers to prepare this review article. I would also like to acknowledge my friend Shikha Gangwar for her precious support for this study. REFERENCES 1. Rosemeyer H. The chemodiversity of purine as a constituent of natural

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Source of support: Nil, Conflict of interest: None Declared