Analogues of purines

Pmines are integral eomponents of RNA, DNA and eoenzyme that are synthesized in proliferaton of eaneer cells. Therefore, an agent that antagonizes the purine will certainly lead to formation of false DNA and these include analogues of natural purine bases, nucleosides and nucleotides. 

A few drugs belonging to this classification are, namely Mercaptopurine and Azathiopurine  

It may be prepared by the interaction of hypoxanthine with phosphorus pentasulphide. Mercaptopurine is found to inhibit experimental orthoimmune encephalomyletis and thyroiditis and hence used in combination with vincristine, methortrexate and prednisone in the treatment of childhood leukemia. As such 6-MP may cause hyperuricamia but it is usually administered with allopurinol—an analogue of hypoxanthine which blocks the conversion of 6-MP to uric acid and hence the dose of 6-MP is reduced and still the desired response is obtained. 

initial for children and adults 2.5 mg per kg body weight daily, but the dosage varies as per individual response and tolerance. 

6-[l-Methyl-4-nitromidazole-5 yl] thio] purine BP USP Imuran (Burroughs Wellcome)  

---

Antimetabolites interfere with normal metabolic pathways. They can be grouped into folate antagonists and analogues of purine or pyrimidine bases. Their action is limited to the S-phase of the cell cycle and therefore they target a smaller fraction of cells as compared with alkylating agents. 

To test whether we could accurately calculate the fold-difference of ADA inhibitory potency between purine riboside (8) and analogues of purine riboside, we selected 8-azapurine riboside (9) for our studies. Compound 9 was reported to be a 400-fold more potent ADA inhibitor relative to 8 despite differing from 8 only by the replacement of C8 with a nitrogen (Figure 8).19 The molecular reason for this enhancement in potency was not determined, but could be due either to enhanced hydration or enhanced ADA binding affinity of the hydrated species or both. To determine the reason,... 

Scheme 40. 1,3,2-Dioxa- (78) and 1,3,2-Benzodioxaboroles (79), Analogues of Purines (80), and Pentaphenylborole (82)...

Jacobson KA, von Lubitz DKJE, Daly JW, Fredholm BB (1996) Adenosine receptor ligands differences with acute and chronic treatment. Trends Pharmacol Sci 17(3) 108-113 Jacobson KA, Ji X-D, Li AH, Melman N, Siddiqui MA, Shin KJ, Marquez VE, Ravi RG (2000) Methanocarba analogues of purine nucleosides as potent and selective adenosine receptor agonists. J Med Chem 43(ll) 2196-2203... 

Some pyrrolo 2,1 -/] [ 1,2,4]triazines which are analogues of purines have been obtained from l-aminopyrrole-2-carbonitrile (or carboxamide) (Scheme 4)[94JHC781]. 

Clearly, the most widespread nucleophilic reaction by heteroatoms is alkylation at ring nitrogen atoms. It is unsurprising that the very great interest in nucleosides of pyrrolo[2,3-d]pyrimidines, as deaza analogues of purine nucleosides, dominates this field. Selected examples of this chemistry... 

Several of the nucleoside analogues of purine have been tested for anticancer activity. Onecompound, viz. (291), was active in vivo against leukemia L 1200 in mice (74JMC1282). 

Schramm VL (2002) Development of transition state analogues of purine nucleoside phosphorylase as anti-T-cell agents. Biochim. Biophys. Acta 1587 107-117... 

Kicska GA, Tyler PC, Evans GB, Furneaux RH, Schramm VL, Kim K (2003) Purine-less death in Plasmodium falciparum induced by Immucillin-H, a transition state analogue of purine nucleoside phosphorylase. J. Biol. Chem. 277 3226-3231... 

The tumor-inhibitory activity of analogues of purine and pyrimidine bases led Shealy and several coworkers to synthesize a series of analogues of the imidazoles in the biosynthetic pathway to purine ribonucleotides and to test these analogues for antineoplastic effects. 59 Beginning... 

Diverse thio analogues of purine have been prepared as anti-Mycobacterium tuberculosis agents. Two of them, 9-(ethylcarboxymethyl)-6-(decylthio)-9//-purine and 9-(ethylcarboxymethyl)-6-(dodecylthio)-9f/-purine proved to be particularly active <04JMC273>. 

Konigk, E. (1978) Purine nucleotide metabolism in promastigotes of Leishmania tropica inhibitory effect on allopurinol and analogues of purine nucleosides. Tropenmed. Parasitol. 29 435-438. 

Molecules of imidazopyridines 1 and 2 (IP) are built from imidazole and pyridine nuclei that have no common nitrogen atom. This distinguishes imidazopyridines 1 and 2 from imidazo[l,2-a]pyridine 2 and imidazo[l,5-a]pyridine 6. The latter two have little in common with purine in terms of molecular structure and chemical properties (66JOC1295, 67JOC2430). Consequently, imidazopyridines 5 and 6 are not analogues of purine and are not considered here. 

Next on the scene came the anti-metabolites of which the following analogues of purines and pyrimidines are in current clinical use cytarabine, fluorouracil, azaribine, 6-mercaptopurine, and 6-thioguanine (see Section 4.0, p. 126) also... 

Carbocyclic analogues of purine lyxo- and ribo-nucleosides have been prepared from intermediates obtained by osmium tetraoxide hydroxylation of an aminocyclopentene derivative. ... 

Secrist JA, Montgomery JA, Shealy YF, O Dell A, Clayton SJ. Resolution of racemic carbocyclic analogues of purine nucleosides through the action of adenosine deaminase. Antiviral activity of the carbocyclic 2 -deoxyguanosine enantiomers. J Med Chem 1987 30 746-749. 

The synthesis and chemistry of heterocyclic analogues of purine nucleosides and nucleotides have been comprehensively reviewed, as have the synthesis and properties of various disaccharide nucleosides.5 Other reviews have discussed the importance of nucleoside analogues in chemotherapy and in other potential therapeutic applications such as immunomodulation or the regulation of gene expression, recent developments in the synthesis of nucleoside analogues with anti-HIV activity, and the synthesis of 2, 3 -dideoxynucleosides, with or widiout substituents at C-2 or C-3, by methods which involve condensations of modified sugars with heterocyclic bases. In a review on progress in free radical chemistry in his laboratories. Barton has discussed applications to the synthesis of C-nucleosides, chain-extended nucleosides and nucleoside phosphonates. ... 

Racemic carbocyclic analogues of purine nucleosides can be resolved using adenosine deaminase thus, the D -isomers of inosine and 2 -deoxyguanosine were obtained, together with the L - forms of the aminated substrates. Further examples of carbocyclic analogues of xylofuranosyl nucleosides have been reported (see Vol. 18, p.202),... 

---