Purine Analogs

Figure 33-12. Selected synthetic pyrimidine and purine analogs.

Mercaptopurine (6-MP) is an oral purine analog that is converted to a ribonucleotide to inhibit purine synthesis. Mercaptopurine is converted into thiopurine nucleotides, which are catabolized by thiopurine S-methyltransferase (TPMT), which is subject to genetic polymorphisms and may cause severe myelosuppression. TPMT status may be assessed prior to therapy to reduce drug-induced morbidity and the costs of hospitalizations for neutropenic events. Mercaptopurine is poorly absorbed, with a time to peak concentration of 1 to 2 hours after an oral dose. The half-life is 21 minutes in pediatric patients and 47 minutes in adults. Mercaptopurine is used in the treatment of acute lymphocytic leukemia and chronic myelogenous leukemia. Significant side effects include myelosuppression, mild nausea, skin rash, and cholestasis. When allopurinol is used in combination with 6-MP, the dose of 6-MP must be reduced by 66% to 75% of the usual dose because allopurinol blocks the metabolism of 6-MP. 

Possible increased toxicity when given concurrently with alkylating agents, radiation, purine analogs, and methotrexate. 

Three fluorescent purine analogs will be described here 2-aminopurine (2AP) [183] and 8-vinyladenine (8VAD), both of which mimic adenine, and N1,N6-ethenoadenine (e-AD). Their structures are shown in Figure 11-15. 2AP is probably the most widely used fluorescent DNA base analog, being utilized as a probe for DNA conformational dynamics [184, 185], due to the environmental specificity of... 

Azathioprme is a purine analog that is converted to 6-mercaptopurine and is thought to interfere with DNA and RNA synthesis. Antirheumatic effects... 

Thioguanine is a purine analog that has been used as an alternative treatment for psoriasis when conventional therapies have failed. The typical dose is 80 mg twice weekly, increased by 20 mg every 2 to 4 weeks the maximum dose is 160 mg three times a week. Adverse effects include bone marrow suppression, GI complications (e.g., nausea, diarrhea), and elevation of liver fimction tests. 6-Thioguanine may be less hepatotoxic and therefore more useful than methotrexate in hepatically compromised patients with severe psoriasis. 

Hadden, J.W., Comaglia-Ferraris, R and Coffey R.G. (1984). Purine analogs as immunomo-dulators. In Progress in Immunology IV (Yamamura, Y. and Tada, T., Eds.). Academic Press, London, pp. 1393-1407. 

Dhainaut, A., Regnier, G., Tizot, A., Pierre, A., Leonce, S., Guilbaud, N., Kraus-Berthier, L. and Atassi, G. (1996) New purines and purine analogs as modulators of multidrug resistance. Journal of Medicinal Chemistry, 39, 4099-4108. 

The drugs aUopurinol (used for gout) and 6-mercaptopurine (antineopiastic) also inhibit PRPP amidotransferase, These drugs are purine analogs that must be converted to their respective nucleotides by HPRT within cells. Also note that ... 

Oxidation of benzotriazoles and other fused triazoles by potassium permanganate is a well-established route to lif-triazole 4,5-dicarboxylic acid derivatives. Many of the triazolo[d]pyrimidines, synthesized as purine analogs, can be degraded to monocyclic triazoles by acidic or basic hydrolysis (in other triazolopyriraidines, however, the triazole ring is cleaved preferentially ), e.g. Scheme 24. 

Methylidene-9-purine analogs were prepared by the reaction of 6-chloropurines with active methylene compounds (94PHA480). A 5-trifluoromethanesulfonylpyrimidine of type 3.1 was prepared (93T5873). 

Following the discovery of the antiviral activity of the azidothymidine analog, and the activity of the 3 -azido-2 -dideoxyguanosine analog [262], the synthesis of a series of 2-amino-6-substituted-(3 azido-2, 3 -dideoxy-b-D-eryfhro-pento-furanosyl)purine analogs 196 was undertaken to explore the structure-activity relationships. 

Chemical Class 6-Mercaptopurine derivative purine analog... 

MP is converted to an inactive metabolite (6-thiouric acid) by an oxidation reaction catalyzed by xanthine oxidase, whereas 6-TG undergoes deamination. This is an important issue because the purine analog allopurinol, a potent xanthine oxidase inhibitor, is frequently used as a supportive care measure in the treatment of acute leukemias to prevent the development of hyperuricemia that often occurs with tumor cell lysis. Because allopurinol inhibits xanthine oxidase, simultaneous therapy with allopurinol and 6-MP would result in increased levels of 6-MP, thereby leading to excessive toxicity. In this setting, the dose of mercaptopurine must be reduced by 50-75%. In contrast, such an interaction does not occur with 6-TG, which can be used in full doses with allopurinol. 

PURINE ANALOGS AZATHIOPRINE 6-MERCAPTOPURINE Pharmacokinetics Pharmacodynamics... 

Azathioprine and 6-MP are important agents in the induction and maintenance of remission of ulcerative colitis and Crohn s disease. Although the optimal dose is uncertain, most patients with normal thiopurine-S-methyltransferase (TPMT) activity (see below) are treated with 6-MP, 1-1.5 mg/kg/d, or azathioprine, 2-2.5 mg/kg/d. After 3-6 months of treatment, 50-60% of patients with active disease achieve remission. These agents help maintain remission in up to 80% of patients. Among patients who depend on long-term glucocorticoid therapy to control active disease, purine analogs allow dose reduction or elimination of steroids in the majority. 

Allopurinol markedly reduces xanthine oxide catabolism of the purine analogs, potentially increasing active 6-thioguanine nucleotides that may lead to severe leukopenia. The dose of 6-MP or azathioprine should be reduced by at least half in patients taking allopurinol. 

Purine analogs and antimetabolites, eg, 6-mercaptopurine, methotrexate Mechanism uncertain may promote apoptosis of immune cells Generalized suppression of immune processes Moderately severe to severe Crohn s disease and ulcerative colitis GI upset, mucositis myelosuppression purine analogs may cause hepatotoxicity, but rare with methotrexate at the low doses used... 

M. J. Bessman, J. R. Lehman, J. Adler, S. B. Zimmerman, E. S. Simms, and A. Komberg, Enzymic synthesis of deoxyribonucleic acid. III. Incorporation of pyrimidine and purine analogs into deoxyribonucleic acid, Proc. Natl. Acad. Sci. USA 44 633 (1958). 

The management of cancer includes treatment with alkylating agents (nitrogen mustards and alkyl sulfonates), antimetabolites (methotrexate and purine analogs), natural products (vinca alkaloids and antibiotics), miscellaneous compounds (hydroxyurea, procarbazine, and cis-platinum), hormones (estrogens and corticosteroids), and radioactive isotopes (see Chapter 62). 

Like the purine analog, CLOGP calculates the tautomers widely different (+0.72 vs -1.54), and the calculated values bracket the measured ones. 

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