Purine analog antimetabolites

Antipurine antimetabolite purine analog inhibits DNA, RNA, protein synthesis metabolized by xanthine oxidase... 

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... 

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). 

A purine analog that acts as an antimetabolite in the S-phase of cell division, 6-thioguanine is approved for treatment of leukemia, but has been used as an alternative treatment for psoriasis for decades when conventional therapies have failed. It appears to be less hepato-toxic than methotrexate and therefore may be more useful in treating hepatically-compromised patients with severe psoriasis. 

From Yeh and Phang (118). Erythrocytes were incubated for 60 minutes with the respective antimetabolites (25 /iM). The concentration of F5C was 0.5 mM. Nucleotides of the respective purine analogs were separated and quantitated by high-pressure liquid chromatography. 

An important group of antimetabolites are the aza analogs of pyrimidine and purine bases which are theoretically derived by a replacement of the methine group of a pyrimidine or purine nucleus with a nitrogen atom. This replacement represents a relatively minor alteration of the structure of these substances as it does not change the functional groups, practically preserves the molecular weight, and produces almost isosteric compounds. The replacement of the methine... 

The 8-aza analogs of purine bases were the first to be studied among all the aza analogs of nucleic acid bases (as early as 1945). Before that time the chemistry of these substances had not been treated in detail from any aspect. Thus the entire chemistry of the u-triazolo [4,5-d]pyrimidines was developed only in connection with the study of antimetabolites of nucleic acid components. Therefore all the papers involved are largely of preparative character and only rarely discuss. theoretical points. 

Antimetabolites. This class of drugs includes purine, pyrimidine, and folic acid analogs that have been successfully used to treat various carcinomas, autoimmune diseases, and dermatological disorders such as psoriasis. Because of their structural similarities to normal components of DNA and RNA synthesis, they are capable of competing with the normal macromolecules and alkylating biological nucleophiles. 

Nucleic-acid-related molecules (nucleotides, nucleosides, purines, pyrimidines) may also be used as dmgs themselves (and not only as dmg receptors). Once again, as discussed in chapters 7 and 9, this is most relevant in the areas of cancer and infectious disease, with purine/pyrimidine analogs being exploited as antimetabolites. 5-Fluorouracil is a well-described antineoplastic agent. Analogously, 5-fluorocytosine is used as an antifungal... 

Cladribine (2-chlorodeoxyadenosine 2-CDA) is a purine nucleoside analog that is resistant to inactivation by adenosine deaminase. The triphosphate form of this agent is incorporated into DNA, resulting in inhibition of DNA synthesis and early chain termination. Cladribine s antitumor activity is unusual for an antimetabolite in that it affects both actively dividing and resting cancer cells. Like fludarabine, cladribine possesses immunosuppressive effects that place patients at risk for serious opportunistic infections. ... 

Antiviral drugs are often antimetabolites that are structural analogs of purine or pyrimidine bases or j their nucleoside forms.. Many are pro-drugs to be activated by host or viral enzymes. The steps in viral j replication and the main sites of action of such antiviral drugs are illustrated in Figure V-3-1. j... 

Fludarabine is a purine antimetabolite. Fludarabine is a fluorinated nucleotide analog of the antiviral agent vidara-bine. Fludarabine s metabolite appears to act by inhibiting DNA polymerase alpha, ribonucleotide reductase, and DNA primase, thus inhibiting DNA synthesis. It is indicated in refactory or progressive chronic B-ceU lymphocytic leukemia. 

The pyrimidine antimetabolites encompass a diverse group of drugs that inhibit RNA and DNA function in a variety of ways. Some, such as the fluoropyrimidines and the purine base analogs (6-mercaptopurine and 6-thioguanine) inhibit the synthesis of essential precursors of DNA. Others, particularly the cytidine and adenosine nucleoside analogs, become incorporated into DNA and block its further elongation and its function. Other metabohc effects of these analogs may contribute to their cytotoxicity and even them ability to induce differentiation. 

Other antimetabolites used to treat cancer are either purine or p)UTmidme analogs. In some cases, the analogs are phosphoiylated to nucleotides, then... 

Figure 8.5 Antimetabolites such as thioguanine are incorporated into DNA where they inhibit repair or replication enzymes. Thioguanine is phosphorylated to thio-GTP which mimics GTP. The exact mechanism by which thio-GTP inhibits enzymes is unknown. The other purine and pyrimidine analogs work by similar mechanisms.

Anesthetics (e.g., halothane, urethan, nitrous oxide, pentobarbital) Antimetabolites (e.g., folic acid, purine and pyrimidine analogs)... 

Nucleoside antibiotics purine or pyrimidine nucleosides with antibiotic activity. They act as antimetabolites of natural substrates, and inhibit the growth of microoiganisms by blocking the metabolism of purines, pyrimidines and proteins Some N.a. (e.g. showdomycin) contain an analog base, others (e.g. gougerotin) contain an analog sugar, or both moieties may be modified (e.g. puromycin) (see Table). 

Tubereidin 6-amino-9-p-D-ribofuranosyl-7-deaza-purine, M, 266.25, m.p. 247-248 °C (d.), [a] j -67° (c = 1, 50% acetic acid), a purine antibiotic (see Nucleoside antibiotics) from Streptomyces tubercidicus, and one of the group of 7-deaza-adenine-nucleoside analogs. The N7 of adenine is replaced by a methylene group. T. is biosynthesized from adenosine (Fig.) the C-atoms of the pyrrole ring are derived from a ribose moiety, which is introduced from 5-phosphoribosyl 1-pyrophosphate. As an antimetabolite of adenosine, T. interferes with purine metabolism. T. can also be eonverted into nicotinamide-dea-za-adenine dinucleotide, which inhibits glycolysis. T. is particularly active against Mycobacterium tuberculosis and Candida albicans. 

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