Pyrimidine nucleoside antimetabolite

The drug is a pyrimidine nucleoside antimetabolite which is cytotoxic to a plethora of cell-types. Precisely the induction of the enzyme nucleotidase into DNA inhibits polymerization via termination of strand synthesis. It is S-phase specific. 

In summary, capecitabine (1), an A -carbamate pyrimidine nucleoside prodrug of cytotoxic antimetabolite 5-fluorouracil, is an FDA-approved anticancer drug that can be administered orally. This compound uses a multilayer of prodrug strategies that not only avoids side effects arising from exposure of toxic metabolites to healthy tissue but is converted to 5-fluorouracil only by enzymes preferentially expressed in many cancer cell types, thus resulting in selective delivery of the drug to tumors. Capecitabine is marketed under the trade name of Xeloda for use in the treatment of metastatic colorectal and breast cancers and metastatic breast cancer that is resistant to paclitaxel or anthracycline therapies. 

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). 

Giller SA, Zhuk RA, Likak MY (1967) Analogs of pyrimidine nucleosides I. N,(a-tetrahydrofuryl) derivatives of natural pyrimidine bases and their antimetabolites. Dokl Chem 176 798-801... 

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... 

A search for antimetabolites, i.e. analogues of essential metabolites that might displace the latter in vital processes, was proposed as a rational approach to the discovery of antibacterial agents, but it has had little success other than the achievements in the folic acid field (Section 1.06.6). Substances that resemble the components of nucleic acids have, however, had considerable success in the chemotherapy of cancer and of some virus diseases and in the suppression of the immune response. They may act by becoming incorporated in false nucleic acids or by blocking the synthesis of nucleic acids, nucleotides, nucleosides or of the pyrimidine and purine bases cytosine (88), thymine (89 R = Me), adenine (90) and guanine (91 X = CH). The simplest antimetabolites are analogues of these bases. 

Many antiviral drugs are antimetabolites that resemble the structure of naturally occurring purine and pyrimidine bases or their nucleoside forms. Antimetabolites are usually pro-drugs requiring metabolic activation by host-cell or viral enzymes—commonly, such bioactivation involves phosphorylation reactions catalyzed by kinases. 

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... 

Another approach is to utilize the antimetabolite concept. The synthetic strategies include two types of chemical modifications of nucleosides. One is to alter the base. In the case of pyrimidines (Fig. 7-16) this usually involves replacement of the 5-CH3 group of 2-deoxythymidine with a halogen or CF3 function. The resulting 2-deoxythymidine analog... 

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. 

---