Pyrimidine analog antimetabolites

Some newly introduced pyrimidine analogs (e.g., azacitidine and decitabine) differ in their mechanism of action to such a degree from the other antimetabolites that they are subgrouped under the heading DNA de- or hypomethylating agents (see below). 

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... 

On the other hand, as previously indicated, the action of 5-fluorouracil (5-FU, or FUra) becomes that of an antimetabolite. Further described as a pyrimidine analog with no biological action in itself, it is converted in the body to other cytotoxic (ceU-toxic) agents that act as the antimetabolites that is, act against cellular metabolism. 

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)... 

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. 

Patients with partial deficiency of this enzyme are at risk of developing severe 5-FU-associated toxicity as DPD is responsible for detoxification of pyrimidine-based antimetabolite analogs, such as 5-FU and capecitabine. The onset of toxicity occurs, on average, twice as fast in patients with low DPD activity compared with patients with normal DPD activity (13-16). 

Antimetabolites are structural analogs of ordinary cellular metabolites such as folic acid, pyrimidines and pyrines, which after being introduced in the body, begin to imitate the structure of ordinary metabolites. They compete with metabolites to block important reactions leading to formation of DNA/RNA. 

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. 

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... 

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