Nucleic acid antimetabolites

An antimetabolite is a compound that is (1) similar to a compound required for normal cellular function and (2) interferes with cellular processes. Based on this definition, many drugs technically qualify as antimetabolites. The term antimetabolite is, however, most closely associated with drugs that interfere with the synthesis or action of nucleic acids. Antimetabolites are commonly discussed in the treatment of cancer, viruses, and bacterial infections. 

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The action of /J-exotoxin induces a group of phenomena completely different from that of endotoxin, proceeded according to a different mechanism. The effect is manifested by teratological phenomena, inhibited pupation, mortality after moulting, and malformation. Therefore, the assumption of several authors seemed to be justified that /S-exotoxin affects the activity of formation of hormones regulating the metamorphosis of insects. On the other hand, the nucleotide structure indicates that /3-exotoxin exerts its action as a nucleic acid antimetabolite (Benz, 1966 Grebelsky and Kandybin, 1974). 

There appears to be a selective concentration of purines into CSF in favour of Hx and X, with AR levels being well below those of plasma. The relevance of such variations in regional purine levels to neurological and vascular function, and to the selective action of nucleic acid antimetabolites, remains to be determined. 

Uracil is used more effectively, in nucleic acid synthesis within a rat hepatoma than in normal liver. This observation appears to have stimulated the synthesis of 5-fluorouracil (1027) as an antimetabolite mainly because the introduction of a fluorine atom involves a minimal increase in size. In the event, 5-fluorouracil did prove to have antineoplastic activity and it is now a valuable drug for treatment of tumors of the breast, colon or rectum, and to a lesser extent, gastric, hepatic, pancreatic, uterine, ovarian and bladder carcinomas. As with other drugs which interfere with DNA synthesis, the therapeutic index is quite low and great care is required during treatment (69MI21301). 

The possibility of interfering with the structure or formation of nucleic acids with the aid of such antimetabolites obviously has great practical significance. An interference with growth of neoplastic tissue and influence on the genetic properties of an organism should be mentioned in the first place. 

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. 

An antimetabolite interferes with the normal cellular metabolites. For instance, it can act as an inhibitor of one or more enzymes whose substrates are metabolites. Others are incorporated into macromolecules instead of the metabolites. Development of antimetabolites exhibiting anti-cancer activity met with the greatest success for analogues of metabolites involved in the biosynthesis of nucleic acids and of cofactors containing nitrogenous bases. Compounds such as 5-fluorouracyl and methotrexate are remarkably effective against human cancers, even though they feature host toxicity. 

Incorporation of false building blocks (3). Unnatural nucleobases (6-mercaptopurine 5-fluorouracil) or nucleosides with incorrect sugars (cytara-bine) act as antimetabolites. They inhibit DNA/RNA synthesis or lead to synthesis of missense nucleic acids. 

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... 

Antimetabolites are analogues of normal DNA components or of coenzymes involved in nucleic acid synthesis. They get incorporated or competitively inhibit utilization of normal substrate to form dysfunctional nucleic acid molecules. 

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. 

Mechanism of Action. Flucytosine is incorporated into susceptible fungi, where it undergoes enzymatic conversion to fluorouracil,7 which acts as an antimetabolite during RNA synthesis in the fungus. Fluorouracil is incorporated into RNA chains but acts as a false nucleic acid. This event ultimately impairs protein synthesis, thus disrupting the normal function of the fungus. 

FIGURE 36-3 Sites of anticancer antimetabolite action. Various drugs interfere with DNA/RNA production by inhibiting nucleic acid biosynthesis at specific sites indicated by the dashed lines. 

The biochemical pathways that have thus far proved to be most vulnerable to antimetabolites have been those relating to nucleotide and nucleic acid synthesis. In a number of instances, when an enzyme is known to have a major effect on pathways leading to cell replication, inhibitors of the... 

Antimetabolites of nucleic acids as antitumor agents 91YGK989. Artemisinine (3,6,9-trimethyl-9,10h-epidioxyperhydropyrano[4,3,2-y/c] benzoxepin-2-one), a new type of antimalarial drug 92CSR85. 

Langen, P. Antimetabolites of Nucleic Acid Metabolism, Gordon and Breach New York, 1975. 

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