New PDF release: Analogues of Nucleic Acid Components: Mechanisms of Action

By P. Roy-Burman Ph. D. (auth.), P. Roy-Burman Ph. D. (eds.)

The purpose for the layout of structural analogues of a typical metabolite is that such compounds could intervene within the usage or functionality of the metabolite. A compound that is powerful during this admire might be known as an antimetabolite. to achieve success in chemotherapy of bacterial, viral, or tumor development, an antimetabolite should still adversely have an effect on a few important metabolic reactions within the parasite or parasitic tissue with out heavily endangering the host tissue. If a metabolic means of the offending development isn't the same as that of the host, it's most likely that the metabolism or job of a compound, structurally on the topic of a metabolite considering that strategy, can be assorted in those cells. Such changes are necessary for devising powerful medicinal drugs with selective activities. Sulfanilamide, a structural analogue of para­ aminobenzoic acid, interferes with the usage of this metabolite within the synthesis of folic acid, a necessary issue for progress. micro organism synthesize their very own folic acid and are incapable of using exogenously to be had folic acid. even though, the location is strictly contrary within the animal host. that's, animal tissues can't synthesize folic acid and are totally based upon exogenous assets. those changes in metabolism make attainable using sulfanilamide as a selective inhibitor of development. different antibacterial or antiparasitic medicines, resembling penicillin (BURCHALL, FERONE and HITCHINGS, 1965) and inhibitors of dihydrofolate reductase (HITCHINGS and BURCHALL, 1965; HITCHINGS, 1964; BURCHALL and HITCHINGS, 1965) have analogous fascinating selective toxicity effects.

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Extra info for Analogues of Nucleic Acid Components: Mechanisms of Action

Example text

This MeMPR-induced stimulation of MP anabolism is apparently related to inhibition of phosphoribosylpyrophosphate amidotransferase by methylthio-IMP accompanied by accummulation of increased concentration of PRPP. Since methylthio-IMP is an analogue of AMP, it may interfere with other reactions involving formation or participation of AMP. Such effects as well as any possible incorporation of the analogue into nucleic acids remain to be investigated. Resistance: MeMPR-resistant sublines have been isolated from Ehrlich ascites carcinoma (CALDWELL, HENDERSON and PATERSON, 1967; Ho and FREI, 1968), and from H.

Thus, interference by xyl-ATP with the formation of PRPP is likely to cause inhibition of cellular growth and multiplication. In addition to the above major inhibitory site, there are other reactions which are known to be affected by xyl-A. It is as effective as adenosine as a feedback inhibitor of purine synthesis in mice by preventing 5' -phosphoribosyl-N-formylglycineamide formation. The feedback inhibition is probably not significant in vivo since adenosine cannot produce the increased survival times observed in mice treated with xyl-A.

However, it should be noted that inosine or guanosine kinases ha ve not been reported to occur in mammalian cells. All facets of the metabolism and inhibitory action of MeMPR are not known; however, it can be said at present that methylthio-IMP is the active form of the inhibitor (Fig. >- Methylthio-IMP _ _ Thio-IMP-E<------MP Fig. 12. Phosphorylation of MeMPR to the active metabolite and the known site of inhibition as indicated by ~ in mouse tissues, Ehrlich ascites carcinoma cells or in cell-free extracts of tumors (CALDWELL, HENDERSON and PATERSON, 1966).

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