5′-Deoxy-5′-methylthioadenosine phosphorylase—IV: Biological activity of 2-fluoroadenine-substituted 5′-deoxy-5′ -methylthioadenosine analogs

doi:10.1016/0006-2952(87)90484-9

Biochemical Pharmacology

Volume 36, Issue 12, 15 June 1987, Pages 1881-1893

https://doi.org/10.1016/0006-2952(87)90484-9 Get rights and content

Abstract

5′-Deoxy-5′-methylthioadenosine phosphorylase (MTAPase) phosphorolyzes 5'-deoxy-5'-methylthioadenosine (MTA) generated during polyamine biosynthesis to adenine and 5-methyl-thioribose-1-phosphate. Two doubly-substituted, 2-fluoroadenine-containing analogs of MTA, 5'-deoxy-2-fluoroadenosine (5'-dFAdo) and 5′-deoxy-5′-iodo-2-fluoroadenosine (5′-IFAdo), were synthesized and studied as substrates of MTAPase: their reaction with this enzyme resulted in the liberation of the cytotoxic base, 2-fluoroadenine, as well as potentially cytotoxic analogs of 5-methylribose-1-phosphate. The activities of these MTA analogs were compared to that of the singly-substituted analog, 5'-deoxy-5'-methylthio-2-fluoroadenosine (5′-MTFAdo). The cytotoxic action of these MTA analogs depended primarily on their conversion to 2-fluoroadenine-containing nucleotides, as a cell line that contains both MTAPase and adenine phosphoribosyltransferase (APRT) activity (HL-60 human promyelocytic leukemia) readily converted these MTA analogs to 2-fluoroadenine-containing nucleotides (especially 2-fluoroadenosine triphosphate) and was highly sensitive to the growth-inhibitory effects of all three compounds (ic₅₀ values in the 10⁻⁸ M range), whereas cell lines lacking MTAPase (CCRF-CEM human T-cell leukemia) or APRT (HL-60/aprt₁cells) did not form analog nucleotides and were relatively insensitive to these compounds (ic₅₀ values in the 10⁻⁵ M range). The doubly-substituted analogs were not more growth inhibitory than 5'-MTFAdo in wild type HL-60 cells as the potent effects of 2-fluoroadenine may mask the activity of the 5-methylthioribose-1-phosphate analogs generated in the reaction of these compounds with MTAPase. 5'-dFAdo and 5'-IFAdo also were irreversible inhibitors of idS-adenosylhomocysteine hydrolase, which may explain in part the weak but observable growth inhibitory action of these compounds against MTAPase-deficient cell lines.

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^☆: This investigation was supported by PHS Grants CA 07340, CA 20892, CA 31943, CA24975, and CA 34200 awarded by the National Cancer Institute, DHHS.

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5′-Deoxy-5′-methylthioadenosine phosphorylase—IV: Biological activity of 2-fluoroadenine-substituted 5′-deoxy-5′ -methylthioadenosine analogs☆

Abstract

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