Molecular design of nucleoside analogs for selective telomerase inhibition based on mechanisms of action.

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Molecular designing of nucleosides and corresponding 5'-triphosphates as potential selective inhibitor for telomerase has been considered ;We investigated the inhibitory effects of some sugar-modified nucleotide analogs on human telomerase. Among them, 3'-azido-2',3'-dideoxyguanosin (AZddG) 5'-triphosphate (AZddGTP), carbocyclic oxetanosin G triphosphate (c-oxtGTP) and some guanine-nucleotides showed more potent inhibitory activity against HeLa cell telomerase than that of thymine counterpart (AZTTP). AZddGTP seemed to be able to act as a chain terminator. AZddGTP did not show significant inhibitory activity against vertebrate DNA polymerase α and δ, suggesting that AZddGTP is a selective inhibitor telomerase. Next, we analyzed whether AZddG could alter telomere length and growth rates of human HL6O cells in culture. As the results, long-term treatment of AZddG caused reproducible telomere shortening, and a slight but steady decrease of cell growth rate. Thus, AZddG is an interesting potential telomerase inhibitor. Although telomere-shortening activity of AZddG was not potentiated when combined with arabinofuranosylcytosine (araC) in a preliminary experiment, further study of telomerase inhibitor as potentiators of conventional antitumor agents is now under way.