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

核苷和相应的5'-三磷酸作为端粒酶的潜在选择性抑制剂的分子设计已被考虑；我们研究了一些糖修饰的核苷酸类似物对人类端粒酶的抑制作用。其中，3′-叠氮-2′、3′-二脱氧鸟苷（AZddG） 5′-三磷酸（AZddGTP）、碳环氧基鸟苷G三磷酸（c-oxtGTP）和部分鸟嘌呤核苷酸对HeLa细胞端粒酶的抑制活性较胸腺嘧啶（AZTTP）强。AZddGTP似乎可以作为链终止器。AZddGTP对脊椎动物DNA聚合酶α和δ无明显抑制作用，提示AZddGTP是一种选择性端粒酶抑制剂。接下来，我们分析了AZddG是否会改变培养的人hl60细胞的端粒长度和生长速度。结果表明，长期使用AZddG可引起可重复性的端粒缩短，细胞生长速率略有稳定下降。因此，AZddG是一种有趣的潜在端粒酶抑制剂。虽然在初步实验中，AZddG与araC联合使用时端粒缩短活性未增强，但端粒酶抑制剂作为常规抗肿瘤药物的增强剂的进一步研究正在进行中。

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.