Grove K L, Guo X, Liu S H, Gao Z, Chu C K, Cheng Y C
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Cancer Res. 1995 Jul 15;55(14):3008-11.
Naturally occurring nucleosides and all anticancer nucleoside analogue drugs are in the beta-D configuration. L-(-)-dioxolane-cytidine [(-)-OddC] is the first L-nucleoside analogue ever shown to have anticancer activity. This compound was converted within cells to its mono-, di-, and triphosphate metabolites and was incorporated into DNA. As with cytosine arabinoside, conversion to the monophosphate was catalyzed by cellular deoxycytidine kinase, which was essential for cytotoxicity. However, unlike cytosine arabinoside, (-)-OddC was not susceptible to degradation by deoxycytidine deaminase. Because (-)-OddC inhibited the growth of hepatocellular and prostate tumors that are generally difficult to treat, it is a promising candidate for additional testing. Our results indicate that there is a great deal of variability in the chiral specificities of cellular enzymes and demonstrate how these differences can be exploited in the design of better anti-viral and anticancer drugs.
天然存在的核苷以及所有抗癌核苷类似物药物均为β-D构型。L-(-)-二氧戊环胞苷[(-)-OddC]是首个被证明具有抗癌活性的L-核苷类似物。该化合物在细胞内转化为其一磷酸、二磷酸和三磷酸代谢产物，并被掺入DNA中。与阿糖胞苷一样，转化为一磷酸是由细胞脱氧胞苷激酶催化的，这对细胞毒性至关重要。然而，与阿糖胞苷不同的是，(-)-OddC不易被脱氧胞苷脱氨酶降解。由于(-)-OddC抑制了通常难以治疗的肝细胞和前列腺肿瘤的生长，它是进一步测试的有希望的候选药物。我们的结果表明，细胞酶的手性特异性存在很大差异，并展示了如何在设计更好的抗病毒和抗癌药物时利用这些差异。
