Bioorg Med Chem. 2013 Dec 15;21(24):7971-80. doi: 10.1016/j.bmc.2013.09.052.
We have synthesised a focused library of derivatives of natural products containing the pyranonaphthoquinone moiety including the first report of such a scaffold with an appended tetrazole functionality. Examples include kalafungin derivatives as well as analogues of nanaomycin and eleutherin. These compounds were assessed for cytotoxic activation by breast cancer cell lines engineered to express the prototypic human one- and two-electron quinone bioreductive enzymes, NADPH: cytochrome P450 oxidoreductase (POR) and
NAD(P)H: quinoneoxidoreductase 1 (NQO1; DT-diaphorase), respectively. Several compounds were observed to be cytotoxic at sub-micromolar level and a pattern of increased aerobic potency was observed in cells over expressing POR. A subset of analogues was assessed under anoxic conditions, where cytotoxicity was reduced, implicating redox cycling as a major mechanism of toxicity. The substrate specificity for reductive enzymes is relevant to the future design of bioreductive prodrugs to treat cancer.
我们合成了一系列含有吡喃萘醌部分的天然产物衍生物的重点库，包括首次报告了具有附加四唑功能的此类支架。其中包括卡拉fungin 衍生物以及 nanaomycin 和 eleutherin 的类似物。这些化合物通过表达原型人类单电子和双电子醌还原酶、NADPH：细胞色素 P450 氧化还原酶 (POR) 和 NAD(P)H：醌氧化还原酶 1 (NQO1; DT-二氢嘧啶脱氢酶)的工程化乳腺癌细胞系评估细胞毒性激活。观察到几种化合物在亚微摩尔水平具有细胞毒性，并且在过表达 POR 的细胞中观察到有氧效力增加的模式。一部分类似物在缺氧条件下进行评估，其中细胞毒性降低，暗示氧化还原循环是毒性的主要机制。还原酶的底物特异性与未来设计用于治疗癌症的还原酶前药有关。
