Sulfoxide-containing aromatic nitrogen mustards as hypoxia-directed bioreductive cytotoxins
Sulfoxide-containing aromatic nitrogen mustards as hypoxia-directed bioreductive cytotoxins
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DOI：
10.1021/jm9904957
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发表时间：
2000-11-02
影响因子：
7.3
通讯作者：
Kwon, CH
中科院分区：
文献类型：
--
作者：
Sun, ZY;Botros, E;Kwon, CH
合成了一系列含二芳基和烷基芳基亚砜的氮芥，并评估了其对 V-79 细胞的体外缺氧选择性细胞毒性以及其与大鼠 S-9 组分的代谢特征。一般来说，二芳基亚砜（4、5 和 7-9）比烷基芳基亚砜（类似于 3 倍）表现出更高的缺氧选择性（11-27 倍）（1 和 3）。另一方面，稠合二苯亚砜（10 和 11）表现出非常低的缺氧选择性（1.3-3 倍）。化合物10在需氧和厌氧条件下均具有高细胞毒性，而11在两种条件下均表现出低细胞毒性。在厌氧条件下，大鼠 S-9 级分对 8 的生物还原被甲萘醌抑制，并被苯甲醛、乙醛或 2-羟基嘧啶增强，表明醛氧化酶参与了亚砜的还原。对选定模型亚砜的生物还原代谢研究表明，二芳基亚砜是比烷芳基亚砜更好的醛氧化酶底物。
A series of diaryl and alkylaryl sulfoxide-containing nitrogen mustards were synthesized and evaluated for their hypoxia-selective cytotoxicity against V-79 cells in vitro as well as for their metabolism profiles with the rat S-9 fractions. In general, the diaryl sulfoxides (4, 5, and 7-9) showed much greater hypoxia selectivity (11-27-fold) than the alkylaryl sulfoxides (similar to3-fold) (1 and 3). The fused diphenyl sulfoxides (10 and 11), on the other hand, showed very low hypoxia selectivity (1.3-3-fold). Compound 10 was highly cytotoxic under both aerobic and anaerobic conditions, while 11 showed low cytotoxicity under both conditions. The bioreduction of 8 by the rat S-9 fraction under anaerobic conditions was inhibited by menadione and enhanced by benzaldehyde, acetaldehyde, or 2-hydroxypyrimidine suggesting the involvement of aldehyde oxidase in the reduction of the sulfoxides. Bioreductive metabolism studies of selected model sulfoxides suggested that diaryl sulfoxides are better substrates for aldehyde oxidase than alkylaryl sulfoxides.