Metabolism of (4-phenoxyphenylsulfonyl)methylthiirane, a selective gelatinase inhibitor
Metabolism of (4-phenoxyphenylsulfonyl)methylthiirane, a selective gelatinase inhibitor
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DOI：
10.1111/j.1747-0285.2008.00632.x
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发表时间：
2008-03-01
影响因子：
3
通讯作者：
Chang, Mayland
中科院分区：
文献类型：
--
作者：
Celenza, Giuseppe;Villegas-Estrada, Adriel;Chang, Mayland
(4-苯氧基苯磺酰基)甲基硫杂环己烷(化合物1)是一种高度选择性和有效的明胶酶抑制剂，在癌症和中风的动物模型中显示出相当大的前景。对化合物1在小鼠体内的代谢进行了研究。在血浆和尿液中鉴定出8种代谢物。1的主要代谢途径是末端苯环对位上的羟基化、α-亚甲基上的羟基化生成亚磺酸和硫杂环半胱氨酸共轭。半胱氨酸加合物是通过将谷胱甘肽加到硫杂环上而产生的。该分子在小鼠体内被广泛代谢和排泄，但在体内表现出活性。
(4-Phenoxyphenylsulfonyl)methylthiirane (compound 1) is a highly selective and potent inhibitor of gelatinases that shows considerable promise in animal models for cancer and stroke. The metabolism of compound 1 was investigated in mice, following intraperitoneal administration at 100 mg/kg. Eight metabolites were identified in plasma and urine. The primary routes of metabolism of 1 were hydroxylation at the para-position of the terminal phenyl ring, hydroxylation at the alpha-methylene to the sulfonyl, which lead to the generation of a sulfinic acid, and cysteine conjugation of the thiirane ring. The cysteine adducts arose through addition of glutathione to the thiirane ring. The molecule is extensively metabolized and excreted in mice, yet it exhibits activity in vivo.