对氨基二苯醚类化合物与细胞色素P450相互作用的定量与活性关系

对氨基二苯醚类化合物是结构色素Ｐ４５０（Ｐ４５０）的一种准不可逆抑制剂。本文测定了１７种这类化合物生成Ｐ４５０代谢中间体络合物的活性和抑制Ｐ４５０催化氧化氨基比林脱甲基的活性。用逐步多元回归分析法导出了这两种活性与Ｈａｎｓｃｈ理化参数或分子轨道指数之间的定量结构与活性关系（ＱＳＡＲ）。结果表明：这两种活性都与取代基的脂溶性参数之（Σπ）和间位的立体性参数Ｅｓ（３′）等Ｈａｎｓｃｈ理化参数或最低未占据分子轨道级（ＥＬＵＭＯ）和原子净电荷的绝对值之和（ΣＱ）等分子轨道指数相关；生成Ｐ４５０代谢中间体络合物的活性还与取代基的电性参数之和（Σσ）和邻位和立体性参数（Ｅｓ（２′）相关。两种活性之间存在很好的相关性。

Quantitative Structure-Activity Relationship for p-Amino-Diphenyl Ether Compounds to Interact with Cytochrome p450

p-Amino-diphenyl ether compounds are quasi-irreversible inhibitors of cytochrome p450(p450). Seventeen kinds of p-amino-diphenyl ether compounds were tested for their activities to form p450 metabolic intermediate complex and to inhibit demethylation of aminopyrine catalyzed by p450. Stepwise multiple regression analysis was utilized to generate quantitative structure-activity relationships between the above two kinds of activity and Hansch' s physico-chemical parameters or molecular orbital indexes. The results showed that both activities were correlated with the sum of the hydrophobic parameters of substituents(Σπ) and the steric parameter of meta-substituent(Es(3')) ,or with the energy level of the lowest unoccupied orbitals(ELUMO) and the sum of the absolute values of net atomic charge(ΣQ).The activity to form p450 metabolic intermediate complex was also correlated with the sum of the electronic parameters of substituents(Σσ) and the steric parameter of orthosubstituent(Es (2')). Good correlations were observed between the two kinds of activities.