Groutas W C, Huang H, Epp J B, Venkataraman R, McClenahan J J, Tagusagawa F
Department of Chemistry, Wichita State University, KS 67260.
Biochim Biophys Acta. 1994 Nov 29;1227(3):130-6. doi: 10.1016/0925-4439(94)90087-6.
A series of dihydrouracil derivatives has been synthesized and investigated for their in vitro inhibitory activity toward human leukocyte elastase (HLE) and cathepsin G (Cath G). Alkyl [sulfonyl(oxy)] uracils 1-2 were found to be efficient, time-dependent inhibitors of elastase (kobs/[I] M-1 s-1 values ranged between 480 and 8110). These compounds formed acyl enzymes that exhibited variable hydrolytic stability which appeared to be dependent on the nature of the R1 group (believed to be accommodated at the primary specificity site, S1). The acyl enzymes formed with cathepsin G deacylated rapidly, leading to a significant regain of enzymatic activity. In sharp contrast, the corresponding phosphorus compounds 3-4 were found to be potent, time-dependent irreversible inhibitors of HLE. Furthermore, the results of the structure-activity relationship studies suggest that the binding modes of compounds 1-2 and 3-4 may be different.
已经合成了一系列二氢尿嘧啶衍生物，并研究了它们对人白细胞弹性蛋白酶（HLE）和组织蛋白酶G（Cath G）的体外抑制活性。发现烷基[磺酰基（氧基）]尿嘧啶1-2是弹性蛋白酶的有效、时间依赖性抑制剂（kobs/[I] M-1 s-1值在480至8110之间）。这些化合物形成了具有可变水解稳定性的酰基酶，其似乎取决于R1基团的性质（据信位于主要特异性位点S1）。与组织蛋白酶G形成的酰基酶迅速脱酰基，导致酶活性显著恢复。形成鲜明对比的是，发现相应的磷化合物3-4是HLE的强效、时间依赖性不可逆抑制剂。此外，构效关系研究结果表明化合物1-2和3-4的结合模式可能不同。
