Schwartz M A, Venkataraman S, Ghaffari M A, Libby A, Mookhtiar K A, Mallya S K, Birkedal-Hansen H, Van Wart H E
Department of Chemistry, Florida State University, Tallahassee 32306.
Biochem Biophys Res Commun. 1991 Apr 15;176(1):173-9. doi: 10.1016/0006-291x(91)90905-m.
A series of sulfhydryl and novel sulfur-based substrate-analog inhibitors has been synthesized and tested against human fibroblast and neutrophil collagenases. Absolute stereospecific synthesis of several sulfhydryl inhibitors establishes that it is the diastereomers with the R-configuration of the P'1 residues, which correspond to the unnatural D-amino acid analogs, that are the most potent inhibitors. The corresponding disulfide, sulfonate, sulfinate, sulfide, sulfoxide and sulfone analogs exhibit widely variable levels of potency, but all less than the sulfhydryl compounds. No correlation between inhibitor potency and any single structural feature of these new compounds is apparent. However, differences in potency can be ascribed to the different affinities of these functional groups for zinc coordination and hydrogen bonding to nearby active site residues.
已合成了一系列巯基和新型硫基底物类似物抑制剂，并针对人成纤维细胞和中性粒细胞胶原酶进行了测试。几种巯基抑制剂的绝对立体定向合成表明，最有效的抑制剂是那些P'1残基具有R构型的非对映异构体，这些残基对应于非天然的D-氨基酸类似物。相应的二硫化物、磺酸盐、亚磺酸盐、硫化物、亚砜和砜类似物表现出广泛不同的效价水平，但都低于巯基化合物。这些新化合物的抑制剂效价与任何单一结构特征之间均无明显相关性。然而，效价的差异可归因于这些官能团与锌配位以及与附近活性位点残基形成氢键的不同亲和力。
