Tao Peng, Fisher Jed F, Mobashery Shahriar, Schlegel H Bernhard
Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202, USA.
Org Lett. 2009 Jun 18;11(12):2559-62. doi: 10.1021/ol9008393.
SB-3CT is a 2-[(arylsulfonyl)methyl]thiirane that achieves potent inhibition, by a thiirane-opening mechanism, of the MMP2 and MMP9 zinc metalloproteases. The deprotonation mechanism for thiirane opening of SB-3CT and for the opening of its oxirane analogue, both relevant to the inhibition of MMP2, was investigated computationally using the acetate anion as the Brønsted base and in methanol and acetonitrile as solvents. The activation barriers for the reaction show a significant stereoelectronic effect. The lowest energy paths have the breaking C-H bond gauche to both sulfone oxygens and with this C-H bond anti to the breaking C-S bond of the thiirane. The calculated primary isotope effect agrees with experimental data.
SB - 3CT是一种2 - [(芳基磺酰基)甲基]硫杂环丙烷，它通过硫杂环丙烷开环机制对MMP2和MMP9锌金属蛋白酶实现强效抑制。以醋酸根阴离子作为布朗斯特碱，在甲醇和乙腈作为溶剂的条件下，通过计算研究了与MMP2抑制相关的SB - 3CT硫杂环丙烷开环及其环氧乙烷类似物开环的去质子化机制。反应的活化能垒显示出显著的立体电子效应。能量最低的路径是断裂的C - H键与两个砜氧原子呈邻位交叉，且该C - H键与硫杂环丙烷断裂的C - S键呈反式。计算得到的一级同位素效应与实验数据相符。
