An octahydroisochromene scaffold has been introduced into a known SARS 3CL protease inhibitor as a novel hydrophobic core to interact with the S2 pocket of the protease. An alkyl or aryl substituent was also introduced at the 1-position of the octahydroisochromene scaffold and expected to introduce additional interactions with the protease. Sharpless-Katsuki asymmetric epoxidation and Sharpless asymmetric dihydroxylation were employed to construct the octahydroisochromene scaffold. The introductions of the P1 site His-al and the substituent at 1-position was achieved using successive reductive amination reactions. Our initial evaluations of the diastereo-isomeric mixtures (16a-d) revealed that the octahydroisochromene moiety functions as a core hydrophobic scaffold for the S2 pocket of the protease and the substituent at the 1-position may form additional interactions with the protease. The inhibitory activities of the diastereoisomerically-pure inhibitors (3a-d) strongly suggest that a specific stereo-isomer of the octahydroisochromene scaffold, (1S, 3S) 3b, directs the P1 site imidazole, the warhead aldehyde, and substituent at the 1-position of the fused ring to their appropriate pockets in the protease.

中文翻译：

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用作新的SARS 3CL蛋白酶抑制剂的八氢异戊二烯支架的评估。

八氢异色烯支架已被引入到已知的SARS 3CL蛋白酶抑制剂中，作为一种新型的疏水核心，可与蛋白酶的S2口袋相互作用。烷基或芳基取代基也被引入八氢异戊二烯支架的1-位，并有望引入与蛋白酶的另外的相互作用。使用Sharpless-Katsuki不对称环氧化和Sharpless不对称二羟基化反应来构建八氢异戊二烯支架。使用连续的还原性胺化反应实现了P1位点His-al和1-位取代基的引入。我们对非对映异构混合物（16a-d）的初步评估表明，八氢异亚戊二烯部分起着蛋白酶S2口袋的核心疏水支架的作用，并且在1位上的取代基可能与蛋白酶形成额外的相互作用。非对映异构纯抑制剂（3a-d）的抑制活性强烈表明，八氢异戊二烯骨架（1S，3S）3b的特定立体异构体将P1位的咪唑，弹头醛和取代基指向1-稠环在蛋白酶中适当位置的位置。