Synthesis of a diverse library of mechanism-based cysteine protease inhibitors
Synthesis of a diverse library of mechanism-based cysteine protease inhibitors
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DOI：
10.1021/cc034008r
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发表时间：
2003-11-01
影响因子：
--
通讯作者：
Ellman, JA
中科院分区：
文献类型：
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作者：
Wood, WJL;Huang, L;Ellman, JA
我们报告了基于机制的半胱氨酸蛋白酶巯基甲基酮抑制剂固相合成方法的改进（Lee, A.；Huang, L.；Ellman, J. A. J. Am. Chem. Soc. 1999, 121, 9907-9914）。具体来说，使用 Fmoc 保护的氯甲基酮，而不是 Alloc 保护的对应物。此外，我们进一步证明了可以在 R-1'、R-1 和 R-2 位点处掺入不同的极性官能团，这与我们之前的努力相反，在这些位置处主要掺入疏水基团。基于这些结果，我们制备了一个包含多种功能的潜在巯基甲基酮抑制剂的 2016 成员库。该文库针对与癌症有关的组织蛋白酶 B 进行了筛选，最终鉴定出单位数纳摩尔抑制剂。由于该文库包含多种功能，因此它应该是许多其他半胱氨酸蛋白酶的有效抑制剂的丰富来源。
We report improvements of our method for the solid-phase synthesis of mechanism-based mercaptomethyl ketone inhibitors of cysteine proteases (Lee, A.; Huang, L.; Ellman, J. A. J. Am. Chem. Soc. 1999, 121, 9907-9914). Specifically, Fmoc-protected chloromethyl ketones were used, rather than the Alloc-protected counterparts. In addition, we further demonstrated that diverse polar functionality can be incorporated at the R-1', R-1, and R-2 sites, in contrast to our previous efforts, where primarily hydrophobic groups were incorporated at these positions. On the basis of these results, a 2016-membered library of potential mercaptomethyl ketone inhibitors was prepared that incorporated diverse functionality. The library was screened against cathepsin B, which is implicated in cancer, resulting in the identification of single-digit nanomolar inhibitors. Because of the diverse functionality incorporated in this library, it should be a rich source of potent inhibitors against many other cysteine proteases.