Peptido Sulfonyl Fluorides as New Powerful Proteasome Inhibitors

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• 作者：Arwin J. Brouwer ; Anika Jonker ; Paul Werkhoven ; Ethan Kuo ; Nan Li ; Nerea Gallastegui ; Johan Kemmink ; Bogdan I. Florea ; Michael Groll ; Herman S. Overkleeft ; Rob M. J. Liskamp
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：December 27, 2012
• 年：2012
• 卷：55
• 期：24
• 页码：10995-11003
• 全文大小：516K
• 年卷期：v.55,no.24(December 27, 2012)
• ISSN：1520-4804

文摘

A new class of potent proteasome inhibitors is described, of which the members contain an amino acid inspired sulfonyl fluoride as the electrophilic trap. In total, 24 peptido sulfonyl fluoride inhibitors have been designed and synthesized, which were inspired by the backbone sequences of the proteasome inhibitors bortezomib, epoxomicin, and Cbz-Leu₃-aldehyde. Nine of them were very potent proteasome inhibitors, the best of which had an IC₅₀ of 7 nM. A number of the peptido sulfonyl fluoride inhibitors were found to be highly selective for the 尾5 proteasome subunit.