Synthesis, kinase activity and molecular modeling of a resorcylic acid lactone incorporating an amide and a trans-enone in the macrocycle

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• 作者：Carmela Napolitano^a ; Viraja R. Palwai^b ; Leif A. Eriksson^a ; ^c ; Paul V. Murphy^a ; ^{paul.v.murphy@nuigalway.ie}
• 关键词：Resorcylic acid lactones ; Kinase inhibitors ; Olefination ; Lactamization
• 刊名：Tetrahedron
• 出版年：2012
• 期刊代码：107_00404020
• 类别：ch
• 出版时间：8 July, 2012
• 卷：68
• 期：27-28
• 页码：5533-5540
• 文件大小：718 K

摘要

Details for the synthesis of a resorcylic acid lactone (RAL) incorporating a trans-enone and an amide in the macrocyclic ring are provided herein. The sequence included the assembly of three fragments by esterification, olefination, and lactamization. The RAL with the lactam was less potent as an inhibitor of kinases than other RALs investigated. The biological results were rationalized by docking and molecular dynamics simulations of the lactam bound to human ERK2 and comparison with hypothemycin.