靶向Mcl-1和Bcl-2的天然鱼藤叶酸促凋亡羧酰胺类似物。
Pro-apoptotic carboxamide analogues of natural fislatifolic acid targeting Mcl-1 and Bcl-2.
作者信息
Gapil Tiamas Shelly, Daressy Florian, Abou Samra Alma, Bignon Jérome, Steinmetz Vincent, Litaudon Marc, Fourneau Christophe, Hoong Leong Kok, Ariffin Azhar, Awang Khalijah, Desrat Sandy, Roussi Fanny
机构信息
Université Paris-Saclay, CNRS, Institut de Chimie des Substances Naturelles, UPR 2301, 91198 Gif-sur-Yvette, France; Department of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia.
Université Paris-Saclay, CNRS, Institut de Chimie des Substances Naturelles, UPR 2301, 91198 Gif-sur-Yvette, France; Université Paris-Saclay, UMR CNRS 8126, Institut Gustave Roussy, 114 rue Edouard-Vaillant, 94805 Villejuif Cedex, France.
出版信息
Bioorg Med Chem Lett. 2020 Apr 1;30(7):127003. doi: 10.1016/j.bmcl.2020.127003. Epub 2020 Feb 3.
A library of 26 novel carboxamides deriving from natural fislatifolic acid has been prepared. The synthetic strategy involved a bio-inspired Diels-Alder cycloaddition, followed by functionalisations of the carbonyl moiety. All the compounds were evaluated on Bcl-xL, Mcl-1 and Bcl-2 proteins. In this series of cyclohexenyl chalcone analogues, six compounds behaved as dual Bcl-xL/Mcl-1 inhibitors in micromolar range and one exhibited sub-micromolar affinities toward Mcl-1 and Bcl-2. The most potent compounds evaluated on A549 and MCF7 cancer cell lines showed moderate cytotoxicities.
已经制备了一个由26种源自天然鱼叶酸的新型羧酰胺组成的文库。合成策略包括仿生狄尔斯-阿尔德环加成反应，随后是羰基部分的官能化。所有化合物都针对Bcl-xL、Mcl-1和Bcl-2蛋白进行了评估。在这一系列环己烯基查耳酮类似物中，六种化合物在微摩尔范围内表现为双Bcl-xL/Mcl-1抑制剂，一种对Mcl-1和Bcl-2表现出亚微摩尔亲和力。在A549和MCF7癌细胞系上评估的最有效化合物显示出中等细胞毒性。
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