Wu Zhenhua, Suppo Jean-Simon, Tumova Sarka, Strope Jonathan, Bravo Fernando, Moy Melody, Weinstein Ethan S, Peer Cody J, Figg William D, Chain William J, Echavarren Antonio M, Beech David J, Beutler John A
Department of Chemistry & Biochemistry, University of Delaware, 163 The Green, Newark, Delaware 19716, United States.
Institute of Chemical Research of Catalonia (ICIQ), 43007 Tarragona, Spain.
ACS Med Chem Lett. 2020 Aug 3;11(9):1711-1716. doi: 10.1021/acsmedchemlett.0c00186. eCollection 2020 Sep 10.
Modifications at the bridgehead position of englerin A were made to explore the effects of variation at this site on the molecule for biological activity, as judged by the NCI 60 screen, in which englerin A is highly potent and selective for renal cancer cells. Replacement of the isopropyl group by other, larger substituents yielded compounds which displayed excellent selectivity and potency comparable to the natural product. Selected compounds were also evaluated for their effect on the ion channel TRPC4 as well as for intravenous toxicity in mice, and these had lower potency in both assays compared to englerin A.
对恩格勒菌素A桥头位置进行修饰，以探索该位点的变化对分子生物活性的影响，这是根据美国国立癌症研究所60细胞系筛选判断的，在该筛选中恩格勒菌素A对肾癌细胞具有高效力和选择性。用其他更大的取代基取代异丙基得到的化合物显示出与天然产物相当的优异选择性和效力。还评估了所选化合物对离子通道TRPC4的作用以及对小鼠的静脉毒性，与恩格勒菌素A相比，这些化合物在这两种测定中的效力较低。
