Erdeljac Nathalie, Bussmann Kathrin, Schöler Andrea, Hansen Finn K, Gilmour Ryan
Institute for Organic Chemistry, WWU Münster, Correnstraße 40, 48149 Münster, Germany.
Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Medical Faculty, Leipzig University, Brüderstraße 34, 04103 Leipzig, Germany.
ACS Med Chem Lett. 2019 Jul 19;10(9):1336-1340. doi: 10.1021/acsmedchemlett.9b00287. eCollection 2019 Sep 12.
A chiral, hybrid bioisostere of the CF and Et groups (BITE) was installed in a series of vorinostat (Zolinza) analogues, and their histone deacetylase (HDAC) inhibitory behavior was studied relative to that of their nonfluorinated counterparts. Several of these compounds containing the 1,2-difluoroethylene unit showed potency greater than that of the clinically approved drug itself against HDAC1. This trend was found to be general with the BITE-modified HDAC inhibitors performing significantly better than the ethyl derivatives. Installed by the direct, catalytic difluorination of terminal alkenes using an I(I)/I(III) manifold, this underexplored chiral bioisostere shows potential in drug discovery.
在一系列伏立诺他（Zolinza）类似物中引入了CF和Et基团的手性杂合生物电子等排体（BITE），并相对于其非氟化类似物研究了它们的组蛋白脱乙酰酶（HDAC）抑制行为。这些含有1,2 - 二氟乙烯单元的化合物中有几种对HDAC1的抑制效力大于临床批准药物本身。发现这种趋势具有普遍性，即BITE修饰的HDAC抑制剂的表现明显优于乙基衍生物。通过使用I(I)/I(III)体系对末端烯烃进行直接催化二氟化引入该基团，这种尚未充分探索的手性生物电子等排体在药物发现中显示出潜力。
