Dawidowski Maciej, Turło Jadwiga
Department of Drug Technology and Pharmaceutical Biotechnology, Medical University of Warsaw, Banacha 1 Str., 02-097 Warsaw, Poland.
Med Chem Res. 2014;23(4):2007-2018. doi: 10.1007/s00044-013-0800-4. Epub 2013 Oct 1.
In this study, a series of diastereomerically pure monocyclic 2,6-diketopiperazine (2,6-DKP) derivatives were synthesized. The key synthetic step involved a multicomponent Ugi five-center, four-component reaction which was used to generate the convertible -butylamidoesters with both good yields and high diastereoselectivity toward the desired bioactive (,) absolute configuration. In subsequent steps, selective butyl cleavage by use of BF·CHCOOH and base-induced intramolecular cyclocondensation gave the final 2,6-DKP derivatives. The relative stereochemistry of the target molecules was confirmed by H NMR experiments. The compounds obtained were submitted to in vivo screening in animal models of epilepsy. Some of them displayed good activity in maximal electroshock seizure and 6 Hz tests.
在本研究中，合成了一系列非对映体纯的单环2,6 - 二酮哌嗪（2,6 - DKP）衍生物。关键的合成步骤涉及多组分Ugi五中心、四组分反应，该反应用于生成具有良好产率且对所需生物活性（，）绝对构型具有高非对映选择性的可转化丁基酰胺酯。在后续步骤中，通过使用BF·CHCOOH进行选择性丁基裂解以及碱诱导的分子内环化缩合反应得到最终的2,6 - DKP衍生物。通过¹H NMR实验确定了目标分子的相对立体化学。所得到的化合物在癫痫动物模型中进行了体内筛选。其中一些化合物在最大电休克惊厥和6 Hz试验中表现出良好的活性。
