Department of Medicinal Chemistry, Center for Natural Product Drug Discovery & Development (CNPD3), College of Pharmacy, University of Florida, Gainesville, Florida 32610, USA.
Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida, Orlando, Florida 32826, USA.
Org Biomol Chem. 2024 Oct 30;22(42):8423-8436. doi: 10.1039/d4ob00853g.
Natural product ring distortion strategies have enabled rapid access to unique libraries of stereochemically complex compounds to explore new chemical space and increase our understanding of biological processes related to human disease. Herein is described the development of a ring-cleavage strategy using the indole alkaloids yohimbine, apovincamine, vinburnine, and reserpine that were reacted with a diversity of chloroformates paired with various alcohol/thiol nucleophiles to enable the rapid synthesis of 47 novel small molecules. Ring cleavage reactions of yohimbine and reserpine produced two diastereomeric products in moderate to excellent yields, whereas apovincamine and vinburnine produced a single diastereomeric product in significantly lower yields. Free energy calculations indicated that diastereoselectivity regarding select ring cleavage reactions from yohimbine and apovincamine is dictated by the geometry and three-dimensional structure of reactive cationic intermediates. These compounds were screened for antiplasmodial activity due to the need for novel antimalarial agents. Reserpine derivative 41 was found to exhibit interesting antiplasmodial activities against parasites (EC = 0.50 μM against Dd2 cultures), while its diastereomer 40 was found to be three-fold less active (EC = 1.78 μM). Overall, these studies demonstrate that the ring distortion of available indole alkaloids can lead to unique compound collections with re-engineered biological activities for exploring and potentially treating human disease.
天然产物的环结构改变策略能够快速获得具有复杂立体化学结构的独特化合物库，从而开拓新的化学空间，增进我们对与人类疾病相关的生物学过程的了解。本文描述了一种利用吲哚生物碱育亨宾、阿朴长春碱、长春质碱和利血平进行环裂解的策略，这些生物碱与各种氯甲酸酯反应，再与不同的醇/硫醇亲核试剂配对，从而能够快速合成 47 种新型小分子。育亨宾和利血平的环裂解反应以中等至优异的收率生成了两种非对映异构体产物，而阿朴长春碱和长春质碱则以明显较低的收率生成了单一的非对映异构体产物。自由能计算表明，育亨宾和阿朴长春碱中环裂解反应的非对映选择性取决于反应性正碳离子中间体的几何形状和三维结构。由于需要新型抗疟药物，因此对这些化合物进行了抗疟原虫活性筛选。发现利血平衍生物 41 对寄生虫具有有趣的抗疟原虫活性（对 Dd2 培养物的 EC = 0.50 μM），而其非对映异构体 40 的活性则低三倍（EC = 1.78 μM）。总的来说，这些研究表明，现有吲哚生物碱的环变形可以产生具有重新设计的生物活性的独特化合物库，用于探索和潜在治疗人类疾病。
