Department of Chemistry, Carl R. Woese Institute for Genomic Biology, Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
Angew Chem Int Ed Engl. 2021 Jul 12;60(29):16119-16128. doi: 10.1002/anie.202104228. Epub 2021 Jun 10.
Structurally complex natural products have been a fruitful source for the discovery and development of new drugs. In an effort to construct a compound collection populated by architecturally complex members with unique scaffolds, we have used the natural product limonin as a starting point. Limonin is an abundant triterpenoid natural product and, through alteration of its heptacyclic core ring system using short synthetic sequences, a collection of 98 compounds was created, including multiple members with novel ring systems. The reactions leveraged in the construction of these compounds include novel ring cleavage, rearrangements, and cyclizations, and this work is highlighted by the discovery of a novel B-ring cleavage reaction, a unique B/C-ring rearrangement, an atypical D-ring cyclization, among others. Computational analysis shows that 52 different scaffolds/ring systems were produced during the course of this work, of which 36 are unprecedented. Phenotypic screening and structure-activity relationships identified compounds with activity against a panel of cancer cell lines.
结构复杂的天然产物一直是发现和开发新药的丰富来源。为了构建一个由具有独特骨架的结构复杂成员组成的化合物库，我们以天然产物柠檬苦素为起点。柠檬苦素是一种丰富的三萜类天然产物，通过用短的合成序列改变其七环核心环系统，创建了一个包含 98 种化合物的集合，其中包括多个具有新颖环系统的成员。构建这些化合物所利用的反应包括新颖的环裂解、重排和环化，这项工作的突出特点是发现了一种新的 B 环裂解反应、独特的 B/C 环重排、非典型的 D 环环化等。计算分析表明，在这项工作过程中产生了 52 种不同的支架/环系统，其中 36 种是前所未有的。表型筛选和构效关系鉴定出了对一系列癌细胞系具有活性的化合物。
