The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300071, China.
Angew Chem Int Ed Engl. 2019 Jul 29;58(31):10587-10590. doi: 10.1002/anie.201904096. Epub 2019 Jun 24.
A concise, scalable, six-step (longest linear sequence) synthetic route to ovatodiolide scaffolds was developed for the first time. This protecting-group-free route features tandem ring-opening metathesis/ring-closing metathesis reactions to install the macrocycle-fused butenolide ring and a tandem allylboration/lactonization to build the α-methylene-γ-lactone. Our syntheses have enabled the determination of the hitherto unknown stereochemical configurations of this family of natural products. Preliminary tests of structure-activity relationships were conducted with four natural ovatodiolides and three analogues. Further assays indicated that the synthetic natural product isoovatodiolide can significantly decrease the population of hepatic cancer stem cells and reduce the tumorsphere-forming capability of HepG2 cells.
首次开发了一种简洁、可扩展的六步（最长线性序列）合成路线，用于ovatodiolide 支架。这条无保护基团的路线的特点是串联开环复分解/闭环复分解反应来安装大环融合的丁烯内酯环，以及串联烯丙基硼化/内酯化反应来构建α-亚甲基-γ-内酯。我们的合成工作确定了这一系列天然产物迄今为止未知的立体化学构型。对四种天然 ovatodiolides 和三种类似物进行了结构-活性关系的初步测试。进一步的检测表明，合成天然产物 isoovatodiolide 可以显著降低肝癌干细胞的数量，并降低 HepG2 细胞的肿瘤球形成能力。
