Structure–activity relationships of semisynthetic mumbaistatin analogs
- 作者：Taek Soon Lee ; Abhirup Das ; Chaitan Khosla
- 关键词：Polyketides ; Natural product biosynthesis ; Target-oriented synthesis ; Type II diabetes ; Mumbaistatin ; Glucose-6-phosphate translocase ; Diabetes ; Semisynthesis
- 刊名：Bioorganic and Medicinal Chemistry
- 出版年：2007
- 期刊代码：9_09680896
- 类别：ch
- 出版时间：1 August 2007
- 卷：15
- 期：15
- 页码：5207-5218
- 文件大小：1190 K
摘要
Mumbaistatin (1), a new anthraquinone natural product, is one of the most potent known inhibitors of hepatic glucose-6-phosphate translocase, an important target for the treatment of type II diabetes. Its availability, however, has been limited due to its extremely low yield from the natural source. Starting from DMAC (5, 3,8-dihydroxyanthraquinone-2-carboxylic acid), a structurally related polyketide product of engineered biosynthesis, we developed a facile semisynthetic method that afforded a variety of mumbaistatin analogs within five steps. This work was facilitated by the initial development of a DMAC overproduction system. In addition to reinforcing the biological significance of the anthraquinone moiety of mumbaistatin, several semisynthetic analogs were found to have low micromolar potency against the translocase in vitro. Two of them were also active in glucose release assays from primary hepatocytes. The synergistic combination of biosynthesis and synthesis is a promising avenue for the discovery of new bioactive substances.