Structure-activity relationships of semisynthetic mumbaistatin analogs
Structure-activity relationships of semisynthetic mumbaistatin analogs
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DOI：
10.1016/j.bmc.2007.05.019
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发表时间：
2007-08-01
影响因子：
3.5
通讯作者：
Khosla, Chaitan
中科院分区：
文献类型：
--
作者：
Lee, Taek Soon;Das, Abhirup;Khosla, Chaitan
Mumbaistatin (1) 是一种新的蒽醌天然产物，是已知最有效的肝葡萄糖-6-磷酸转位酶抑制剂之一，肝葡萄糖-6-磷酸转位酶是治疗 II 型糖尿病的重要靶点。然而，由于天然来源的产量极低，其可用性受到限制。从 DMAC（5, 3,8-二羟基蒽醌-2-羧酸）（一种结构相关的工程生物合成聚酮化合物产品）开始，我们开发了一种简便的半合成方法，可在五个步骤内提供多种孟巴他汀类似物。 DMAC 过量生产系统的初步开发促进了这项工作。除了增强孟巴他汀蒽醌部分的生物学意义外，还发现几种半合成类似物在体外对易位酶具有低微摩尔效力。其中两个在原代肝细胞的葡萄糖释放测定中也很活跃。生物合成和合成的协同组合是发现新生物活性物质的有前途的途径。 (c) 2007 Elsevier Ltd. 保留所有权利。
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. (c) 2007 Elsevier Ltd. All rights reserved.