Structure-activity relationships of semisynthetic mumbaistatin analogs.
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.
Lee
Taek Soon
TS
Department of Chemistry, Stanford University, Stanford, CA 94305, USA.
Das
Abhirup
A
Khosla
Chaitan
C
D000818:Animals; D000880:Anthraquinones / Q000737:chemistry* / Q000494:pharmacology*; D017920:Antiporters / Q000037:antagonists & inhibitors; D022781:Hepatocytes / Q000201:enzymology; D020128:Inhibitory Concentration 50; D008297:Male; D015394:Molecular Structure; D009004:Monosaccharide Transport Proteins / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D000880:Anthraquinones; D017920:Antiporters; D009004:Monosaccharide Transport Proteins; C503533:Slc37a4 protein, rat; C430985:mumbaistatin