Synthesis of analogues of DAQ B1 as potential anti-diabetic drugs

Diabetes mellitus affects about 6% of the U.S. population. While insulin is the most important drug to treat diabetes mellitus, it cannot be taken by mouth because it would be destroyed by digestion. The search for an "insulin pill" has been fruitless until the recent discovery of demethylasterriquinone B1 (DAQ B1) by Merck. DAQ B1 was reported to selectively activate insulin receptor tyrosine kinase and mimic the action of insulin. DAQ B1 belongs to the asterriquinone family of natural products, many of which have shown interesting biological properties by interfering with protein-protein interactions. The goal of our research includes the synthesis of analogues of DAQ B1 for screening of drug candidates and studying the mechanism of action of DAQ B1.; Based on our preliminary results, two optimized protocols have been developed for the conjugate addition of indoles to dichlorobenzoquinone, producing 2,5-dichloro-3-(indol-3-yl)benzoquinone targets. These methods, involving either H2SO4 or CH 3COOH as the catalyst, accommodate a wide variety of indoles substituted with halogen, alkyl, alkoxy and aryl groups. After alkaline hydrolysis of the dichlorides, 37 "half molecule" analogues of DAQ B1 have been prepared. In order to improve the observed inhibition activities of these analogues against Cdc25 phosphatases, two indoles were synthesized and converted to dihydroxyindolylbenzoquinones. The key steps of the synthesis are a Stille coupling reaction and a Bartoli indole synthesis. A biotin-demethylasterriquinone conjugate was also synthesized for use as an affinity reagent. DAQ B1 analogues with quinone replacements were synthesized in order to avoid potential toxicity from the quinone substructure. Kojic acid, pyridone and tropolone were selected to replace the quinone ring. Stille coupling reactions connected the indole ring and quinone replacements.