Total synthesis of DAQ-B1 and combinatorial synthesis of its analogues as potential anti-diabetic drugs

Diabetes affects 5% of the U.S. population. Insulin is the most important drug in treating diabetes mellitus, however, it is not orally active. Demethylasterriquinone B1 (DAQ-B1) is a natural product that was reported to be insulin mimetic and have oral anti-diabetic activity. Dihydroxybisindolylbenzoquinone, the general structure of DAQ compounds, may be potentially a general structural class of growth factor mimetics. The goal of our research has been to study the total synthesis of DAQ-B1 and synthesis of its analogues for the purpose of studying the mechanism of DAQ-B1's activity and develop a combinatorial synthesis of DAQ libraries for screening of drug candidates with higher anti-diabetic activities.; The reaction between indoles and dichlorobenzoquinone was studied and an efficient acid catalyzed condensation reaction was developed as a method to synthesize indolylquinone, the key structure of DAQ-B1. A total synthesis of DAQ-B1 was accomplished based on this acid-catalyzed condensation reaction and a Stille coupling reaction. This acid-catalyzed condensation reaction was also used in the synthesis of compounds similar to DAQ-B1, such as dihydroxymonoindolylbenzoquinones and dihydroxyindolylnaphthoquinones.; Lewis acid-catalyzed reactions between monoindolylquinones and indoles were studied to introduce indoles to monoindolylquinones, which cannot be accomplished by Brønsted acid catalyst. High throughput combinatorial synthesis of dihydroxybisindolylbenzoquinones was established based on the Lewis acid-catalyzed reaction. A library of DAQ compounds was made via this high throughput method. These compounds will be subjected to bioactivity testing as mimetics of both insulin and other growth factors.