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PREPARATION AND EVALUATION OF DECONSTRUCTION ANALOGS OF 7-DEOXYKALAFUNGIN AS AKT INHIBITORSKorwar, Sudha 27 July 2012 (has links)
Pyranonaphthoquinone lactones have been recently found to be selective inhibitors of the serine-threonine kinase AKT/PKB. AKT/PKB plays a major role in tumorigenesis, hence these compounds have a great potential to act as anti-cancer agents. They act by a novel bioreductive alkylation mechanism of inhibition of AKT/PKB. In this work, 7-deoxykalafungin, a pyranonaphthoquinone lactone and its deconstruction analogs were synthesized. The structural features of the compounds necessary to inhibit AKT1 potently and selectively were determined. It was observed that compounds with a pyran ring were more potent in inhibiting AKT1. Conversely, flexible compounds were found to be weak inhibitors of AKT1. Also, presence of a lactone ring was found to be favorable in inhibiting AKT1. Of the compounds tested, 7-deoxykalafungin was the most potent inhibitor of AKT1 (IC50 = 0.28 µM against AKT1) and compound 4-61 was the most potent inhibitor of PKA (IC50 = 0.43 µM against PKA).
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