PREPARATION AND EVALUATION OF DECONSTRUCTION ANALOGS OF 7-DEOXYKALAFUNGIN AS AKT INHIBITORS

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).

Name thesis:degree_name

Master of Science

Level thesis:degree_level

Thesis

Discipline thesis:degree_discipline

Pharmaceutical Sciences

Year dc:date.available

2012

Author dc:creator

• Korwar, Sudha

Contributors dc:contributor

• Keith Ellis

• 7-Deoxykalafungin
• AKT inhibitors
• Heck coupling
• Sharpless asymmetric dihydroxylation
• Oxa-Pictet Spengler cyclization
• Medicine and Health Sciences
• Pharmacy and Pharmaceutical Sciences

Statement dc:rights

• © The Author

Identifier

https://scholarscompass.vcu.edu/etd/387

OAI identifier oai:identifier

oai:scholarscompass.vcu.edu:etd-1386