The rational design of a novel potent analogue of the 5'-AMP-activated protein kinase inhibitor compound C with improved selectivity and cellular activity.

We have designed and synthesized analogues of compound C, a non-specific inhibitor of 5'-AMP-activated protein kinase (AMPK), using a computational fragment-based drug design (FBDD) approach. Synthesizing only twenty-seven analogues yielded a compound that was equipotent to compound C in the inhibition of the human AMPK (hAMPK) α2 subunit in the heterotrimeric complex in vitro, exhibited significantly improved selectivity against a subset of relevant kinases, and demonstrated enhanced cellular inhibition of AMPK.

Studies on the intramolecular Kulinkovich-de Meijere reaction of disubstituted alkenes bearing carboxylic amide groups.

1,2-Disubstituted olefins bearing an acetamide group were found to undergo intramolecular Kulinkovich-de Meijere cyclopropanation in moderate yield but almost complete diastereoselectivity.