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.

Development of the suzuki-miyaura cross-coupling reaction: use of air-stable potassium alkynyltrifluoroborates in aryl alkynylations.

The palladium-catalyzed cross-coupling reaction of potassium alkynyltrifluoroborates with aryl halides or triflates proceeds readily with moderate to excellent yields. The potassium alkynyltrifluoroborates are air- and moisture-stable crystalline solids that can be stored indefinitely, which will provide an advantage in applications to combinatorial chemistry. The alkynyl cross-coupling reaction can be effected using 9 mol % of PdCl2(dppf).CH2Cl2 as catalyst in THF or THF-H2O in the presence of Cs2CO3 as the inorganic base. A variety of functional groups are tolerated in both partners.