The flavonoid quercetin has been previously shown to be a weak competitive inhibitor of caspase-3. An analysis of quercetin binding to caspase-3 using a combination of docking studies and a water map of the caspase active site has led to the design of quercetin analogue 1   with an amide-linked �-alanine moiety at the 3'-position. We hypothesize that the carboxylate in 1  may displace an energetically unfavorable water molecule in the caspase-3 active site, thus resulting in tighter binding to caspase-3 than quercetin. A de novo synthesis of an appropriately modified quercetin derivative 1  has been designed, based on the Algar-Flynn-Oyamada coupling reaction. Progress in the synthesis of 1  and its evaluation as an inhibitor of caspase-3 will be presented.

Design of a tight-binding flavonoid-based caspase inhibitor

243rd National Meeting (2012)

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