Benzofulvenes and relevant indene derivatives have been studied as promising pharmaceutical lead compounds due to their unique structure. Among them, sulindac has a 1,2,3-trisubstitued indene framework with a (Z)-benzylidene moiety which makes it challenging to synthesize. Interestingly, not only anti-inflammatory, but also anti-cancer and antiproliferative activities of novel sulindac derivatives have been revealed. With highly applicable and well organized synthetic method, it is possible to explore the uncharted territory of sulindac derivatives and establish their structure-activity relationships. Herein, we describe our efforts toward synthesis of sulindac and its unprecedented analogues. Our synthetic strategy, the construction of (Z)-selective sulindac skeleton via stereoselective vinylogous Stork enamine Claisen-Schmidt condensation, allows the feasible derivatization from key enamine precursors in a various manner. Furthermore, the biological evaluation toward discovery of novel sulindac analogues with anti-cancer activities are currently in progress.

Divergent synthetic studies of sulindac and its unprecedented analogues

ACS Fall 2021

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