Current drug discovery programs, which often use combinatorially-derived libraries or commercial compound screening collections to discover potent hits, are limited by low structural diversity and minimal complexity.  We present a new synthetic approach, termed Complexity to Diversity (CtD), to obtain small molecules possessing novel, complex architectures from readily available natural products in 2-5 steps.  The plant hormone gibberellic acid was identified as an optimal natural product for this strategy, and a series of ring distortion reactions were employed to reorganize the original scaffold into five structurally-distinct and unique core skeletons that contain points for further derivatization.  All compounds synthesized through the CtD paradigm were subjected to further biological screening to identify new active compounds.  One such compound, GA4, has shown potent anticancer activity in cell lines and in vivo, and kills via an unusual mechanism.

Synthesis of structurally diverse compounds from gibberellic acid enables the discovery of a novel anticancer compound

243rd National Meeting (2012)

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