The colchicine site located primarily on the beta-subunit of the tubulin heterodimer, remains a promising target for highly effective and selective small-molecule inhibitors designed to function as therapeutic agents for the treatment of cancer. Natural products such as colchicine and combretastatin A-4 (CA4) have inspired countless analogues that incorporate relevant structural and electronic features important for binding efficacy. Previous work in our laboratory has established a variety of structurally diverse lead molecules, including a series of benzosuberene-based analogues, that have profound anti-proliferative activity (low nM to pM IC50 values) across various cancer cell lines and act as potent inhibitors of tubulin polymerization. These molecules show a dual mechanism of action through their additional activity as vascular disrupting agents (VDAs) that selectively damage tumor-associated microvessels. Guided by structure-activity relationship (SAR) considerations, several new benzosuberene analogues were synthesized and subjected to preliminary biological evaluation. A sub-set of these molecules incorporated a second benzylic double bond motif within the fused 7-membered ring and demonstrated outstanding activity as inhibitors of tubulin polymerization (submicromolar IC50 values). Further SAR studies of a lead benzosuberene, KGP18, led to the serendipitous preparation of a unique tetracyclic analogue, KGP521, through reaction of protected-KGP18 with chlorosulfonyl isocyanate (CSI). This tetracyclic analogue demonstrated potent inhibition of tubulin polymerization (IC50 = 1.8 µM) and was identified as a VDA through a preliminary in vivo bioluminescence imaging study in a mouse model bearing RENCA kidney tumors. The in vivo study was facilitated by a water-soluble phosphate prodrug salt (KGP556) synthesized from the parent compound KGP521. The promising activity of KGP521 inspired further exploration of related benzosuberene analogues through conversion to their corresponding tetracyclic compounds upon reaction with CSI. Further details regarding the design and synthesis of these novel tetracyclic analogues along with their preliminary biological evaluation will be presented.

Synthesis of benzosuberene-based analogues inspired by natural products: Their action as inhibitors of tubulin polymerization as potential anti-cancer agents

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