The design and synthesis of small-molecule inhibitors of tubulin polymerization remains a promising approach for the development of new therapeutic agents for cancer treatment. The natural products colchicine and combretastatin A-4 (CA4) have inspired significant drug discovery campaigns targeting the colchicine site located on the beta-tubulin heterodimer, but so far these efforts have not resulted in a therapeutic agent that has reached FDA approval. Further interest in the colchicine site was catalyzed by the discovery that a subset of inhibitors of tubulin polymerization that bind to the colchicine site demonstrate dual functionality as both potent cytotoxins and effective vascular disrupting agents (VDAs). Our previous studies led to the discovery and development of a 2-aryl-3-aroyl-indole analogue (OXi8006) that potently inhibited tubulin polymerization and cancer cell growth (low nM IC50 values). A water-soluble phosphate prodrug salt (OXi8007), synthesized from OXi8006, functioned as a promising VDA in mouse models of cancer. In an effort to gain structure-activity relationship (SAR) knowledge, a series of indole analogues were synthesized that incorporated an oxetane functional group as a ketone surrogate. The synthesis featured a Lewis acid catalyzed Friedel-Crafts alkylation reaction to construct the key tertiary center associated with the oxetane bridge between the indole core and the pendant aryl ring. While these oxetane bearing molecules proved inactive as inhibitors of tubulin polymerization, certain analogues demonstrated encouraging cytotoxicity against human cancer cell lines (GI50 = 0.47 µM against MCF-7 human breast cancer cells, as one example). As part of an ongoing search for novel chemotypes as inhibitors of tubulin polymerization, a series of 6-aryl-3-aroyl-indole analogues were synthesized and evaluated for their inhibition of tubulin polymerization and cytotoxicity against human cancer cell lines. Several structurally diverse molecules in this small library proved to be strong inhibitors of tubulin polymerization and demonstrated potent cytotoxicity against the MCF-7 cell line (GI50 = 23-73 nM, for several analogues). Continuing studies will evaluate the most promising analogues for their ability to function as VDAs.

Synthesis and biological evaluation of structurally diverse indole-based analogues as inhibitors of tubulin polymerization

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.