Synthesis, modeling, and biological evaluation of anti-tubulin indole-substituted furanones

  • Bioorg Med Chem Lett. 2023 Jun 15;90:129347. doi: 10.1016/j.bmcl.2023.129347.
Brianna Hurysz  1 ,  Blake A Evans  2 ,  Reuben N Laryea  3 ,  Brooke E Boyer  2 ,  Taylor E Coburn  2 ,  Molly S Dexter  4 ,  Marissa A Edwards  2 ,  Grace V Faulkner  2 ,  Rebecca L Huss  2 ,  Megan M Lafferty  2 ,  Maegan Manning  1 ,  Matthew McNulty  1 ,  Sophia J Melvin  2 ,  Christina M Mitrow  2 ,  Roslyn R Patel  2 ,  Kelsey Pierce  1 ,  Jack Russo  2 ,  Allie M Seminer  2 ,  Kaitlynn A Sockett  2 ,  Nathan R Webster  2 ,  Kathryn E Cole  5 ,  Patricia Mowery  6 ,  Erin T Pelkey  7
Affiliations
  • 1. Department of Biology, Hobart and William Smith Colleges, Geneva, NY 14456, USA.
  • 2. Department of Chemistry, Hobart and William Smith Colleges, Geneva, NY 14456, USA.
  • 3. Department of Molecular Biology and Chemistry, Christopher Newport University, Newport News, VA 23606, USA.
  • 4. Department of Chemistry, Hobart and William Smith Colleges, Geneva, NY 14456, USA; Department of Biology, Hobart and William Smith Colleges, Geneva, NY 14456, USA.
  • 5. Department of Molecular Biology and Chemistry, Christopher Newport University, Newport News, VA 23606, USA. Electronic address: [email protected].
  • 6. Department of Biology, Hobart and William Smith Colleges, Geneva, NY 14456, USA. Electronic address: [email protected].
  • 7. Department of Chemistry, Hobart and William Smith Colleges, Geneva, NY 14456, USA. Electronic address: [email protected].
PMID: 37236376 DOI: 10.1016/j.bmcl.2023.129347
Abstract

Due to the central role of tubulin in various cellular functions, it is a validated target for anti-cancer therapeutics. However, many of the current tubulin inhibitors are derived from complex natural products and suffer from multidrug resistance, low solubility, toxicity issues, and/or the lack of multi-cancer efficacy. As such, there is a continued need for the discovery and development of new anti-tubulin drugs to enter the pipeline. Herein we report on a group of indole-substituted furanones that were prepared and tested for anti-cancer activity. Molecular docking studies showed positive correlations between favorable binding in the colchicine binding site (CBS) of tubulin and anti-proliferative activity, and the most potent compound was found to inhibit tubulin polymerization. These compounds represent a promising new structural motif in the search for small heterocyclic CBS Cancer inhibitors.

Keywords
Antiproliferative; Antitubulin; Heterocyclic; Indole.
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