Ortho group activation of a bromopyrrole ester in Suzuki-Miyaura cross-coupling reactions: Application to the synthesis of new microtubule depolymerizing agents with potent cytotoxic activities

  • Bioorg Med Chem. 2017 Jun 15;25(12):3206-3214. doi: 10.1016/j.bmc.2017.04.012.
John T Gupton  1 ,  Scott Yeudall  2 ,  Nakul Telang  2 ,  Megan Hoerrner  2 ,  Ellis Huff  2 ,  Evan Crawford  2 ,  Katie Lounsbury  2 ,  Michael Kimmel  2 ,  William Curry  2 ,  Andrew Harrison  2 ,  Wen Juekun  2 ,  Alex Shimozono  2 ,  Joe Ortolani  2 ,  Kristin Lescalleet  2 ,  Jon Patteson  2 ,  Veronica Moore-Stoll  2 ,  Cristina C Rohena  3 ,  Susan L Mooberry  3 ,  Ahmad J Obaidullah  4 ,  Glen E Kellogg  4 ,  James A Sikorski  5
Affiliations
  • 1. Department of Chemistry, University of Richmond, Richmond, VA 23173, USA. Electronic address: [email protected].
  • 2. Department of Chemistry, University of Richmond, Richmond, VA 23173, USA.
  • 3. Department of Pharmacology and Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
  • 4. Department of Medicinal Chemistry & Institute of Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, VA 23298, USA.
  • 5. Chemistry and Drug Discovery, Chesterfield, MO 63005, USA.
PMID: 28433513 DOI: 10.1016/j.bmc.2017.04.012
Abstract

New microtubule depolymerizing agents with potent cytotoxic activities have been prepared with a 5-cyano or 5-oximino group attached to a pyrrole core. The utilization of ortho activation of a bromopyrrole ester to facilitate successful Suzuki-Miyaura cross-coupling reactions was a key aspect of the synthetic methodology. This strategy allows for control of regiochemistry with the attachment of four completely different groups at the 2, 3, 4 and 5 positions of the pyrrole scaffold. Biological evaluations and molecular modeling studies are reported for these examples.

Keywords
Cytotoxic activity; Marine natural products; Microtubule inhibitors; Pyrrole; Suzuki-Miyaura cross-coupling.