Developing novel C-4 analogues of pyrrole-based antitubulin agents: weak but critical hydrogen bonding in the colchicine site

  • Medchemcomm. 2013;4(2):417-421. doi: 10.1039/C2MD20320K.
Chenxiao Da  1 ,  Nakul Telang  2 ,  Kayleigh Hall  2 ,  Emily Kluball  2 ,  Peter Barelli  2 ,  Kara Finzel  2 ,  Xin Jia  2 ,  John T Gupton  2 ,  Susan L Mooberry  3 ,  Glen E Kellogg  1
Affiliations
  • 1. Department of Medicinal Chemistry & Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, Virginia, USA 23298-0540.
  • 2. Department of Chemistry, Gottwald Center for the Sciences, University of Richmond, Richmond, Virginia, USA 23173.
  • 3. Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA 78229-3900.
PMID: 23457660 DOI: 10.1039/C2MD20320K
Abstract

The synthesis, biological evaluation and molecular modeling of a series of pyrrole compounds related to 3,5-dibromo-4-(3,4-dimethoxyphenyl)-1H-pyrrole-2-carboxylic acid that evaluates and optimizes C-4 substituents are reported. The key factor for microtubule depolymerization activity appears to be the presence of an appropriately positioned acceptor for Cys241β in the otherwise hydrophobic subpocket A.