Design, synthesis, and structure–activity relationships of pyrimido[4,5-b]indole-4-amines as microtubule depolymerizing agents that are effective against multidrug resistant cells

Ravi Kumar Vyas Devambatla, Wei Li, Nilesh Zaware, Shruti Choudhary, Ernest Hamel, Susan L. Mooberry, Aleem Gangjee

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

To identify the structural features of 9H-pyrimido[4,5-b]indoles as microtubule depolymerizers, pyrimido[4,5-b]indoles 2–8 with varied substituents at the 2-, 4- and 5-positions were designed and synthesized. Nucleophilic displacement of 2,5-substituted-4-chloro-pyrimido[4,5-b]indoles with appropriate arylamines was the final step employed in the synthesis of target compounds 2–8. Compounds 2 and 6 had two-digit nanomolar potency (IC50) against MDA-MB-435, SK-OV-3 and HeLa cancer cells in vitro. Compounds 2 and 6 also depolymerized microtubules comparable to the lead compound 1. Compounds 2, 3, 6 and 8 were effective in cells expressing P-glycoprotein or the βIII isotype of tubulin, mechanisms that are associated with clinical drug resistance to microtubule targeting drugs. Proton NMR and molecular modeling studies were employed to identify the structural basis for the microtubule depolymerizing activity of pyrimido[4,5-b]indoles.

Original languageEnglish (US)
Pages (from-to)3423-3430
Number of pages8
JournalBioorganic and Medicinal Chemistry Letters
Volume27
Issue number15
DOIs
StatePublished - 2017

Keywords

  • Conformational restriction
  • Microtubule depolymerizing agents
  • Microtubules
  • Multidrug resistance
  • Pyrimido[4,5-b]indoles

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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