Sterically induced conformational restriction: Discovery and preclinical evaluation of novel pyrrolo[3,2-d]pyrimidines as microtubule targeting agents

Roheeth Kumar Pavana, Khushbu Shah, Taylor Gentile, Nicholas F. Dybdal-Hargreaves, April L. Risinger, Susan L. Mooberry, Ernest Hamel, Aleem Gangjee

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

The discovery, synthesis and biological evaluations of a series of nine N5-substituted-pyrrolo[3,2-d]pyrimidin-4-amines are reported. Novel compounds with microtubule depolymerizing activity were identified. Some of these compounds also circumvent clinically relevant drug resistance mechanisms (expression of P-glycoprotein and βIII tubulin). Compounds 4, 5, and 8–13 were one to two-digit nanomolar (IC50) inhibitors of cancer cells in culture. Contrary to recent reports (Banerjee et al. J. Med. Chem. 2018, 61, 1704–1718), the conformation of the most active compounds determined by 1H NMR and molecular modeling are similar to that reported previously and in keeping with recently reported X-ray crystal structures. Compound 11, freely water soluble as the HCl salt, afforded statistically significant inhibition of tumor growth in three xenograft models [MDA-MB-435, MDA-MB-231 and NCI/ADR-RES] compared with controls. Compound 11 did not display indications of animal toxicity and is currently slated for further preclinical development.

Original languageEnglish (US)
Pages (from-to)5470-5478
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume26
Issue number20
DOIs
StatePublished - Nov 1 2018

Keywords

  • Microtubule depolymerizers
  • Microtubule targeting agents
  • P-glycoprotein
  • Preclinical agents
  • Pyrrolo[3, 2-d]pyrimidines
  • βIII tubulin

ASJC Scopus subject areas

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

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