Structure-activity relationship and in vitro and in vivo evaluation of the potent cytotoxic anti-microtubule agent N-(4-methoxyphenyl)-N,2,6-trimethyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-aminium chloride and its analogues as antitumor agents

Aleem Gangjee, Ying Zhao, Sudhir Raghavan, Cristina C. Rohena, Susan L. Mooberry, Ernest Hamel

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

A series of 21 substituted cyclopenta[d]pyrimidines were synthesized as an extension of our discovery of the parent compound (±)-1·HCl as an anti-microtubule agent. The structure-activity relationship indicates that the N-methyl and a 4N-methoxy groups appear important for potent activity. In addition, the 6-substituent in the parent analogue is not necessary for activity. The most potent compound 30·HCl was a one to two digit nanomolar inhibitor of most tumor cell proliferations and was up to 7-fold more potent than the parent compound (±)-1·HCl. In addition, 30·HCl inhibited cancer cell proliferation regardless of Pgp or βIII-tubulin status, both of which are known to cause clinical resistance to several anti-tubulin agents. In vivo efficacy of 30·HCl was demonstrated against a triple negative breast cancer xenograft mouse model. Compound 30·HCl is water-soluble and easily synthesized and serves as a lead compound for further preclinical evaluation as an antitumor agent.

Original languageEnglish (US)
Pages (from-to)6829-6844
Number of pages16
JournalJournal of Medicinal Chemistry
Volume56
Issue number17
DOIs
StatePublished - Sep 12 2013

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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