Design, Synthesis, and Preclinical Evaluation of 4-Substituted-5-methyl-furo[2,3-d]pyrimidines as Microtubule Targeting Agents That Are Effective against Multidrug Resistant Cancer Cells

Ravi Kumar Vyas Devambatla, Ojas A. Namjoshi, Shruti Choudhary, Ernest Hamel, Corena V. Shaffer, Cristina C. Rohena, Susan L. Mooberry, Aleem Gangjee

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

The design, synthesis, and biological evaluations of eight 4-substituted 5-methyl-furo[2,3-d]pyrimidines are reported. Synthesis involved N4-alkylation of N-aryl-5-methylfuro[2,3-d]pyrimidin-4-amines, obtained from Ullmann coupling of 4-amino-5-methylfuro[2,3-d]pyrimidine and appropriate aryl iodides. Compounds 3, 4, and 9 showed potent microtubule depolymerizing activities, while compounds 6-8 had slightly lower potency. Compounds 4, 6, 7, and 9 inhibited tubulin assembly with IC50 values comparable to that of combretastatin A-4 (CA-4). Compounds 3, 4, and 6-9 circumvented Pgp and βIII-tubulin mediated drug resistance, mechanisms that can limit the efficacy of paclitaxel, docetaxel, and the vinca alkaloids. In the NCI 60-cell line panel, compound 3 exhibited GI50 values less than 10 nM in 47 of the cell lines. In an MDA-MB-435 xenograft model, compound 3 had statistically significant antitumor effects. The biological effects of 3 identify it as a novel, potent microtubule depolymerizing agent with antitumor activity.

Original languageEnglish (US)
Pages (from-to)5752-5765
Number of pages14
JournalJournal of Medicinal Chemistry
Volume59
Issue number12
DOIs
StatePublished - Jun 23 2016

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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