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 journalArticle

14 Citations (Scopus)

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

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Pyrimidines
docetaxel
Tubulin
Microtubules
Vinca Alkaloids
Cell Line
Alkylation
Iodides
Paclitaxel
Drug Resistance
Heterografts
Antineoplastic Agents
Inhibitory Concentration 50
Amines
Neoplasms
pyrimidine
fosbretabulin

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

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

In: Journal of Medicinal Chemistry, Vol. 59, No. 12, 23.06.2016, p. 5752-5765.

Research output: Contribution to journalArticle

Devambatla, Ravi Kumar Vyas ; Namjoshi, Ojas A. ; Choudhary, Shruti ; Hamel, Ernest ; Shaffer, Corena V. ; Rohena, Cristina C. ; Mooberry, Susan L ; Gangjee, Aleem. / 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. In: Journal of Medicinal Chemistry. 2016 ; Vol. 59, No. 12. pp. 5752-5765.
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