Discovery of novel antitumor antimitotic agents that also reverse tumor resistance

Aleem Gangjee, Jianming Yu, Jean E. Copper, Charles Smith

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

We have discovered a novel series of 7-benzyl-4-methyl-5-[(2-substituted phenyl)ethyl]-7H-pyrrolo[2,3-d]-pyrimidin-2-amines, which possess antimitotic and antitumor activities against antimitotic-sensitive as well as resistant tumor cells. These agents bind to a site on tubulin that is distinct from the colchicine, vinca alkaloid, and paclitaxel binding sites and some, in addition to their antitumor activity, remarkably also reverse tumor resistance to antimitotic agents mediated via the P-glycoprotein efflux pump. The compounds were synthesized from N-(7-benzyl-5-ethynyl-4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 2-yl)-2,2-dimethylpropanamide 11 or the corresponding 5-iodo analog 14 via Sonogashira couplings with appropriate iodobenzenes or phenylacetylene followed by reduction and deprotection to afford the target analogs. Sodium and liquid NH3 afforded the debenzylated analogs. The most potent analog 1 was one to three digit nanomolar against the growth of both sensitive and resistant tumor cells in culture. Compounds of this series are promising novel antimitotic agents that have the potential for treating both sensitive and resistant tumors.

Original languageEnglish (US)
Pages (from-to)3290-3301
Number of pages12
JournalJournal of Medicinal Chemistry
Volume50
Issue number14
DOIs
StatePublished - Jul 12 2007

Fingerprint

Antimitotic Agents
Antineoplastic Agents
Iodobenzenes
Neoplasms
Vinca Alkaloids
Colchicine
P-Glycoprotein
Tubulin
Paclitaxel
Amines
Cell Culture Techniques
Sodium
Binding Sites
Growth

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Gangjee, Aleem ; Yu, Jianming ; Copper, Jean E. ; Smith, Charles. / Discovery of novel antitumor antimitotic agents that also reverse tumor resistance. In: Journal of Medicinal Chemistry. 2007 ; Vol. 50, No. 14. pp. 3290-3301.
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Discovery of novel antitumor antimitotic agents that also reverse tumor resistance. / Gangjee, Aleem; Yu, Jianming; Copper, Jean E.; Smith, Charles.

In: Journal of Medicinal Chemistry, Vol. 50, No. 14, 12.07.2007, p. 3290-3301.

Research output: Contribution to journalArticle

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