Single agents with designed combination chemotherapy potential: Synthesis and evaluation of substituted pyrimido[4,5-b]indoles as receptor tyrosine kinase and thymidylate synthase inhibitors and as antitumor agents

Aleein Gangjee, Nilesh Zaware, Sudhir Raghavan, Michael Ihnat, Satyendra Shenoy, Roy L. Kisliuk

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

Combinations of antiangiogenic agents (AAs) with cytotoxic agents have shown significant promise in cancer treatment, and several such clinical trials are currently underway. We have designed, synthesized, and evaluated two compounds that each inhibit vascular endothelial growth, factor receptor-2 (VEGFR-2) and platelet-derived growth, factor receptor-β (PDGFR-β) for antiangiogenic effects and also inhibit human thymidylate synthase (hTS) for cytotoxic effects in single agents. The synthesis of these compounds involved, the nucleophilic displacement of the common intermediate 5-chloro-9H-pyrimido[4, 5-b]indole-2,4-diamine with appropriate benzenethiols. The inhibitory potency of both these single agents against VEGFR-2, PDGFR-β, and hTS is better than or close to standards. In a. COLO-205 xenograft mouse model, one of the analogs significantly decreased tumor growth (tumor growth inhibition (TGI) = 76% at 35 mg/kg), liver metastases, and tumor blood vessels compared with a standard drug and with control and thus demonstrated potent tumor growth inhibition, inhibition of metastasis, and antiangiogenic effects in vivo. These compounds afford combination chemotherapeutic potential in single agents.

Original languageEnglish (US)
Pages (from-to)1563-1578
Number of pages16
JournalJournal of Medicinal Chemistry
Volume53
Issue number4
DOIs
StatePublished - Feb 25 2010

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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