Novel water-soluble substituted pyrrolo[3,2-d]pyrimidines: Design, synthesis, and biological evaluation as antitubulin antitumor agents

Aleem Gangjee, Roheeth K. Pavana, Wei Li, Ernest Hamel, Cara Westbrook, Susan L. Mooberry

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Purpose: To study the effects of a regioisomeric change on the biological activities of previously reported water soluble, colchicine site binding, microtubule depolymerizing agents. Methods: Nine pyrrolo[3,2-d]pyrimidines were designed and synthesized. The importance of various substituents was evaluated. Their abilities to cause cellular microtubule depolymerization, inhibit proliferation of MDA-MB-435 tumor cells and inhibit colchicine binding to tubulin were studied. One of the compounds was also evaluated in the National Cancer Institute preclinical 60 cell line panel. Results: Pyrrolo[3,2-d] pyrimidine analogs were more potent than their pyrrolo[2,3-d]pyrimidine regioisomers. We identified compounds with submicromolar potency against cellular proliferation. The structure-activity relationship study gave insight into substituents that were crucial for activity and those that improved activity. The compound tested in the NCI 60 cell line is a 2-digit nanomolar (GI50) inhibitor of 8 tumor cell lines. Conclusion: We have identified substituted pyrrolo[3,2-d]pyrimidines that are water-soluble colchicine site microtubule depolymerizing agents. These compounds serve as leads for further optimization.

Original languageEnglish (US)
Pages (from-to)3033-3039
Number of pages7
JournalPharmaceutical Research
Volume29
Issue number11
DOIs
StatePublished - Nov 2012

Keywords

  • antitubulin
  • colchicine-site binders
  • drug design
  • microtubule depolymerizer
  • pyrrolo[3,2-d]pyrimidines

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)

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