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 journalArticle

11 Citations (Scopus)

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

Fingerprint

Pyrimidines
Colchicine
Microtubules
Antineoplastic Agents
Cells
Water
Tumors
Cell Line
National Cancer Institute (U.S.)
Structure-Activity Relationship
Tubulin
Tumor Cell Line
Depolymerization
Bioactivity
Binding Sites
Cell Proliferation
Neoplasms

Keywords

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

ASJC Scopus subject areas

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

Cite this

Novel water-soluble substituted pyrrolo[3,2-d]pyrimidines : Design, synthesis, and biological evaluation as antitubulin antitumor agents. / Gangjee, Aleem; Pavana, Roheeth K.; Li, Wei; Hamel, Ernest; Westbrook, Cara; Mooberry, Susan L.

In: Pharmaceutical Research, Vol. 29, No. 11, 11.2012, p. 3033-3039.

Research output: Contribution to journalArticle

Gangjee, Aleem ; Pavana, Roheeth K. ; Li, Wei ; Hamel, Ernest ; Westbrook, Cara ; Mooberry, Susan L. / Novel water-soluble substituted pyrrolo[3,2-d]pyrimidines : Design, synthesis, and biological evaluation as antitubulin antitumor agents. In: Pharmaceutical Research. 2012 ; Vol. 29, No. 11. pp. 3033-3039.
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