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Pharmaceutical Research

, Volume 29, Issue 11, pp 3033–3039 | Cite as

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 Paper

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.

KEY WORDS

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

Notes

Acknowledgments and Disclosures

National Cancer Institute for performing the in vitro antitumor evaluation in their 60 tumor preclinical screening program.

Grant from the National Institute of Health, National Cancer Institute, CA142868 (AG,SLM).

NSF equipment grant for the NMR (NMR: CHE 0614785) and the CTRC Cancer Center Support Grant, P30 CA054174

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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Aleem Gangjee
    • 1
  • Roheeth K. Pavana
    • 1
  • Wei Li
    • 1
  • Ernest Hamel
    • 2
  • Cara Westbrook
    • 3
  • Susan L. Mooberry
    • 3
    • 4
  1. 1.Division of Medicinal ChemistryGraduate School of Pharmaceutical Sciences, Duquesne UniversityPittsburghUSA
  2. 2.Screening Technologies Branch Developmental Therapeutics Program Division of Cancer Treatment & Diagnosis Frederick National Laboratory for Cancer Research National Cancer InstituteFrederickUSA
  3. 3.Department of PharmacologyUniversity of Texas Health Science Center at San AntonioSan AntonioUSA
  4. 4.Cancer Therapy & Research Center University of Texas Health Science Center at San AntonioSan AntonioUSA

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