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Gangjee, A. et al.

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

Novel Water-Soluble Substituted Pyrrolo[3,2-d]pyrimidines: Design, Synthesis, and Biological Evaluation as Antitubulin Antitumor Agents.

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 (GI(50)) 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.[1]

References

Novel Water-Soluble Substituted Pyrrolo[3,2-d]pyrimidines: Design, Synthesis, and Biological Evaluation as Antitubulin Antitumor Agents. Gangjee, A., Pavana, R.K., Li, W., Hamel, E., Westbrook, C., Mooberry, S.L. Pharm. Res. (2012) [Pubmed]

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