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

Autor: Gangjee A; Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, Pennsylvania 15282, USA. gangjee@duq.edu, Pavana RK, Li W, Hamel E, Westbrook C, Mooberry SL
Jazyk: angličtina
Zdroj: Pharmaceutical research [Pharm Res] 2012 Nov; Vol. 29 (11), pp. 3033-9. Date of Electronic Publication: 2012 Jul 20.
DOI: 10.1007/s11095-012-0816-3
Abstrakt: 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.
Databáze: MEDLINE
Externí odkaz: