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

作者：Gangjee, Aleem^*; Pavana, Roheeth K.; Li, Wei; Hamel, Ernest; Westbrook, Cara; Mooberry, Susan L.

来源：Pharmaceutical Research, 2012, 29(11): 3033-3039.

DOI：10.1007/s11095-012-0816-3

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

To study the effects of a regioisomeric change on the biological activities of previously reported water soluble, colchicine site binding, microtubule depolymerizing agents. @@@ 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. @@@ 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. @@@ 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.

• 出版日期2012-11