Identification and Characterization of a New Tubulin-Binding

We studied the mechanism of action of 3,5-dibromo-4-(3,4-dimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester (JG-03-14) and found that it is a potent microtubule depolymerizer. JG-03-14 caused a dose-dependent loss of cellular microtubules, formation of aberrant mitotic spindles, accumulation of cells in the G2/M phase of the cell cycle, and Bcl-2 phosphorylation. These events culminated in the initiation of apoptosis, as evidenced by the caspase 3-dependent cleavage of poly(ADP-ribose) polymerase (PARP). JG-03-14 has antiproliferative activity against a wide range of cancer cell lines, with an average IC50 value of 62 nM, and it is a poor substrate for transport by P-glycoprotein. JG-03-14 inhibited the polymerization of purified tubulin in vitro, consistent with a direct interaction between the compound and tubulin. JG-03-14 potently inhibited the binding of [3H]colchicine to tubulin, suggesting that it bound to tubulin at a site overlapping the colchicine site. JG-03-14 had antitumor effects in the PC3 xenograft model, in which it caused greater than 50% reduction in tumor burden after 14 days of treatment. Molecular modeling studies indicated that the dimethoxyphenyl group of JG-03-14 occupies a space similar to that of the trimethoxyphenyl group of colchicine. However, the 2,3,5-trisubstituted pyrrole group, which is connected to the dimethoxyphenyl moiety, interacted with both α and β tubulin in space not shared with colchicine, suggesting significant differences compared with colchicine in the mechanism of binding to tubulin. Our results suggest that this tetransubstituted pyrrole represents a new, biologically active chemotype for the colchicine site on tubulin

The Application Of Vinylogous Iminium Salt Derivatives To An Efficient Synthesis Of The Pyrrole Containing Alkaloids Rigidin And Rigidin E

Studies directed on the synthesis of the pyrrole containing marine natural products Rigidin and Rigidin E via vinylogous iminium salts are described. The successful strategy relies on the formation of a 2,4-disubstituted pyrrole from a vinamidinium salt followed by acylation at the 5-position of pyrrole. Halogenation and aminocarbonylation at the 3-position of pyrrole followed by hydrolysis of the ester group at C-2 and subsequent Curtius rearrangement generates the pyrrolopyrimidine skeleton. A final deprotection step completes the synthesis of Rigidin and Rigidin E. © 2006 Elsevier Ltd. All rights reserved