Synthesis and Cellular Pharmacology Studies of a Series of 2-amino-3-aroyl-4-substituted Thiophene Derivatives

Romeo      Romagnoli; Pier      Giovanni Baraldi; Maria      Giovanna Pavani; Olga      Cruz-Lopez; Ernest      Hamel; Jan      Balzarini; Eleonora      Brognara; Cristina      Zuccato; Roberto      Gambari

doi:10.2174/157340610793563974

Abstract

Microtubules are dynamic structures that play a crucial role in cellular division and are recognized as an important target for cancer therapy. In search of new compounds with strong antiproliferative activity and simple molecular structure, we have synthesized four different series of compounds in which different substituents were linked to the 4- or 5-position of the 2-amino-3-(3,4,5-trimethoxybenzoyl) thiophene system. When these compounds were analyzed in vitro for their inhibition of cell proliferation, the 4-aryl substituted derivatives had little activity. In contrast, the presence of a methylene, oxymethyl, aminomethyl or methylenepiperazino moiety between the aryl and the 4-position of the thiophene ring resulted in statistically significant improvement in activity relative to the 4-aryl substituted derivatives. It is noteworthy that the antiproliferative effects of the synthesized compounds were more pronounced against human Molt/4 and CEM as compared with murine L1210 and FM3A cells. The effects of a selected series of compounds on cell cycle progression correlated well with their strong antiproliferative activity and inhibition of tubulin polymerization. We found that the antiproliferative effects of the most active compounds were associated with increase of the proportion of cells in the G2/M and sub-G1 phases of the cell cycle. The structure-activity relationships observed in the series of compounds described here should permit the design of more active molecules.

Keywords: Thiophene, inhibition of tubulin polymerization, inhibition of tumor cell growth, antiproliferative agents, Microtubules, L1210, FM3A, Combretastatin A-4, CA-4, 1, Combretaceae, phenstatin, colchicine, podophyllotoxin, Piperazine, N-bromosuccinimide, toluene, NMR, Knoevenagel's adduct, column chromatography, tetrakis, flash chromatography, GIBCO, ZF-Coulter Counter, recording spectrophotometer, FACScan, ANOVA