Rationale, synthesis and biological evaluation of substituted 1-(4-(phenylthio)phenyl)imidazolidin-2-one, urea, thiourea and amide analogs and derivatives designed to target the colchicine-binding site

Abstract

Microtubules and antimicrotubule agents are important in cancer chemotherapy. Indeed, microtubule are essential to form the mitotic spindle during cell division and in cell morphogenesis. In this study, we modified the sections of the structure of the novel family of antimicrotubule agents named phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates (PIB-SOs) to evaluate the effect of replacing 1) the sulfonate bridge of PIB-SOs by a thioether bridge and 2) the imidazolidin-2-one group by either various substituted urea moieties, an ethylthiourea or a butyramide. To that end, we designed, prepared and biologically evaluated 42 new analogs and derivatives of PIB-SOs namely 1-(4-(phenylthio)phenyl)imidazolidin-2-ones (TPIs), 1-(4-(phenylthio)phenyl)ureas (TPUs), 1-ethyl-3-(4-(phenylthio)phenyl)thioureas (TPTs) and N-(4-(phenylthio)phenyl)butyramides (TPAs). The antiproliferative activity of the most potent derivatives on HT-1080, HT-29, M21 and MCF7 human cancer cell lines are in the nanomolar to the low micromolar ranges. The most potent TPUs and TPIs arrest the cell cycle progression in G2/M phase and cause cytoskeleton disruption. TPIs bind to the colchicine-binding site and the antiproliferative activity of TPU and TPI derivatives is generally not or weakly hampered in antimicrotubule- and multidrug-resistant cell lines. They also have suited theoretical physicochemical, pharmacokinetics and drug-likeness properties supporting further preclinical evaluation. Lastly, TPIs 40 and 43 show low toxicity in chick embryos suggesting that they are a new promising family of antimitotics.