Conception And Preparation Of New Potent Antimicrotubule Agents.

Abstract Cancer is still to this day one of the first causes of death in industrialized countries. Despite great progress made so far, there is still no treatment completely efficient and without toxicity. Therefore, the development of new anticancer drugs is sought. To this end, we developed a novel family of potent antimicrotubule agents designated as N-phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates (PIB-SOs). Our previous structure-activity relationship studies were focused on the aromatic rings A and B of PIB-SOs leaving the sulfonate bridge poorly studied. In the present study, we have designed, prepared and evaluated in vitro new PIB-SO analogs by replacing the sulfonate moiety with a sulfur atom. The new PIB-SO analogs were prepared using classical organic chemistry tools. The antiproliferative activity of PIB-SO analogs was assessed on HT-1080 fibrosarcoma, HT-29 colon adenocarcinoma, M21 skin melanoma and MCF7 estrogen-dependent breast adenocarcinoma. Then, the most potent analogs were assessed for their effect on the cell cycle progression, their capacity to disrupt the microtubules and their ability to bind to the colchicine-binding site (C-BS). Lastly, their theoretical properties were calculated with SwissADME tool. The new PIB-SO analogs bearing the sulfur bridge exhibit antiproliferative activities in the low nanomolar to mid micromolar ranges. The most potent compounds block the cell cycle progression in G2/M phase, disrupt microtubules and bind to the C-BS. Finally, their theoretical pharmacokinetic profiles show that they are potentially suitable for animal experiments. In addition to show that the sulfonate moiety of PIB-SOs can be modulated with a sulfur atom, our study led to the discovery of a new family of potent antimicrotubule agents targeting the C-BS. This study will contribute in the long term to the development of new treatments for cancer patients. Citation Format: Mathieu Gagné-Boulet, Chahrazed Bouzriba, Atziri Corin Chavez Alvarez, Sébastien Fortin. Conception and preparation of new potent antimicrotubule agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 286.