Vincent Ouellette

University Laval, Canada

Design, synthesis and biological evaluation of 4-(3-alkyl-2-oxoimidazolidin-1-yl)-N-phenylbenzenesulfonamide salts as novel hydrosoluble antimitotic prodrugs selectively bioactivated by cytochrome P450 1A1 in breast cancer cells

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Biography

Vincent Ouellette obtained his undergraduate degree from University du Quebec a Trois-Rivieres with a Bachelor of Science (BSc) in Chemistry (Forensics profile) in 2016. He then continued his studies to graduate school and received his Master’s degree (MSc) in Chemistry at the same university in 2019 working on the development of new testosterone-platinum hydrids for the treatment of prostate cancers. Afterwards, he started his doctorate (PhD) in Sciences pharmaceutiques at University Laval in 2019 under the supervision of Dr Sébastien Fortin. As a medicinal chemist, his project is to develop new anticancer compounds and their salts with favorable biopharmaceutical properties for the treatment of cancer, especially breast cancers.

Abstract

Our research group developed new potent prodrugs designated as 4-(3-alkyl-2-oxoimidazolidin-1-yl)-N-phenylbenzenesulfonamides (PAIB-SAs) that are bioactivated by cytochrome P450 1A1 (CYP1A1) expressed in breast cancers into their potent 4-(2-oxoimidazolidin-1-yl)-N-phenylbenzenesulfonamides (PIB-SAs) antimitotic metabolites. One of the predominant problems is the poor solubility of PAIB-SAs in aqueous solutions which is hampering their galenic formulation and administration in animal studies. To circumvent that impediment, salt formation is a widely used strategy to improve hydrosolubility. In this study, we report the design, synthesis, evaluation of the aqueous solubility, antiproliferative activity and mechanism of action of 18 new Na+, K+ and Li+ salts of PAIB-SAs. Our results evidenced that the new PAIB-SA salts are up to 39 000-times more soluble in aqueous solution than their neutral counterparts. Moreover, they still exhibit cytocidal activity and selectivity against CYP1A1-expressing MCF7 and MDA-MB-468 cancer cells compared to MDA-MB-231 and HaCaT cells that are devoid of CYP1A1. The most potent PAIB-SA salts arrest the cell cycle progression in the G2/M phase and disrupt the cytoskeleton dynamic assembly leading to cell death. Finally, they still bioactivated by CYP1A1 via their N-dealkylation into their potent PIB-SA metabolites. In conclusion, our results show that we have significantly increased the hydrosolubility of PAIB-SAs by designing new salts. Our results show notably that sodium salts still exhibit potent antiproliferative efficacy and that they remain prone to CYP1A1 bioactivation. This important achievement will allow us to optimize our galenic formulations in view of further biopharmaceutical and pharmacodynamical studies.