Abstract 284: Design, synthesis and biological evaluation of novel water-soluble salts of the antimitotic prodrugs 4-(3-alkyl-2-oxoimidazolidin-1-yl)-<i>N</i>-phenylbenzenesulfonamides selectively bioactivated by cytochrome p450 1A1 in breast cancer cells
Authors: Vincent Ouellette, Atziri Corin Chavez Alvarez, Sébastien Fortin
Journal: Cancer Research (2021)

Abstract One of the predominant problems in drug development is the solubility of new molecules in aqueous solutions. New potent antimitotics developed in our research group do not avoid this issue. Our molecules are poorly soluble in aqueous solution which represent a significant impediment for biopharmacological and pharmacodynamical studies. To circumvent that difficulty, salt formation is a widely used strategy to improve hydrosolubility. Moreover, it is estimated that approximately 50% of the drugs used in clinics are administered as salt formulations. It is in that context that we studied the salt formation of our new family of poorly hydrosoluble antimitotics prodrugs referred to as 4-(3-alkyl-2-oxoimidazolidin-1-yl)-N-phenylbenzenesulfonamides (PAIB-SAs) that are selectively bioactivated by cytochrome p450 1A1 (CYP1A1) in breast cancers. We propose that this will significantly increase their aqueous solubility without altering their selectivity and their anticancer activity. The synthesis of the various salts of PAIB-SAs prepared was based on varying the counterion bound onto the sulfonamide group of the most promising compounds. These salts were synthesized using classical organic chemistry and their maximum aqueous solubility was measured. Their antiproliferative activity was then assessed in vitro using the sulforhodamine B colorimetric assay on MCF7 and MDA-MB-468 human breast cancer cells expressing CYP1A1, and MDA-MB-231 cells devoid of CYP1A1. The bioactivation of PAIS-SAs salts into its cytotoxic metabolites by CYP1A1 Supersomes was assessed by UHPLC. The effect of PAIB-SA salts on cell cycle progression and on microtubule integrity were also assessed by flow cytometry and by immunofluorescence, respectively. We hereby report the synthesis of 18 new salts of PAIB-SAs using either sodium, potassium or lithium as the cation of 6 most promising PAIB-SAs and their biological evaluation. Our results evidenced that the new PAIB-SA salts are highly soluble in water comparatively to their neutral counterparts. They also exhibited high selective cytocidal activity toward MCF7 and MDA-MB-468 expressing CYP1A1 as compared to MDA-MB-231 lacking CYP1A1. They are bioactivated by N-dealkylation by CYP1A1 into potent antimitotic agents. They arrested the cell cycle progression in the G2/M phase and disrupted the microtubule dynamics assembly. In conclusion, we have significantly increased the hydrosolubility of PAIB-SAs by designing new salts. PAIB-SAs water-soluble salts showed similar antiproliferative efficacy and CYP1A1 bioactivation to their neutral counterparts. This important achievement will allow us to optimize our galenic formulations in view of further biopharmaceutical and pharmacodynamical studies. Citation Format: Vincent Ouellette, Atziri Corin Chavez Alvarez, Sébastien Fortin. Design, synthesis and biological evaluation of novel water-soluble salts of the antimitotic prodrugs 4-(3-alkyl-2-oxoimidazolidin-1-yl)-N-phenylbenzenesulfonamides selectively bioactivated by cytochrome p450 1A1 in breast cancer cells [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 284.