Pyridinyl 4-(2-oxoalkylimidazolidin-1-yl)benzenesulfonates and Their Hydrochloride Salts As Novel Water Soluble Antimitotic Prodrugs Bioactivated by Cytochrome P450 1A1 in Breast Cancer Cells

Overview

Journal RSC Med Chem

Publisher Royal Society of Chemistry

Specialty Chemistry

Date 2024 Sep 16

PMID 39281801

Authors

Vincent Ouellette

Chahrazed Bouzriba

Atziri Corin Chavez Alvarez

Quentin Bruxelles

Genevieve Hamel-Cote

Sebastien Fortin

Affiliations

Soon will be listed here.

Abstract

We developed first-in-class antimitotic prodrugs phenyl 4-(2-oxo-alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs) bioactivated by cytochrome P450 (CYP) 1A1 that are highly selective toward several breast cancer cells. However, they show sparingly water solubility. Therefore, we replaced their phenyl ring B with a substituted pyridinyl group preparing novel pyridinyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates (PYRAIB-SOs) and their hydrochloride salts. Our results evidence that PYRAIB-SO hydrochloride salts show higher water solubility compared to their neutral and PAIB-SO counterparts by up to 625-fold. PYRAIB-SOs with a nitrogen atom at position 3 of the pyridinyl ring exhibited strong antiproliferative activity (IC: 0.03-3.3 μM) and high selectivity (8->1250) toward sensitive CYP1A1-positive breast cancer cells and cells stably transfected with CYP1A1. They induce cell cycle arrest in the G2/M phase and disrupt microtubule dynamic assembly. Enzymatic assays confirmed that CYP1A1 metabolizes PYRAIB-SOs into their active form with hepatic half-lives (55-120 min) in rodent and human liver microsomes. Overall, this will allow to increase drug concentration for studies.

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