Design, synthesis and biological evaluation of <i>N</i>-pyridinyl ureidobenzenesulfonates and their hydrochloride salts as novel water-soluble dihydroorotate dehydrogenase inhibitors inducing differentiation of acute myeloid leukemia cells.

ABSTRACT: A series of novel dihydroorotate dehydrogenase (DHODH) inhibitors designated as N-pyridinyl ureidobenzenesulfonates (PYRUB-SOs) and their hydrochloride salts were designed, synthesized, and evaluated for their biological activity. PYRUB-SOs exhibit antiproliferative activity at submicromolar to low micromolar concentrations on various cancer cell lines, including notably acute myeloid leukemia (AML) MOLM-13, THP-1 and HL-60 cells. Moreover, PYRUB-SO salts display higher aqueous solubility (up to 10 times) compared to their neutral counterparts. Additionally, the most potent PYRUB-SOs and their salts effectively arrest the progression of the cell cycle in the S-phase and induce the phosphorylation of histone H2AX, an indicator of replicative stress. They also inhibit DHDOH activity (

SUBMITTER: Ouellette V 

PROVIDER: S-EPMC12302228 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature