Lead optimization-hit expansion of new asymmetrical pyridinium/quinolinium compounds as choline kinase α1 inhibitors. (24th July 2018) - Rubbini, Gianluca
Aim: Choline kinase α inhibitors represent one of the newest classes of cytotoxic drugs for cancer treatment, since aberrant choline metabolism is a characteristic shared by many human cancers.Results: Here, we present a new class of asymmetrical pyridinium/quinolinium derivatives developed and designed based on drug optimization.Conclusion: Among all compounds described here, compound8, bearing a 7-chloro-4N-methyl-p-chloroaniline quinolinium moiety, exhibited the greatest inhibitory activity at the enzyme (IC50 = 0.29 μM) and antiproliferative activity in cellular assays (GI50 = 0.29–0.92 μM). Specifically, compound8 strongly induces a cell-cycle arrest in G1 phase, but it does not significantly induce apoptosis while causing senescence in the MDA-MB-231 cell line. Graphical abstracts: