The Oncolytic Efficacy and in Vivo Pharmacokinetics of [2-(4-Chlorophenyl)quinolin-4-yl](piperidine-2-yl)methanol (Vacquinol-1) Are Governed by Distinct Stereochemical Features

Glioblastoma
remains an incurable brain cancer. Drugs developed
in the past 20 years have not improved the prognosis for patients,
necessitating the development of new treatments. We have previously
reported the therapeutic potential of the quinoline methanol Vacquinol-1
(1) that targets glioblastoma cells and induces cell
death by catastrophic vacuolization. Compound 1 is a
mixture of four stereoisomers due to the two adjacent stereogenic
centers in the molecule, complicating further development in the preclinical
setting. This work describes the isolation and characterization of
the individual isomers of 1 and shows that these display
stereospecific pharmacokinetic and pharmacodynamic features. In addition,
we present a stereoselective synthesis of the active isomers, providing
a basis for further development of this compound series into a novel
experimental therapeutic for glioblastoma.