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 (<b>1</b>) that targets glioblastoma cells and induces cell death by catastrophic vacuolization. Compound <b>1</b> 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 <b>1</b> 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

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 (<b>1</b>) that targets glioblastoma cells and induces cell death by catastrophic vacuolization. Compound <b>1</b> 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 <b>1</b> 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

Col2a1-CreERT2/R26DTA mouse embryo E17.5

Col2a1-CreERT2/R26DTA mouse embryo injected with 2.5 mg tamoxifen at E12.5 and analysed at embryonic day E17.

(INV6b-C2)/(DEL-90-C2) E17.5

Inversion of the genomic region (INV6b-C2) and Deletion of the genomic region (DEL-90-C2) analyzed at embryonic day E17.

Heterozygous (DEL-90-C2) embryo E17.5

Heterozygous deletion of the genomic region (DEL-90-C2) analyzed at embryonic day E17.

Col2a1-CreERT2/R26DTA mouse embryo E15.5

Col2a1-CreERT2/R26DTA mouse embryo injected with 2.5 mg tamoxifen at E12.5 and analysed at embryonic day E15.

Six1, Six4, double knockout E18.5

Six1, Six4, double knockout analyzed at embryonic day E18.

Nkx2.2-Cre/Shhfloxed/floxed embryos E12.5

Nkx2.2-Cre/Shhfloxed/floxed mouse embryo analyzed at embryonic day E12.

mouse control embryo E17.5

mouse control embryo analyzed at embryonic day E17.

Shh hypomorph mouse embryo E17.5

Shh hypomorph mouse embryo analyzed at embryonic day E17.