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

Abstract

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.

Cell and small animal models for phenotypic drug discovery

“…The overall goal is to identify a lead compound that rescues or ameliorates the disease phenotype without necessarily knowing the target or mechanism (Figure 1). Such screens have been successfully performed for identifying leads selectively killing cancer cells3 or alleviating various disorders 4–7. This approach allows new targets and signaling pathways to be identified3 and, most importantly, decreases false-positive hits.…”

“…Such screens have been successfully performed for identifying leads selectively killing cancer cells3 or alleviating various disorders 4–7. This approach allows new targets and signaling pathways to be identified3 and, most importantly, decreases false-positive hits. PDD screens also allow the possibility to identify cell type-specific features.…”

“…PDD screens also allow the possibility to identify cell type-specific features. A recent study using the PDD approach identified acquired a vulnerability of cancer cells to macropinocytosis 3. The entire PDD approach in this study was designed with the concept that oncogenic transformation results in the cell acquiring new characteristic features that may not necessarily be associated with its pathophysiology.…”

Institutional Profile: the National Swedish Academic Drug Discovery & Development Platform at Scilifelab

“…Services from the Hit2Lead facility is the quality control of the initial active compounds and further design and synthesis of compounds suitable for drug discovery [31,32]. Quality control of the initial data during hit-lead generation includes verification of the hit compounds identified during the lead generation activities.…”

(5-Chloroquinolin-8-yl)-2-fluorobenzoate. The Halogen Bond as a Structure Director

“…The N-heterocycles such as quinolines are important starting pharmacophores for preparing therapeutic agents with a wide spectrum of biological activities, such as antimalarial [1], antiviral [2], antibacterial [3], anti-inflammatory [4], and mainly antitumor [5][6][7] activities. The incorporation of diverse halogen atoms into their structures, especially chlorine and fluorine, can lead to important changes in their chemical, pharmacological and physical properties [8][9][10].…”