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

J Med Chem. 2016 Sep 22;59(18):8577-92. doi: 10.1021/acs.jmedchem.6b01009.

Lars G J Hammarström ¹, Robert K Harmel, Mikael Granath ², Rune Ringom ², Ylva Gravenfors ³, Katarina Färnegårdh ³, Per H Svensson ⁴, David Wennman ⁴, Göran Lundin ⁴, Ylva Roddis ⁴, Satish S Kitambi, Alexandra Bernlind ⁴, Fredrik Lehmann ², Patrik Ernfors

Affiliations

1 Glionova Therapeutics , Västra Trädgårdsgatan 15, SE-111 53 Stockholm, Sweden.
2 OnTargetChemistry AB , Virdings Allé 18, SE-754 50 Uppsala, Sweden.
3 Drug Discovery and Development Platform, Science for Life Laboratory, Department of Organic Chemistry, Stockholm University , Box 1030, SE-171 21 Solna, Sweden.
4 SP Process Development , Forskargatan 20J, SE-151 36 Södertälje, Sweden.

PMID: 27607569 DOI: 10.1021/acs.jmedchem.6b01009

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.

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