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.

Hammarström LG, Harmel RK, Granath M, Ringom R, Gravenfors Y, Färnegårdh K, Svensson PH, Wennman D, Lundin G, Roddis Y, Kitambi SS, Bernlind A, Lehmann F, Ernfors P

J. Med. Chem. 59 (18) 8577-8592 [2016-09-22; online 2016-09-09]

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.

Chemical Biology Consortium Sweden (CBCS) [Collaborative]

Drug Discovery and Development (DDD) [Collaborative]

QC bibliography QC xrefs

PubMed 27607569

DOI 10.1021/acs.jmedchem.6b01009

Crossref 10.1021/acs.jmedchem.6b01009

10.1021/acs.jmedchem.6b01009

Laboratories for Chemical Biology at Karolinska Institutet (LCBKI)
Medicinal Chemistry – Hit2Lead