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.
Glionova Therapeutics , Västra Trädgårdsgatan 15, SE-111 53 Stockholm, Sweden.
Lars G J
LG
Hammarström
Robert K
RK
Harmel
OnTargetChemistry AB , Virdings Allé 18, SE-754 50 Uppsala, Sweden.
Mikael
M
Granath
OnTargetChemistry AB , Virdings Allé 18, SE-754 50 Uppsala, Sweden.
Rune
R
Ringom
Drug Discovery and Development Platform, Science for Life Laboratory, Department of Organic Chemistry, Stockholm University , Box 1030, SE-171 21 Solna, Sweden.
Ylva
Y
Gravenfors
Drug Discovery and Development Platform, Science for Life Laboratory, Department of Organic Chemistry, Stockholm University , Box 1030, SE-171 21 Solna, Sweden.
Katarina
K
Färnegårdh
SP Process Development , Forskargatan 20J, SE-151 36 Södertälje, Sweden.
Per H
PH
Svensson
SP Process Development , Forskargatan 20J, SE-151 36 Södertälje, Sweden.
David
D
Wennman
SP Process Development , Forskargatan 20J, SE-151 36 Södertälje, Sweden.
Göran
G
Lundin
SP Process Development , Forskargatan 20J, SE-151 36 Södertälje, Sweden.
Ylva
Y
Roddis
Satish S
SS
Kitambi
SP Process Development , Forskargatan 20J, SE-151 36 Södertälje, Sweden.
Alexandra
A
Bernlind
OnTargetChemistry AB , Virdings Allé 18, SE-754 50 Uppsala, Sweden.
Fredrik
F
Lehmann
Patrik
P
Ernfors
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D010880:Piperidines / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011804:Quinolines / Q000493:pharmacokinetics* / Q000494:pharmacology*; D013237:Stereoisomerism; D015027:Zebrafish
D000970:Antineoplastic Agents; D010880:Piperidines; D011804:Quinolines; C000588923:vacquinol-1