Synthesis and pharmacological activity of the stereoisomers of GP-88, a propafenone-type modulator of multidrug resistance.
All four stereoisomers of the propafenone-type MDR-modulator GP-88 (1) were synthesized using a combined approach with chiral pool building blocks and an acetalic protective group, which allows not only diastereoseparation but also assignment of absolute configuration via NMR spectroscopy. Those isomers with different configuration on the center of chirality in the propanolamine side chain showed statistically different PGP-inhibitory activity. Generally, the (R)-configured isomers were by a factor of nearby two higher active than the (S)-isomers. No differences in activity were observed for isomers with different configuration on the benzylic center of chirality.
Chiba
P
P
Institute of Pharmaceutical Chemistry, University of Vienna, Wien, Austria.
Rebitzer
S
S
Richter
E
E
Hitzler
M
M
Ecker
G
G
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D003630:Daunorubicin / Q000493:pharmacokinetics; D018432:Drug Resistance, Multiple; D006801:Humans; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D010647:Phenyl Ethers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011405:Propafenone / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020005:Propanols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; C116626:GP-88, propafenone-type MDR-modulator; D007202:Indicators and Reagents; D010647:Phenyl Ethers; D020005:Propanols; D011405:Propafenone; D003630:Daunorubicin