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 diaster eoseparation but also assignment of absolute configuration via NMR spe ctroscopy. Those isomers with different configuration on the center of chirality in the propanolamine side chain showed statistically differ ent PGP-inhibitory activity. Generally, the (R)-configured isomers wer e by a factor of nearby two higher active than the (S)-isomers. No dif ferences in activity were observed for isomers with different configur ation on the benzylic center of chirality. (C) 1998 Elsevier Science L td. All rights reserved.