title: Studies on propafenone-type modulators of multidrug-resistance IV1): synthesis and pharmacological activity of 5-hydroxy and 5-benzyloxy derivatives.
abstract: A series of 5-hydroxy and 5-benzyloxy analogs of the antiarrhythmic and multidrug resistance (MDR) modulating drug propafenone was synthesized and the MDR-modulating activity of the compounds was evaluated using a daunomycin efflux assay system. The key step of the synthesis is the selective reduction of the double bond in 1 without cleavage of the benzyl group thus leading to the phenol 3. Alkylation with epichlorohydrine followed by nucleophilic epoxide ring opening gave the benzylated target compounds 5a-d. Subsequent cleavage of the benzyl group gave the 5-hydroxy analogs 6a-d. Structure activity relationship studies showed, that the 5-hydroxy derivates 6a-d fit the log P/log potency correlation line previously established for a series of propafenone analogs. In contrast, all four 5-benzyloxy analogs 5a-d showed almost identical EC50 values, independent of their log P value.
authors.affiliation: Institute of Medical Chemistry, University of Vienna, Austria.
authors.forename: P
authors.initials: P
authors.lastname: Chiba
authors.forename: B
authors.initials: B
authors.lastname: Tell
authors.forename: W
authors.initials: W
authors.lastname: Jäger
authors.forename: E
authors.initials: E
authors.lastname: Richter
authors.forename: M
authors.initials: M
authors.lastname: Hitzler
authors.forename: G
authors.initials: G
authors.lastname: Ecker
mesh_terms: D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics; D002460:Cell Line; D003630:Daunorubicin / Q000493:pharmacokinetics; D004347:Drug Interactions; D018432:Drug Resistance, Multiple; D006801:Humans; D011405:Propafenone / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000889:Anti-Arrhythmia Agents; D000903:Antibiotics, Antineoplastic; D011405:Propafenone; D003630:Daunorubicin