title: Synthesis and ABCG2 inhibitory activity of novel fumitremorgin C analogs--specificity and structure activity correlations.
abstract: The Ko family of fumitremorgin C analogs are potent and selective ABCG2 inhibitors. However, the most potent Ko compounds carry an ester linkage in their side-chain that makes them chemically and metabolically less stable. We have synthesized 16 tricyclic and 28 tetracyclic novel analogs devoid of ester linkages and tested them for ABCG2 inhibition potency and specificity. Unlike in the tricyclic analog group, potent ABCG2 inhibitory compounds were found among the tetracyclic analogs. The most potent compounds carried the 3S,6S,12aS configuration. We observed a marked stereospecificity as compounds with the 3S,6S,12aS configuration were at least 18-fold more potent inhibitors than their diastereoisomeric pairs with a 3S,6R,12aS configuration. This stereospecificity was not observed in ABCB1 and ABCC1 inhibition. Therefore, a single chiral center confers specificity for ABCG2 over ABCB1 and ABCC1. This is quite unexpected considering the large multivalent drug binding site these transporters harbor.
authors.affiliation: Department of Medical Chemistry, Faculty of General Medicine, University of Szeged, 6720 Szeged Dóm tér 8., Hungary.
authors.forename: Orsolya
authors.initials: O
authors.lastname: Szolomajer-Csikós
authors.forename: Erzsébet
authors.initials: E
authors.lastname: Beéry
authors.forename: Levente
authors.initials: L
authors.lastname: Kósa
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Rajnai
authors.forename: Márton
authors.initials: M
authors.lastname: Jani
authors.forename: Anasztázia
authors.initials: A
authors.lastname: Hetényi
authors.forename: Katalin Tauber
authors.initials: KT
authors.lastname: Jakab
authors.forename: Péter
authors.initials: P
authors.lastname: Krajcsi
authors.forename: Gábor K
authors.initials: GK
authors.lastname: Toth
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D007211:Indoles; D009363:Neoplasm Proteins; C010522:tryptoquivaline