title: Dregamine and tabernaemontanine derivatives as ABCB1 modulators on resistant cancer cells.
abstract: Dregamine (1) and tabernaemontanine (2), two epimeric monoterpene indole alkaloids isolated in large amount from the roots of the African plant Tabernaemontana elegans, were derivatized, yielding ten imine derivatives, as previously described (3-12). In the present study, aiming at increasing the pool of analogues for establishing structure-activity relationships (SAR), compounds 1 and 2 were further submitted to several chemical transformations, yielding thirteen new derivatives (13-25). Their structures were assigned by spectroscopic methods, including 1D and 2D NMR experiments. Compounds 1-25 were evaluated for their effects on the reversion of multidrug resistance (MDR) in cancer cells mediated by P-glycoprotein (P-gp/ABCB1), through combination of functional and chemosensitivity assays, using a human ABCB1-transfected mouse T-lymphoma cell model. SAR analysis showed that different substituents at C-3 and at the indole nitrogen led to different ABCB1 modulatory effects. When compared to the parent compounds, a remarkable enhancement in MDR reversal activity was found for derivatives sharing a new aromatic moiety. Thus, the strongest ability as MDR reversers, and a manifold activity when compared to verapamil, was found for compound 8, the epimeric compounds 9 and 10, and compound 15, bearing pyrazine, bromo-pyridine, and methoxybenzyloxycarbonyl moieties, respectively. In drug combination assays, all compounds tested were revealed to interact synergistically with doxorubicin. Collectively, the results indicate that some of these derivatives may be promising leads for overcoming MDR in cancer.
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal.
authors.forename: Angela
authors.initials: A
authors.lastname: Paterna
authors.affiliation: Department of Medical Microbiology and Immunobiology, Faculty of Medicine, University of Szeged, Dóm tér 10, H-6720 Szeged, Hungary.
authors.forename: Annamária
authors.initials: A
authors.lastname: Kincses
authors.affiliation: Department of Medical Microbiology and Immunobiology, Faculty of Medicine, University of Szeged, Dóm tér 10, H-6720 Szeged, Hungary.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Spengler
authors.affiliation: Centro de Estudos Moçambicanos e de Etnociências (CEMEC), Faculty of Natural Sciences and Mathematics, Pedagogical University, 21402161 Maputo, Mozambique.
authors.forename: Silva
authors.initials: S
authors.lastname: Mulhovo
authors.affiliation: Department of Medical Microbiology and Immunobiology, Faculty of Medicine, University of Szeged, Dóm tér 10, H-6720 Szeged, Hungary.
authors.forename: Joseph
authors.initials: J
authors.lastname: Molnár
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal. Electronic address: mjuferreira@ff.ulisboa.pt.
authors.forename: Maria-José U
authors.initials: MU
authors.lastname: Ferreira
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D026121:Indole Alkaloids / Q000494:pharmacology*; D016399:Lymphoma, T-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D039821:Monoterpenes / Q000494:pharmacology*; D010936:Plant Extracts / Q000494:pharmacology*; D018517:Plant Roots / Q000737:chemistry; D013329:Structure-Activity Relationship; D030014:Tabernaemontana / Q000737:chemistry
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D026121:Indole Alkaloids; D039821:Monoterpenes; D010936:Plant Extracts; C000617031:dregamine; C000617032:dregamine 4-methoxybenzylcarbazone; C570162:tabernaelegantine B; D004317:Doxorubicin
keywords: ABCB1; Apocynaceae; Monoterpene indole alkaloids; Multidrug resistance; P-glycoprotein; Tabernaemontana elegans