title: Triterpenoids from Momordica balsamina: Reversal of ABCB1-mediated multidrug resistance.
abstract: The ability as P-glycoprotein (P-gp, ABCB1) modulators of thirty (1-30) triterpenoids of the cucurbitane-type was evaluated on human L5178 mouse T-lymphoma cell line transfected with the human MDR1 gene, through the rhodamine-123 exclusion assay. Compounds (1-26, and 29, 30) were previously obtained from the African medicinal plant Momordica balsamina, through both isolation (1-15) and molecular derivatization (16-26 and 29, 30). Compounds 27-28 are two new karavilagenin C (34) derivatives having succinic acid moieties. Apart from 4, 6, 8, 10 and 11, most of the isolated compounds (1-15) displayed strong MDR reversing activity in a dose-dependent mode, exhibiting a many-fold activity when compared with verapamil, used as positive control. At the lowest concentration tested, compounds 2 and 7 were the most active. However, a decrease of activity was found for the acyl derivatives (16-30). In a chemosensitivity assay, the MDR reversing activity of some of the most active compounds (1-3, 5, 7, 12-15) was further assessed on the same cell model. All the tested compounds, excepting 15, corroborated the results of the transport assay, revealing to synergistically interact with doxorubicin. Structure-activity relationship studies, taking into account previous results, showed that different substitution patterns, at both the tetracyclic nucleus and the side chain, play important role in ABCB1 reversal activity. An optimal lipophilicity was also recognized.
authors: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal. Electronic address: catiar@uatlantica.pt.
authors: Cátia
authors: C
authors: Ramalhete
authors: Centro de Estudos Moçambicanos e de Etnociências, Faculty of Natural Sciences and Mathematics, Pedagogical University, 21402161 Maputo, Mozambique.
authors: Silva
authors: S
authors: Mulhovo
authors: Department of Medical Microbiology and Immunobiology, Faculty of Medicine, University of Szeged, Dóm tér 10, H-6720 Szeged, Hungary.
authors: Joseph
authors: J
authors: Molnar
authors: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal. Electronic address: mjuferreira@ff.ulisboa.pt.
authors: Maria-José U
authors: MU
authors: Ferreira
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D008968:Molecular Conformation; D029775:Momordica / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014315:Triterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000972:Antineoplastic Agents, Phytogenic; D014315:Triterpenes
keywords: ABCB1; Cucurbitane; MDR reversers; Momordica balsamina; Multidrug resistance; P-glycoprotein; Triterpenes