title: Colon adenocarcinoma multidrug resistance reverted by Euphorbia diterpenes: structure-activity relationships and pharmacophore modeling.
abstract: Multidrug resistance (MDR) is a limiting step on the success of cancer chemotherapy. The drug efflux mediated by P-gp (Pglycoprotein) is one of the best studied mechanisms of MDR. This paper focuses on the inhibitory P-gp efflux activity, pharmacophore modeling and structure-activity relationships studies of sixteen macrocyclic diterpenes and polycyclic derivatives obtained from Euphorbia species. The MDR human colon adenocarcinoma cells (COLO 320 MDR) overexpressing P-gp were used as the biological model to screen for P-gp dependent efflux inhibitors. Most of the compounds showed potential as MDR reversal agents. Combined analysis of two different statistic algorithms, K-means clustering and Principal Component Analysis discriminated two clusters and showed a strong correlation between log P and MDR reversal activity for compounds 1-5. The most effective compounds (1-4 and 11-12) were tested in combination with doxorubicin and all potentiated its activity lowering the ID50. Pharmacophore modeling allowed the definition of an aromatic moiety as an additional feature to a previous published P-gp pharmacophore, creating a new five-point pharmacophore with enhanced selectivity for the most active compounds of the present study. Docking results also show the importance of an aromatic moiety, positively identifying the most relevant residues that can be linked to an inhibitory activity increase.
authors.affiliation: Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculdade de Farmacia, Universidade de Lisboa, Av. Prof. Gama Pinto 1649-003, Lisboa, Portugal. mjuferreira@ff.ul.pt
authors.forename: Mariana
authors.initials: M
authors.lastname: Reis
authors.forename: Ricardo J
authors.initials: RJ
authors.lastname: Ferreira
authors.forename: Julianna
authors.initials: J
authors.lastname: Serly
authors.forename: Noélia
authors.initials: N
authors.lastname: Duarte
authors.forename: Ana M
authors.initials: AM
authors.lastname: Madureira
authors.forename: Daniel J V A
authors.initials: DJ
authors.lastname: Santos
authors.forename: Joséph
authors.initials: J
authors.lastname: Molnár
authors.forename: Maria-José U
authors.initials: MJ
authors.lastname: Ferreira
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004224:Diterpenes / Q000737:chemistry* / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D028481:Euphorbia / Q000737:chemistry*; D006801:Humans; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship; D015854:Up-Regulation
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D004224:Diterpenes; D004317:Doxorubicin