title: QSAR studies of macrocyclic diterpenes with P-glycoprotein inhibitory activity.
abstract: Multidrug resistance (MDR) represents a major limitation for cancer chemotherapy. There are several mechanisms of MDR but the most important is associated with P-glycoprotein (P-gp) overexpression. The development of modulators of P-gp that are able to re-establish drug sensitivity of resistant cells has been considered a promising approach for overcoming MDR. Macrocyclic lathyrane and jatrophane-type diterpenes from Euphorbia species were found to be strong MDR reversing agents. In this study we applied quantitative structure-activity relationship (QSAR) methodology in order to identify the most relevant molecular features of macrocyclic diterpenes with P-gp inhibitory activity and to determine which structural modifications can be performed to improve their activity. Using experimental biological data at two concentrations (4 and 40 μg/ml), we developed a QSAR model for a set of 51 bioactive diterpenic compounds which includes lathyrane and jatrophane-type diterpenes and another model just for jatrophanes. The cross-validation correlation values for all diterpenes QSAR models developed for biological activities at compound concentrations of 4 and 40 μg/ml were 0.758 and 0.729, respectively. Regarding the prediction ability, we get R²(pred) values of 0.765 and 0.534 for biological activities at compound concentrations of 4 and 40 μg/ml, respectively. Applying the cross-validation test to jatrophanes QSAR models, we obtained 0.680 and 0.787 for biological activities at compound concentrations of 4 and 40 μg/ml concentrations, respectively. For the same concentrations, the obtained R²(pred) values for jatrophanes models were 0.541 and 0.534, respectively. The obtained models were statistically valid and showed high prediction ability.
authors.affiliation: Centro de Química da Madeira, Centro de Competência de Ciências Exatas e da Engenharia, Universidade da Madeira, Campus da Penteada, 9000-390 Funchal, Portugal.
authors.forename: Inês J
authors.initials: IJ
authors.lastname: Sousa
authors.affiliation: Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.
authors.forename: Maria-José U
authors.initials: MJ
authors.lastname: Ferreira
authors.affiliation: Department of Medical Microbiology and Immunobiology, University of Szeged, H-6720 Szeged, Hungary.
authors.forename: Joseph
authors.initials: J
authors.lastname: Molnár
authors.affiliation: Centro de Química da Madeira, Centro de Competência de Ciências Exatas e da Engenharia, Universidade da Madeira, Campus da Penteada, 9000-390 Funchal, Portugal. Electronic address: mxf@uma.pt.
authors.forename: Miguel X
authors.initials: MX
authors.lastname: Fernandes
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology; D001185:Artificial Intelligence; D001692:Biological Transport / Q000187:drug effects; D045744:Cell Line, Tumor; D004224:Diterpenes / Q000737:chemistry* / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005456:Fluorescent Dyes / Q000378:metabolism; D006801:Humans; D047028:Macrocyclic Compounds / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009994:Osmolar Concentration; D021281:Quantitative Structure-Activity Relationship; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D020112:Rhodamine 123 / Q000378:metabolism
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000972:Antineoplastic Agents, Phytogenic; D004224:Diterpenes; D005456:Fluorescent Dyes; D047028:Macrocyclic Compounds; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; C530345:jatrophane; C530347:lathyrane; D020112:Rhodamine 123