Optimizing the macrocyclic diterpenic core toward the reversal of multidrug resistance in cancer.
From a dataset obtained by chemical derivatization of a macrocyclic diterpenic scaffold, in silico approaches identified which structural features correlate with experimental modulation of P-gp activity. Results/methodology: Ninety-two percent of the strongest MDR modulators were positively identified within the dataset by virtual screening. Quantitative structure-activity relationships models with high robustness and predictability were obtained for both MDR1-transfected L5178Y mouse lymphoma T-cells (q(2) 0.875, R(2) pred 0.921) and human colon adenocarcinoma (q(2) 0.820, R(2) pred 0.951) cell lines. A new pharmacophoric model suggests that charge distribution within the molecule is important for biological activity.



For the studied diterpenes, the conformation of the macrocyclic scaffold and its substitution pattern are the main determinants for the biological activity, being related with steric and electrostatic factors.
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.
Rafael
R
Baptista
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.
Ricardo J
RJ
Ferreira
REQUIMTE, Department of Chemistry & Biochemistry, Faculty of Sciences, University of Porto, Rua do Campo Alegre, 4169-007 Porto, Portugal.
Daniel Jva
DJ
Dos Santos
Instituto Universitario de Tecnologías Biomédicas (ITB), Universidad de La Laguna, 38200, La Laguna, Spain.
Miguel X
MX
Fernandes
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.
Maria-José U
MJ
Ferreira
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D004224:Diterpenes / Q000737:chemistry* / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D028481:Euphorbia / Q000737:chemistry; D006801:Humans; D047028:Macrocyclic Compounds / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D008968:Molecular Conformation; D021281:Quantitative Structure-Activity Relationship
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D004224:Diterpenes; D047028:Macrocyclic Compounds
P-gp; efflux modulation; macrocyclic diterpenes; multidrug resistance; pharmacophores; structure–activity relationships; virtual screening