Optimizing the macrocyclic diterpenic core toward the reversal of multidrug resistance in cancer

Rafael Baptista, Ricardo J. Ferreira, Daniel Jva Dos Santos, Miguel X. Fernandes, Maria-José U. Ferreira

Research output: Contribution to journalArticlepeer-review

11 Citations (SciVal)


Background: 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.

Conclusion: 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.

Original languageEnglish
Pages (from-to)629-645
Number of pages17
JournalFuture Medicinal Chemistry
Issue number6
Publication statusPublished - 22 Apr 2016
Externally publishedYes


  • ATP-Binding Cassette, Sub-Family B, Member 1
  • Animals
  • Antineoplastic Agents, Phytogenic
  • Cell Line, Tumor
  • Diterpenes
  • Drug Resistance, Multiple
  • Drug Resistance, Neoplasm
  • Drug Screening Assays, Antitumor
  • Euphorbia
  • Humans
  • Macrocyclic Compounds
  • Mice
  • Molecular Conformation
  • Quantitative Structure-Activity Relationship
  • Journal Article


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