Synergistic interaction between p-glycoprotein modulators and epirubicine on resistant cancer cells.

Abstract

The macrocyclic lathyrane diterpene latilagascene B, previously isolated from Euphorbia lagascae, was acylated to afford three new diterpene esters, latilagascenes G (1), H (2), and I (3), whose structures were assigned by spectroscopic methods. These acyl derivatives, and the macrocyclic diterpenes of the jatrophane-type, tuckeyanols A (4) and B (5), and euphotuckeyanol (6), isolated from Euphorbia tuckeyana, were tested for P-gp modulating properties on human MDR1 gene-transfected and parental L5178 mouse lymphoma cell lines. All the compounds displayed very strong activity. The molecular orbital energies (HOMO and LUMO) of diterpenes 1-6 and 7-13, previously isolated, have also been calculated in order to estimate their probable charge transfer interactions with P-gp. Structure-activity relationships (SAR) are discussed. Furthermore, compounds (1-6) were assayed, in vitro, for their antiproliferative effects in combination with epirubicine and all of them synergistically enhance the effect of the antitumor drug.

• Authors: Noélia Duarte, Anett Járdánházy, Joseph Molnár, Andreas Hilgeroth, Maria-José U Ferreira
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 16 Issue 20 Pg. 9323-30 (Oct 15 2008) ISSN: 1464-3391 [Electronic] England
• PMID: 18824363 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Epirubicin

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors, metabolism)
• Animals
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Drug Synergism
• Epirubicin (chemistry, pharmacology)
• Humans
• Magnetic Resonance Spectroscopy
• Mice
• Molecular Structure
• Structure-Activity Relationship