Apoptosis induction and modulation of P-glycoprotein mediated multidrug resistance by new macrocyclic lathyrane-type diterpenoids.

Abstract	The macrocyclic lathyrane diterpenes, latilagascenes D-F (1-3) and jolkinol B (4), were isolated from the methanol extract of Euphorbia lagascae, and evaluated for multidrug resistance reversing activity on mouse lymphoma cells. All compounds displayed very strong activity compared with that of the positive control, verapamil. The structure-activity relationship is discussed. The evaluation of compounds 1 and 4, and of latigascenes A-C (5-7), isolated from the same species, as apoptosis-inducers was also carried out. Compound 1 was the most active. Furthermore, in the model of combination chemotherapy, the interaction between the doxorubicine and latilagascene B (6) was studied in vitro, on human MDR1 gene transfected mouse lymphoma cells, showing that the type of interaction was synergistic. Latilagascenes D-F (1-3) are new compounds whose structures were established on the basis of spectroscopic methods, including 2D NMR experiments (COSY, HMQC, HMBC and NOESY).
Authors	Noélia Duarte, Andras Varga, Georg Cherepnev, Rita Radics, Joseph Molnár, Maria-José U Ferreira
Journal	Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 15 Issue 1 Pg. 546-54 (Jan 01 2007) ISSN: 0968-0896 [Print] England
PMID	17035027 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	ATP Binding Cassette Transporter, Subfamily B, Member 1 Diterpenes latilagascene A latilagascene D latilagascene E latilagascene F jolkinol B Doxorubicin Verapamil
Topics	ATP Binding Cassette Transporter, Subfamily B, Member 1 (drug effects) Animals Antineoplastic Combined Chemotherapy Protocols (pharmacology) Apoptosis (drug effects) Cell Line, Tumor Diterpenes (chemistry, isolation & purification, pharmacology) Doxorubicin (pharmacology) Drug Resistance, Multiple (drug effects) Drug Resistance, Neoplasm (drug effects) Drug Screening Assays, Antitumor Drug Synergism Euphorbia (chemistry) Genes, MDR (drug effects) Humans Lymphoma (drug therapy, genetics) Magnetic Resonance Spectroscopy Mice Molecular Conformation Sensitivity and Specificity Stereoisomerism Structure-Activity Relationship Verapamil (pharmacology)

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