Apoptosis induction and modulation of P-glycoprotein mediated multidrug resistance by new macrocyclic lathyrane-type diterpenoids.
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).
Duarte
Noélia
N
CECF, Faculty of Pharmacy, University of Lisbon, Av. das Forças Armadas, 1600-083 Lisbon, Portugal.
Varga
Andras
A
Cherepnev
Georg
G
Radics
Rita
R
Molnár
Joseph
J
Ferreira
Maria-José U
MJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004224:Diterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D028481:Euphorbia / Q000737:chemistry; D019450:Genes, MDR / Q000187:drug effects; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy* / Q000235:genetics; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008968:Molecular Conformation; D012680:Sensitivity and Specificity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004224:Diterpenes; C517135:latilagascene A; C517133:latilagascene D; C517132:latilagascene E; C517134:latilagascene F; C042195:jolkinol B; D004317:Doxorubicin; D014700:Verapamil