Reversion of human Pgp-dependent multidrug resistance by new sesquiterpenes from Zinowiewia costaricensis.
In an intensive study of South American medicinal plants, herein we report the isolation, structure elucidation and biological activity of fourteen new and five known dihydro-beta-agarofuran sesquiterpenes from the leaves of Zinowiewia costaricensis (1-19). Their structures were determined by means of (1)H and (13)C NMR spectroscopic studies, including homonuclear and heteronuclear correlation experiments. The absolute configurations of the new compounds were determined by CD studies, chemical correlations or biogenetic grounds. All the natural compounds and derivative 20 have been tested on human MDR1-transfected NIH-3T3 cells, to determine their ability to revert the multidrug resistance phenotype due to P-glycoprotein overexpression. Six compounds from this series (1, 8, 11, 12, 13 and 14) showed similar effectiveness to the classical P-glycoprotein modulator verapamil when reversing resistance to daunorubicin, but it is up to sixteen times greater than that of verapamil when reversing resistance to vinblastine. The structure-activity relationships are discussed.
Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, Parque Tecnológico de Ciencias de la Salud, Avda. del Conocimiento s/n, 18100 Armilla, Granada, Spain.
Francisco
F
Muñoz-Martínez
Cristina R
CR
Mendoza
Isabel L
IL
Bazzocchi
Santiago
S
Castanys
Ignacio A
IA
Jiménez
Francisco
F
Gamarro
D016475:3T3 Cells; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects*; D000818:Animals; D003630:Daunorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D010946:Plants, Medicinal; D027824:Rosaceae; D012717:Sesquiterpenes / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014162:Transfection; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D012717:Sesquiterpenes; D014700:Verapamil; D003630:Daunorubicin