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.
Multidrug resistance (MDR) is one of the main challenges in the chemotherapy of cancer, malaria, and other important diseases. Here, we report the inhibitory activity of a series of 76 dihydro-beta-agarofuran sesquiterpenes, tested on NIH-3T3 cells expressing the human P-glycoprotein (Pgp) multidrug transporter, to establish quantitative comparisons of their respective abilities to block the drug transport activity. The screening was performed on the basis of the ability of sesquiterpenes to modulate the intracellular accumulation of the classical Pgp substrate daunorubicin. To understand the structural basis for inhibitory activity and guide the design of more potent Pgp inhibitors, we have performed a three-dimensional quantitative structure-activity relationship model using the comparative molecular similarity indices analysis (CoMSIA). The most salient features of these requirements are in the region of the substituents at the C-2, C-3, and C-8 positions, which seem to be critical for determining the overall effectiveness of sesquiterpenes as Pgp inhibitors.
Seven new sesquiterpenes (1-7) with a 'dihydro-beta-agarofuran' (= 5,11-epoxy-5beta,10alpha-eudesmane) skeleton were isolated from Crossopetalum tonduzii. Their structures were elucidated spectroscopically, especially by means of homo- and heteronuclear NMR correlation (COSY, ROESY, HSQC, and HMBC). The absolute configurations of the new compounds were determined by circular dichroism (CD) studies and by chemical correlations via the derivatives 8-11. The new compounds showed moderate antitumor-promoting effects with respect to the activation of the Epstein-Barr virus early antigen (EBV-EA).
Five dihydro‐β‐agarofuran sesquiterpenes, chiapene A (Ia), chiapene B (Ib), chiapene C (II), chiapene D (III), and chiapene E (IV) are isolated from Maytenus chiapensis and tested for their inhibitory effects on Epstein—Barr virus early antigen activation.
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