Reversion of Human Pgp-Dependent Multidrug Resistance by New Sesquiterpenes from Zinowiewia costaricensis

Abstract

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.

Dihydro‐β‐agarofurans from the Australian Endemic Rainforest Plant Denhamia pittosporoides Inhibit Leucine Transport in Prostate Cancer Cells

“…Comparison of the ECD spectra (Figure ) and specific rotations of compounds 1 and 3 indicated that both compounds had the same absolute configuration. Consequently, the structure of compound 3 was identified as (1 R ,2 S ,4 R ,5 S ,6 R ,7 R ,9 S ,10 S )‐1,2,6,15‐tetraacetoxy‐9‐benzoyloxy‐8‐oxodihydro‐ β ‐agarofuran, in agreement with the absolute configuration reported in the original paper …”

“…The chemical structures of the known dihydro‐ β ‐agarofurans, 1 α ,2 α ,6 β ,15‐tetraacetoxy‐9 α ‐benzoyloxy‐8‐oxodihydro‐ β ‐agarofuran ( 3 ), wilforsinine F ( 4 ), 1 α ,2 α ,6 β ,8 α ,15‐pentaacetoxy‐9 α ‐benzoyloxydihydro‐ β ‐agarofuran ( 5 ), and 1 α ,2 α ,6 β ,15‐tetraacetoxy‐9 β ‐benzoyloxydihydro‐ β ‐agarofuran ( 6 ), were determined by comparison of the NMR, MS, and specific rotation data with literature values. Herein, we also include the electronic circular dichroism (ECD) data of known compounds 3 – 6 , which were not reported in the original publications.…”

A New Dihydroagarofuranoid Sesquiterpene from Microtropis fokienensis with Antituberculosis Activity

“…The CD spectrum of 1 showed a split curve with a first Cotton effect at 236.7 nm (De ¼ À 13.9), and a second one at 220.8 nm (De ¼ þ 5.33), very similar to that of (1R,2S,4R,5S,6R,7R,8S,9R,10S)-8,9-dibenzoyloxy-1,2,6,15-tetraacetoxy-dihydro-bagarofuran [11], indicating identical absolute configurations.…”

Strategies to Overcome or Circumvent P-Glycoprotein Mediated Multidrug Resistance

“…A large number of active compounds have been identified, including Stemona curtisii root extract [34], Diosmin which is a flavonoid glycoside in citrus fruits [35], Triterpenoids from the Red Sea sponge Siphonochalina siphonella [36]. Sesquiterpenes from Zinowiewia costaricensis [37], extracts of monoterpenoids contained in Zanthoxyli Fructus [38], Kendarimide A which is a novel peptide from a marine sponge of Haliclonasp [39], and lathyrane diterpenoids from the seeds of the caper spurge (E. lathyris) [40] are also under development. However, the approach seems rather similar to that of serendipity and screening from the available compounds.…”