Dihydro-β-agarofuran-Type Sesquiterpenoids from the Seeds of Celastrus virens and Their Multidrug Resistance Reversal Activity against the KB/VCR Cell Line

Abstract

Twenty-nine dihydro-β-agarofuran-type sesquiterpenoids, including 17 new and 12 known compounds, were obtained from the seeds of Celastrus virens. The structures of the new isolates were characterized by spectroscopic methods and Xray diffraction analysis. Among these, 20 sesquiterpenoids were evaluated for their multidrug resistance (MDR) reversal activity against the KB/VCR cell line. As a result, compounds 6 and 8 were found to exhibit MDR-reversal activity of more than 10-fold at a concentration of 2 μM, and the reversal fold (RF) ratios of compounds 19, 21, and 24 were >97.9 at a 20 μM nontoxic concentration level.E ven though it is one of the prime treatments for cancer, chemotherapy may not always be successful, due to the emergence of multidrug resistance (MDR), which may impede the effectiveness of the cancer treatment administered. MDR manifests as a cross-tolerance of multiple anticancer drugs irrespective of structure and activity. Extensive research on MDR has shown that overexpression of P-glycoprotein (P-gp) is the most crucial cause of reducing drug accumulation and increasing drug resistance in tumor cells. 1−3 A number of important anticancer drugs, such as paclitaxel (TAX), doxorubicin (DOX), and vincristine (VCR), are known substrates of P-gp. 4−6 P-gp inhibitors have been divided into four generations based on potency, selectivity, and drug−drug interaction potential. 7 The first generation P-gp inhibitors included verapamil (VRP) and cyclosporin A, 8,9 while devilapamil and valspodar belong to the second generation, 10,11 and the third generation includes tariquidar, zosuquidar, and various tyrosine kinase inhibitors. 12−16 Unfortunately, due to drug−drug interactions and unacceptable toxic and side effects, only a few of these P-gp inhibitors, such as Nuedexta, Restasis, Oraxol, and Kalydeco, have been approved for marketing. 17−19 The exploitation of the fourthgeneration P-gp inhibitors includes the screening of natural products and their purified bioactive constituents. 20,21 Dihydro-β-agarofuran sesquiterpenoids are characteristic metabolites of the family Celastraceae, 22 which exhibit a broad spectrum of biological activities, including cytotoxicity, 23 insecticidal, 24 antitumor-promoting, 25 MDR-reverting, 26 antitubercular, 27 neuroprotective, 28 immunosuppressive, 29 anti-HIV, 30 anti-inflammatory, 31 and lifespan-extending effects. 32 Celastrus virens (Wang et Tang) C. Y. Chent et T. C. Kao (Celastraceae), an endemic plant of mainland China, is distributed mainly in Yunnan, Guangdong, and several other provinces. 33 To date, preliminary chemical investigations of the leaves and root bark of C. virens have led to the identification of several triterpenoid, steroid, and fatty acid constituents. 34 Herein, we report the isolation and structural characterization of 17 new and 12 known dihydro-β-agarofuran-type sesquiterpenoids from the seeds of C. virens, as well as the bioassay results of 20 of the more abundant isolates obtained for their MDR-reverting activity against the KB/V...

Computational methods and points for attention in absolute configuration determination

“…The bioactive metabolite phyllostin (31) was isolated from Phyllosticta cirsii fungus (Evidente et al, 2008); its relative configuration was established as (3R,4aS,8R,8aS) by NMR and X-ray analyses (Tuzi et al, 2010) while its AC remained unknown. Total synthesis (Muralidharam et al, 1990) and the ECD exciton chirality method (Isogai et al, 1985;Mu et al, 2021) permitted the determination of the AC of its C8 epimer. The ORD study gave the same conclusion: (-)-(3S,4aR,8S,8R)-31 (Figure 5B) (Mazzeo et al, 2013).…”