In a search for revertants of multidrug-resistance in cancer cells, a novel (1) and two known (2, 3) sesquiterpene esters were isolated from the root of Celastrus orbiculatus. The structure of 1 was elucidated as 1 ,2 -diacetoxy-6R,9R-bis(benzoyloxy)dihydro--agarofuran. Compounds 1-3 partially or completely reversed resistance to adriamycin, vinblastine, and paclitaxel of multidrug-resistant KB-V1 and MCF7/ADR cells. One of the major problems of cancer chemotherapy is intrinsic or acquired

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... drug resistance (MDR). A primary mechanism of MDR is attributed to the overexpression of P-glycoprotein (P-gp) in the plasma membrane of resistant cells where the P-gp acts as an energy-dependent efflux pump, reducing intracellular accumulation of anticancer drugs. 1 A number of drugs, such as, calcium channel blockers, calmodulin inhibitors, and indole alkaloids, are known to reverse MDR by competing with anticancer drugs for binding to P-gp. 2 However, they have not been proven clinically useful yet. For example, verapamil, the most extensively studied MDR reversing agent, induces cardiovascular toxicity at the concentration that it reverses MDR. 2 Thus, there remains a need to develop new classes of MDR reversing agents with less toxicity to the host. Celastrus orbiculatus Thunb. (Celastraceae) has been used as a treatment for rheumatoid arthritis and bacterial infection in folk medicine. 3 Several sesquiterpene esters were reported as chemical constituents of C. orbiculatus seed oil. 4,5 The family of Celastraceae has been known to produce various dihydro--agarofuran derivatives, 6 some of which exhibited insecticidal or insect antifeedant activities and antitumor activities. 7,8 Recently, the antitumor-promoting activity of dihydro--agarofuran compounds has also been reported. 9 In our search for MDR reversing agents from natural product, the MeOH extract of the roots of C. orbiculatus was found to strongly potentiate the activities of anticancer drugs in multidrug-resistant KB-V1 cells at nontoxic concentrations. Bioactivity-guided fractionation of the MeOH extract of the plant, followed by repeated column chromatography, led to isolation of a novel sesquiterpene ester 1, and two known compounds, celafolin A-1 (2) and celorbicol ester (3). Compounds 1, 2, and 3 reversed resistance to adriamycin (ADR), vinblastine (VLB), and paclitaxel (TX) of human multidrug-resistant cell lines, KB-V1 and MCF7/ADR, partially or completely. The structure elucidation of a novel sesquiterpene ester 1 along with the effect of the isolates on the MDR is described. The IR spectrum of 1 showed a carbonyl absorption at 1716 cm -1 , and the UV spectrum showed the presence of an aromatic moiety (231 and 275 nm). The 13 C NMR spectrum revealed four methyls, two methylenes, six methines, three quaternary carbons, and four ester carbonyl carbons. The 1 H NMR spectrum revealed the presence of two acetyl groups (δ 1.62 and 2.02), two benzoyl esters [δ 8.06 (4H, d, J ) 7.5 Hz), 7.49 (2H, t, J ) 7.5 Hz), 7.44 (2H, t, J ) 7.5 Hz), 7.62 (1H, t, J ) 7.5 Hz), 7.56 (1H, t, J ) 7.5 Hz)], three tertiary methyl groups (δ 1.53, 1.44, 1.45), and one secondary methyl group (δ 1.25). The signals observed at δ 5.62 (2H, br s), 5.66 (1H, s), and 5.02 (1H, d, J ) 6.8 Hz) were assigned to the four protons attached to the carbons bearing secondary esters. These facts agreed well with the molecular formula, C 33 H 38 O 9 , which was supported by HRMS data. The NMR spectra of 1 were almost identical with those of 4, triptogelin C-2. 10