Twenty-eight compounds related to dehydrozingerone (1), isoeugenol (3), and 2-hydroxychalcone (4) were synthesized and evaluated in vitro against human tumor cell replication. Except for isoeugenol analogs 27−35, most compounds exhibited moderate or strong cytotoxic activity against KB, KB-VCR (a multi-drug resistant derivative), and A549 cell lines. In particular, chalcone 15 showed significant cytotoxic activity against the A549 cell line with an IC 50 value of 0.6 μg/mL. Furthermore, dehydrozingerone analog 11 and chalcones 16 and 17 showed significant and similar cytotoxic activity against both KB (IC 50 values of 2.0, 1.0, and 2.0 μg/mL, respectively) and KB-VCR (IC 50 values of 1.9, 1.0, and 2.0 μg/mL, respectively) cells, suggesting that they are not substrates for the p-glycoprotein drug efflux pump.Dehydrozingerone (1), isolated from ginger (Zingiber officinale), 1,2 is a well known phenolic natural product with anti-inflammatory, antioxidant, and antitumor promoting activities. 3 It is the structural half analog, as well as biosynthetic intermediate, 4 of curcumin (2), which possesses various remarkable bioactivities such as cytotoxic effects on cancer cell lines 5-8 and induction of apoptotic cell death in human promyelocytic leukemia HL-60 and human oral squamous carcinoma HSC-4 cells. 9 Dehydrozingerone (1), isoeugenol (3) and 2-hydroxychalcone (4) (Figure 1) have similar structures (acetyl, methyl and benzoyl, respectively, attached to a styrene skeleton). Both 3 and 4 are also prominent bioactive compounds. 10,11 Thus, we expected that 1-analogs should show a wide range of pharmacological activities. In spite of the interesting and simple structure of 1, we found only a few literature reports on analog syntheses and structure-activity relationships (SAR), 12,13 although we recently reported the cytotoxic effects of curcumin analogs. 7,14,15 It is known that the presence of a prenyl or geranyl group on flavonoids, including chalcones, can lead to a remarkable increase in bioactivity. 16,17 As dehydrozingerone (1) is structurally related to chalcones, the introduction of a prenyl or geranyl group on any position of 1 might also increase activity. In fact, most prenylflavonoids and geranylflavonoids as well as related compounds are known to have potent cytotoxic effects. 18-21 Furthermore, with respect to cancer research, a prenyl moiety has been demonstrated to be essential for chemopreventive
Esterification of glycyrrhetinic acid (GA) with dehydrozingerone (DZ) resulted in a novel cytotoxic GA-DZ conjugate. Based on this exciting finding, we conjugated eleven different DZ analogs with GA or other triterpenoids, including oleanoic acid (OA) or ursolic acid (UA). In an in vitro anti-cancer assay using nine different human tumor cell lines, most of the GA-DZ conjugates showed significant potency. Particularly, compounds 5, 29, and 30 showed significant cytotoxic effects against LN-Cap, 1A9, and KB cells with ED(50) values of 0.6, 0.8, and 0.9 microM, respectively. Similar conjugates between DZ and OA or UA were inactive suggesting that the GA component is critical for activity. Notably, although GA-DZ conjugates showed potent cytotoxic activity, the individual components (GA and DZ analogs) were inactive. Thus, GA-DZ conjugates are new chemical entities and represent interesting hits for anti-cancer drug discovery and development.
Dehydrozingerone analogs and related compounds were screened as potential antitumor promoters by using the in vitro short-term 12-O-tetradecanphorbol-13-acetate (TPA)-induced Epstein-Barr virus early antigen (EBV-EA) activation assay. Among 40 synthesized compounds, the prenylated analogs 16 and 34-36 showed the most significant and promising activity (100% inhibition of activation at 1×10 3 mol ratio/TPA, and 82-80%, 37-35%, 13-11% inhibition at 5×10 2 , 1×10 2 , 1×10 mol ratio/TPA, respectively) in this screening. Their activity profiles were comparable to that of the reference standard curcumin. While a prenyl moiety conferred potent chemopreventive activity, an extended prenyl unit such as a farnesyl moiety did not improve activity. Because in vitro inhibitory effects in this assay generally correlate well with in vivo inhibitory effects on tumor promotion, our results strongly suggested that prenylated 16 and 34-36 are likely to be promising antitumor promoters.
BackgroundA powdered ethanolic extract of Glycyrrhiza aspera root exhibits antimutagenic activity against N-methyl-N-nitrosourea (MNU) based on the Ames assay with Salmonella typhimurium TA1535. The aim of this study was to identify the antimutagenic components of the powdered ethanolic extract of G. aspera root.ResultsThe powdered ethanolic extract of G. aspera root was sequentially suspended in n-hexane, carbon tetrachloride, dichloromethane, ethyl acetate, and ethanol, and each solvent soluble fraction and the residue were assayed for antimutagenic activity against MNU in S. typhimurium TA1535. The dichloromethane soluble fraction exhibited the highest antimutagenicity and was fractionated several times by silica gel chromatography. The fraction with the highest antimutagenic activity was further purified using HPLC, and the fractions were assayed for antimutagenicity against MNU in S. typhimurium TA1535. Finally, five components with antimutagenic activity against MNU were identified as glyurallin A, glyasperin B, licoricidin, 1-methoxyphaseollin, and licoisoflavone B.ConclusionsThe five components were demonstrated to possess an antigenotoxic effect against carcinogenic MNU for the first time. It is important to prevent DNA damage by N-nitrosamines for cancer chemoprevention.Electronic supplementary materialThe online version of this article (doi:10.1186/s41021-016-0068-2) contains supplementary material, which is available to authorized users.
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