Conjugates of 3α-methoxyserrat-14-en-21β-ol (PJ-1) and 3β-methoxyserrat-14-en-21β-ol (PJ-2) as cancer chemopreventive agents

3α-Methoxyserrat-14-en-21β-ol (PJ-1) and 3β-methoxyserrat-14-en-21β-ol (PJ-2) were conjugated with well-known phenolic compounds, narigenin, hesperetin, genistein, and daidzein (1–8). Other conjugates of PJ-2–3,5-dihydroxy-4-methoxybenzoic acid (9), PJ-2–pyrogallol (10), and derivatives of PJ-1, PJ-2–3,3-dimethyl-succinates (11, 12), PJ-1, PJ-2–succinates (13, 14), PJ-2–glycine (15), PJ-2–piperidine acetic acid (16), and PJ-1 epoxy–3,3-dimethyl-succinate (17) were tested for their inhibitory effects on Epstein–Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). The inhibitory effects of 11 (IC50 = 251), 12 (IC50 = 248), and 17 (IC50 = 230 mol ratio/32 pmol/TPA), were 2-fold stronger than those of the other compounds such as oleanolic acid (IC50 = 449). Compounds 10, 11, and 17 inhibited mouse skin tumor promotion in an in vivo two-stage carcinogenesis model. The in vivo two-stage mouse-skin carcinogenesis test employed 7,12-dimethylbenz[a]anthracene (DMBA) as an initiator and TPA as a promoter.

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► PJ-1 and PJ-2 were modified and coupled with natural occurring phenolics to afford novel conjugates (1–17).
► Compounds 11, 12, and 17 showed stronger inhibitory effects on EBV-EA than other conjugates, in vitro.
► Moreover, 10 and 11 potently inhibited mouse skin tumor promotion in in vivo two-stage carcinogenesis model using mouse-skin papillomas induced by DMBA/TPA.