Melanogenesis‐Inhibitory and Cytotoxic Activities of Limonoids, Alkaloids, and Phenolic Compounds from Phellodendron amurense Bark

Abstract

Four limonoids, 1 – 4, five alkaloids, 5 – 9, and four phenolic compounds, 10 – 13, were isolated from a MeOH extract of the bark of Phellodendron amurense (Rutaceae). Among these, compound 13 was new, and its structure was established as rel‐(1R,2R,3R)‐5‐hydroxy‐3‐(4‐hydroxy‐3‐methoxyphenyl)‐6‐methoxy‐1‐(methoxycarbonylmethyl)indane‐2‐carboxylic acid methyl ester (γ‐di(methyl ferulate)) based on the spectrometric analysis. Upon evaluation of compounds 1 – 13 against the melanogenesis in the B16 melanoma cells induced with α‐melanocyte‐stimulating hormone (α‐MSH), four compounds, limonin (1), noroxyhydrastinine (6), haplopine (7), and 4‐methoxy‐1‐methylquinolin‐2(1H)‐one (8), exhibited potent melanogenesis‐inhibitory activities with almost no toxicity to the cells. Western blot analysis revealed that compound 6 inhibited melanogenesis, at least in part, by inhibiting the expression of protein levels of tyrosinase, TRP‐1, and TRP‐2 in α‐MSH‐stimulated B16 melanoma cells. In addition, when compounds 1 – 13 were evaluated for their cytotoxic activities against leukemia (HL60), lung (A549), duodenum (AZ521), and breast (SK‐BR‐3) cancer cell lines, five compounds, berberine (5), 8, canthin‐6‐one (9), α‐di‐(methyl ferulate) (12), and 13, exhibited cytotoxicities against one or more cancer cell lines with IC50 values in the range of 2.6 – 90.0 μm. In particular, compound 5 exhibited strong cytotoxicity against AZ521 (IC50 2.6 μm) which was superior to that of the reference cisplatin (IC50 9.5 μm).