Key words Mammea siamensis; mammeasin; aromatase inhibitor; geranylated coumarin; Calophyllaceae Mammea siamensis (MIQ.) T. ANDERS. is a species of flowering plant in the Calophyllaceae family and is widely distributed in Thailand, Laos, Cambodia, Vietnam, and Myanmar. The flowers of this plant have been used for preparing a heart tonic in Thai traditional medicine ("Sarapi" in Thai). [1][2][3][4][5][6][7][8][9][10] Several coumarins, [1][2][3][4][5][6][7] xanthones, 8,9) triterpenoids, 10) and steroids 10) have been isolated from the flowers, 1,2,6,7,10) seeds, 3,9) twigs, 4,8) and bark 5) of this plant. In the course of our characterization studies on bioactive constituents in Thai natural medicine, 1,[11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] we reported that the methanol extract of the flowers of M. siamensis and its coumarin constituents showed inhibitory effects on nitric oxide production in lipopolysaccharide-activated RAW264.7 cells.1) Further studies revealed that the methanol extract inhibited enzymatic activity against aromatase. Separation of the active constituents in the extract allowed us to isolate two new geranylated coumarins, mammeasins C (1) and D (2). This paper describes the isolation and structure elucidation of these new coumarins (1, 2) and the inhibitory effects of the coumarin constituents (1-26) on aromatase.
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Results and Discussion
Effects of the Methanol Extract from the Flowers of M. siamensis against Human Recombinant AromataseBreast cancer is one of the most common reasons for mortality in women. 26,27) Estrogens and estrogen receptors are well known to play an important role in the development and progression of hormone-dependent breast cancer; for this reason, estrogens and estrogen receptors are widely studied molecular targets. [28][29][30] The presence of high concentrations of estrogen in breast tissue increases the risk of developing breast cancer and the ability of immature breast tissue cells to strongly bind to carcinogens, decreasing their DNA repair capacity. 31,32) Aromatase, a CYP19 enzyme, is the rate-limiting enzyme in the conversion of testosterone and androstenedione to the estrogens, estrone and estradiol. [26][27][28][29][30][32][33][34] It is involved in the final step of the estrogen biosynthetic pathway and its selective inhibition will not affect the production of other steroids in the pathway. 32,[35][36][37] The source of estrogen production in breast cancer tissues is intratumoral aromatase, and thus, inhibition of aromatase may inhibit the growth stimulation effect of estrogens in breast cancer tissues. Therefore, aromatase is considered a useful therapeutic target in the treatment and prevention of estrogen-dependent breast cancer.
32)The dried flowers of M. siamensis (collected from Nakhonsithammarat Province, Thailand) were extracted with methanol under reflux (25.66% from the dried flowers). The methanol extract was partitioned into an EtOAc-H 2 O (1 : 1, v/v) mixture to furnish an EtOAc-soluble fraction (6.84%) and an aqueous ...
