Aromatase Inhibitory Activity of Geranylated Coumarins, Mammeasins C and D, Isolated from the Flowers of <i>Mammea siamensis</i>

Abstract

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. 26) 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 ...

Geranylated Coumarins From Thai Medicinal Plant Mammea siamensis With Testosterone 5α-Reductase Inhibitory Activity

“…6-9 (102.9 mg), and Fr. 6-10 (96.5 mg)] as reported previously (Morikawa et al, 2012;Ninomiya et al, 2016). Fraction 6-4 (536.2 mg) was purified by HPLC [Cosmosil 5C 18 -MS-II, MeOH−1% aqueous AcOH (90:10, v/v)] to give kayeassamin I (1, 7.2 mg, 0.0032%) (Win et al, 2008b), mammeasin E (2, 16.5 mg, 0.0073%), and 35 (11.0 mg, 0.0049%) together with mammeasins A (4, 65.8 mg, 0.0293%) and B (5, 21.6 mg, 0.0096%), surangin B (12, 58.2 mg, 0.0259%), 17 (17.0 mg, 0.0076%), mammea A/AB (18, 10.7 mg, 0.0048%), and 19 (112.6 mg, 0.0501%).…”

“…5-5 (119.2 mg), and Fr. 5-6 (110.0 mg)] as reported previously (Ninomiya et al, 2016). Fraction 5-2 (517.0 mg) was purified by HPLC [Cosmosil 5C 18 -MS-II, MeOH−1% aqueous AcOH (85:15, v/v)] to give mammea A/AC cyclo F (35, 4.6 mg, 0.0019%) (Morel et al, 1999;Prachyawarakorn et al, 2000;Guilet et al, 2001) together with mammeas A/AA (17, 101.2 mg, 0.0418%), A/AC (19, 112.9 mg, 0.0466%), A/AA cyclo D (24, 2.7 mg, 0.0011%), E/BC cyclo D (29, 14.0 mg, 0.0058%), and E/BD cyclo D (30, 1.8 mg, 0.0015%) (Mahidol et al, 2002).…”

“…The flowers of Mammea siamensis were collected from the Nakhonsithammarat Province, Thailand, in September 2006, as described previously (Morikawa et al, 2012;Ninomiya et al, 2016). The plant material was identified by one of the authors (Y. P.).…”

“…is a small evergreen tree distributed in Thailand (locally called "Sarapi" or "Saraphi"), Laos, Cambodia, Vietnam, and Myanmar. The flowers of this plant have traditionally been used as a heart tonic, fever-lowering, and enhancement of appetite in Thailand (Morikawa et al, 2012;Tung et al, 2013;Ninomiya et al, 2016;Sangkaruk et al, 2017). Previous chemical studies on the flowers (Kaweetripob et al, 2000;Prachyawarakorn et al, 2000Prachyawarakorn et al, , 2006aMahidol et al, 2002;Morikawa et al, 2012;Ninomiya et al, 2016), seeds (Laphookhieo et al, 2006(Laphookhieo et al, , 2007, twigs (Poobrasert et al, 1998;Prachyawarakorn et al, 2006a,b), and bark (Ngo et al, 2010) of M. siamensis reported on the isolation of several coumarins and xanthones, etc.…”

“…The flowers of this plant have traditionally been used as a heart tonic, fever-lowering, and enhancement of appetite in Thailand (Morikawa et al, 2012;Tung et al, 2013;Ninomiya et al, 2016;Sangkaruk et al, 2017). Previous chemical studies on the flowers (Kaweetripob et al, 2000;Prachyawarakorn et al, 2000Prachyawarakorn et al, , 2006aMahidol et al, 2002;Morikawa et al, 2012;Ninomiya et al, 2016), seeds (Laphookhieo et al, 2006(Laphookhieo et al, , 2007, twigs (Poobrasert et al, 1998;Prachyawarakorn et al, 2006a,b), and bark (Ngo et al, 2010) of M. siamensis reported on the isolation of several coumarins and xanthones, etc. With regard to the biological studies on M. siamensis and its constituents, cytotoxicity, antiproliferative, and apoptotic effects against several tumor and cancer cell lines (Ngo et al, 2010;Tung et al, 2013;Noysang et al, 2014;Uto et al, 2016;Sangkaruk et al, 2017), suppressive effects on inducible nitric oxide synthase expression in RAW264.7 cells (Morikawa et al, 2012), and aromatase inhibitory activity (Ninomiya et al, 2016;Tanabe et al, 2017) have been reported.…”