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Journal of Chemistry, Vol 45 (Special issue), P 111 - 121, 2007 REVIEW: STUDY ON BENZOPYRANS AND OTHER ISOLATED COMPOUNDS FROM MALLOTUS APELTA Received 15 October 2007 NGUYEN HOAI NAM , NGUYEN HAI DANG1, PHAN VAN KIEM1, LUU VAN CHINH1, PHAN THI BINH2, LA DINH MOI3, AND CHAU VAN MINH1 Institute of Natural Products Chemistry, VAST Institute of Chemistry, VAST Institute of Ecology and Biological Reources, VAST SUMMARY During the last decades, dozens of compounds have been isolated from Mallotus apelta These compounds which are classified under the categories viz terpenoids, steroids, flavonoids, cumarino-lignoids, cembrane diterpenoids, and benzopyranoids They were known to exhibit interesting biological activities The phytochemical investigations revealed that malloapelta B which was the major component of M apelta, showed strong NF- B and NFAT transcription factor inhibitory and cytotoxic activities Numerous studies on the synthesis of some derivatives of malloapelta B were carried out This paper reviews the progress on the isolation, structure elucidation and biological activities of secondary metabolites from M apelta, especially, the new structures of benzopyrans Chemical modifications of malloapelta B and structure-activity relationship were also discussed Keywords: Mallotus, mallotus apelta, benzopyran, malloapelta b I - INTRODUCTION Ba bet (Mallotus) genus comprises about 140 species, distributed in regions from South to South-East Asia, such as in Malaysian region (about 75 species), in China (about 40 species) and in Vietnam (about 40 species) [1] Mallotus species have been used in traditional medicine to treat various diseases For example Mallotus apelta has been used to treat chronic hepatitis, hepatalgia, enteritis, diarrhea, lymphopathy, Mallotus repandus has been used to treat influenza and fever, Mallotus barbatus has been used in both Vietnamese and Chinese folk medicine as antipyretic, diuretic, relieving pain and curing cholera, Mallotus macrostachyus has been used to treat wounds and pimple, Mallotus paniculatus has been used to treat traumatic injuries and swelling [2, 3] To improve the efficiency of using Mallotus species in traditional medicine, it is neccesary to know their chemical components and pharmaceutical activity However, herbal medicine and its extracts contain hundreds of unknown components, which are often only present in a low amount Moreover, variability usually exists within the same herbal materials [4, 5] The chemical components may vary depending on harvest seasons, plant origins, drying processes and other factors [6] Therefore, investigation on the chemical components of the plant is important for pharmaceutical studies Since the 111 last decades the scientists have been searching for the chemical components, pharmaceutical activity of Mallotus species and synthesizing derivatives from isolated compounds from these species The purpose of this review is to present an overview of the studies on M apelta including the isolation and structure elucidation of bioactive compounds, chemical modifications and synthetic processes the world The efforts have led to the isolation of a number of physiologically active compounds viz terpenoids, steroids, flavonoids, cumarino-lignoids, cembrane diterpenoids, benzopyranoids We are actively working on the synthesis of some new derivatives of malloapelta B, a major component of M apelta, with an aim to find new derivatives having stronger bioactivity Various compounds isolated from M apelta in different areas have been classified under the categories terpenoids, steroids, flavonoids, cumarino-lignoids, cembrane diterpenoids, benzopyranoids and miscellaneous compounds as listed in figures 15 II - PHYTOCHEMISTRY The chemistry of M apelta has been widely examined and the biological activity investigations were carried out from all over of R1 R H3C R3 R2 R1 O O R HO R1 H R2 R1 R CH3(CH)CH2OH H H CH3(CH)CH2 CH2(C)CH2OH H O - OH, -H - OH, -H OH COOH R2 R3 H CH3 CH3 H R2 10 11 R -OH -OGla -OH H R R1 HO R -(CH2)2CH(C2H5)CH(CH3)2 -(CH2)2CH(C2H5)CH(CH3)2 -CH2=CH-CH(C2H5)CH(CH3)2 R 12 13 O -OH, -H 14 Figure 1: Terpenoids and steroids isolated from M apelta 112 H Terpenoids and steroids The phytochemistry of M apelta has been extensively studied since the early 1980s One of the earlier phytochemical reports was published in 1985, it described the isolation of four triterpenes , 29-dihydroxylupane (1), erythrodiol-3-acetate (7), acetylursolic acid (8) and -sitosterol (9) from the roots of this plant [7] This plant also contains a variety of other pentacyclic terpenoids Based on the spectral and chemical evidence, their structures were determined to be hennadiol (3), friedelin (4), friedelanol (5), epifriedelanol (6), taraxerone (12), and epitaraxerol (13) [14, 16] and a new pentacyclic triterpene, named malloapelta A (2) [15, 16, 19] From the methanol extract of M apelta, daucosterol (10), stigmasterol (11), and ergosterol (14) were isolated and purified using column chromatography over silica gel [19] Flavonoids Two flavonoids quercitrin (15) and astilbin (16) were identified from M apelta collected in Vietnam [19] OH OH OH OH HO O OH O HO O O O CH3 OH O 15 O OH HO OH O HO OH 16 CH3 OH Figure 2: Flavonoids isolated from M apelta Cumarino-lignoids A method for the isolation and purification of three coumarino-lignoids aquillochin (17), cleomiscosin A (18) and 5’-demethylaquillochin (19) from M apelta has been reported by Cheng et al [12] H3CO R2 O R1 O O O O CH2OH R2 R1 R3 17 18 19 Cembrane diterpenoids Recently, several cembrane diterpenoids 10hydroxycembren-5-one (20), 6hydroxycembrene-5,10-dione (21) [9] 10,14Dihydroxy-5-isopropenyl-2,8,12-trimethylcyclotetradeca-2,8,12-trienone (22) [10,11] have been isolated from M apleta R OCH OCH OCH R OH OH OH R OCH3 H OH 20 21 22 R OH,H O OH,H R H OH OH Figure 3: Cumarino-lignoids and cembrane diterpenoids isolated from M apelta 113 Benzopyranoids In 2001, An et al have isolated seven benzopyran derivatives 4-hydroxy-2,6-dimethyl6-(3,7-dimethyl-2,6-octadienyl)-8-(3-methyl-2butenyl)-2H-1-benzopyran-5,7(3H,6H)-dione (23), 4-hydroxy-2,6,8-trimethyl-6-(3,7dimethyl-2,6-octadienyl)-2H-1-benzopyran5,7(3H,6H)-dione (24), 5-hydroxy-2,8dimethyl-6-(3-methyl-2-butenyl)-8-(3,7dimethyl-2,6-octadiennyl)-2H-1-benzopyran- 4,7(3H,8H)-dione (25), 5-hydroxy-2,8,6trimethyl-8-(3,7-dimethyl-2,6-octadiennyl)-2H1-benzopyran-4,7-(3H,8H)-dione (26), 2,3dihydro-5,7-dihydroxy-2,6-dimethyl-8-(3methyl-2-butenyl)-4H-1-benzopyran-4-one (27), 2,3-dihydro-5,7-dihydroxy-2,8-dimethyl-6-(3methyl-2-butenyl)-4H-1-benzopyran-4-one (28), and 2,3-dihydro-5,7-dihydroxy-2,6,8-trimethyl4H-1-benzopyran-4-one (29) from the leaves of M apelta [13] R2 CH O O R1 CH OH 23 CH -CH =C(CH )-(CH ) -CH=C(CH ) 24 CH -CH =C(CH )-(CH ) -CH=C(CH ) O CH R1 R2 25 CH -CH =C(CH ) 26 CH R1 OH O OH O R R1 H CO O R2 OCH R2 R3 R2 27 CH -CH=C(CH ) 28 CH 29 CH O CH -CH=C(CH )-(CH ) -CH=C(CH ) CH -CH=C(CH )-(CH ) -CH=C(CH ) R1 R3 HO CH -CH=C(CH ) CH O R2 O R2 R1 CH -CH -CH=C(CH ) CH CH CH CH R2 R1 30 -CO-CH=CH-CH 31 -CO-CH -CH(OH)-CH CH 32 -CO-CH -CH(CH )-OCOCH H CH 33 34 H 35 H O H 36 HC CH C CH O H H H -CO-CH=CH-CH -CO-CH -CH(OH)-CH -CO-CH -CH (CH )-OCH H Figure 4: Benzopyranoids isolated from M apelta In recent years, a number of biologically active secondary metabolites have been isolated from M apelta which is widely distributed in the northern areas of Vietnam From the methanol extract of the M apelta, a new chromene derivative with benzopyran skeleton 114 was isolated and identified as 1-(5,7-dimethoxy2,2-dimethyl-2H-chromen-8-yl)-but-2-en-1-one or malloapelta B (30) with high yield Different chromatographic techniques were applied to purify compounds 8-(1’-oxo-3’(R)-hydroxybutyl)-5,7-dimethoxy-2,2-dimethyl-2H-1- Miscellaneous compounds benzopyran (31), 8-(acetic acid 1’-oxo-3’(R)hydroxy-butyl ester)-5,7-dimethoxy-2,2dimethyl-2H-1-benzopyran (32); 6-(1’-oxo-2’en-butyl)-5,7-dimethoxy-2,2-dimethyl-2H-1benzopyran (33), 6-[1'-oxo-3'(R)-hydroxybutyl]-5,7-dimethoxy-2,2-dimethyl-2H-1benzopyran (34), 6-[1'-oxo-3'(R)-methoxybutyl]-5,7-dimethoxy-2,2-dimethyl-2H-1benzopyran (35), and 6-(1’-oxo-2’,3’-epoxybutyl)-5,7-dimethoxy-2,2-dimethyl-2H-1benzopyran (36) from the leaves of M apelta which were named as malloapelta C, D, E, F, G, and H, respectively [17, 18] These compounds were evaluated their NF- B inhibitory, NFAT transcription factor inhibitory and cytotoxic activities (The cytotoxic assay was evaluated on two cancer cell lines (Human hepatocellular carcinoma, Hep-G2) and rhabdosarcoma, RD) Interestingly, malloapelta B showed strong NFB inhibitory activity, NFAT transcription factor inhibitory and cytotoxic activities, the other compounds showed significant cytotoxic activities against the two mentioned human cancer cell lines [17, 18] Recently, the Chinese scientists carried out an extensive screening for effective anti-HIV natural products Notably, the extract of the roots of M apelta showed significant activity [8] Based on the bioassay guided fractionation, malloapeltine (37), 4-methoxy-3-cyano-pyridine 1-oxide (38), along with 4,5,4’-trimethyl-ellagic acid (39) were purified from the roots of this plant [9] These compounds were evaluated for their anti-HIV activity, among them 37 demonstrated a significant inhibitory activity [9] The following phytochemical examination of the M apelta by Cheng et al led to the isolation of two compounds named as ,4 ,15,16-tetrahydroxydolabradan (40), malloapeltin (37) [10,11] By repeated chromatography on silicagel column, isopimpinellin (41), -tocopherol (42), transphytol (43), squalene (44) -carotene (45), lutein (46), and betulaprenol 10 (47) were isolated from the methanol extract of this plant which were identified by comparison with the spectral data reported in the literatures [15, 16, 19] OH O OCH O H CO OH O CN HO H 3CO N OH N+ N O O- O OCH OH O 37 40 39 38 OCH3 HO O O O O OCH3 44 42 41 2 O H 46 OH 45 OH CH2OH n n=9 43 47 Figure 5: Other compounds isolated from M apelta 115 III - CHEMICAL MODIFICATIONS AND SYNTHESES To investigate the relationship between the structure and their bioactivity as well as to find new derivatives having stronger effect, Binh et al synthesized the derivatives of malloapelta B by using electro organic synthetic method (see scheme 1) As a result, a new compound named as bimalloapelta (48) and a known compound 8-[1’-oxo-3’(R)-methoxy-butyl]-5,7-dimethoxy-2,2dimethyl-2H-1-benzopyran (49) were afforded (see scheme 2) [22, 23] CH3 H 3C O -e - H 3C H3C O OCH3 CH3 H 3C CH3 CH H C H 3C O CH3 H 3C O O O O +C lO - + 2e - +ClO - O 48 Scheme 1: Modifications of malloapelta B to produce 48 [22] H3C O CH3 -e- H3C CH3 H3C O O O H3CO CH3 H3C O O H3CO + CH3OH, -H H3C H3CO OCH3 H3C OCH3 H3CO OCH3 49 Scheme 2: Modifications of malloapelta B to produce 49 [23] O O H3CO O +ROH H2 C H3CO CH3 C H O (C2H5)2NH H3CO +ROH O (C2H5)2NH OCH3 OCH3 OCH3 49 R=CH3 OR CH3 O 50 R=CH2CH3 51 R=CH2CH2CH3 52 R=CH(CH3)2 Scheme 3: Modifications of malloapelta B to produce 49 - 52 [25] O O H3CO O HNO3/H2SO4 H3CO O CHCl3 OCH3 NO2 OCH3 53 Scheme 4: Modification of malloapelta B to produce 53 [25] 116 As part of our ongoing studies to look for new derivatives having stronger bioactivities, nine benzopyrans 8-[1’-oxo-3’(R)-methoxy-butyl]-5,7-dimethoxy-2,2-dimethyl-2H-1-benzopyran (49), 8-[1’-oxo-3’(R)-ethoxy-butyl]-5,7-dimethoxy-2,2-dimethyl-2H-1-benzopyran (50), 8-[1’-oxo-3’(R)propoxy-butyl]-5,7-dimethoxy-2,2-dimethyl-2H-1-benzopyran (51), 8-[1’-oxo-3’(R)-isopropoxybutyl]-5,7-dimethoxy-2,2-dimethyl-2H-1-benzopyran (52), 8-[1’-oxo-2’-en-butyl]-5,7-dimethoxy-3nitro-2,2-dimethyl-2H-1-benzopyran (53), 8-[1’-oxo-3’(R)-methyl-4’-acetyl-5’-oxo-hexyl]-5,7dimethoxy-2,2-dimethyl-2H-1-benzopyran (54), 8-(1’-oxo-3’(R)-methyl-4’(S/R)-(methylformiate)5’-oxo-hexyl)-5,7-dimethoxy-2,2-dimethyl-2H-1-benzopyran (55), 8-(1’-oxo-3’(R)-methyl-4’(S/R)(ethylformiate)-5’-oxo-hexyl)-5,7-dimethoxy-2,2-dimethyl-2H-1-benzopyran (56), and 1-(5,7dimethoxy-2,2-dimethyl-2H-chromen-8-yl)butan-1-one (57) were synthesized by addition, nitration and Michael reactions from malloapleta B [24, 25, 26] H 3C R O O H3CO O H3CO CH3COCH 2R O Michael reaction OCH3 O CH3 54 R= O CH3 55 R= CH3 OCH3 O CH3 56 R= OCH3 O OCH2CH3 O O Scheme 5: Modifications of malloapelta B to produce 54 - 56 [24] COOCH3 CH3 CO OCH O O H 3C O CH3 O H 3C O CH3 CH CH3 D im ethy l m alonate N aO C H CH3 CH3 O O O O H 3C O CH3 O H 3C O H /P d-C 15 psi 58 OCH3 10 -1 C O O CH3 CH3 57 CH3 CH3 1) C H C H M gB r 2) N H C l/H O OCH3 CH3 H 3C O OCH3 O H 3C O 62 N aB H /M eO H CH3 H 3C O CH3 CH3 CH3 OCH3 63 O CH H /P d -C 30 p si 59 OCH3 O H 3C O ) L iA lH ) H O /M eO H CH3 CH3 HO O H 3C O CH3 CH3 OCH3 60 CH3 OCH3 61 Scheme 6: Modifications of malloapelta B to produce 57 - 63 [26] 117 The other method for synthesizing of malloapelta B’s derivatives has been reported by Chinh et al [26] Compounds 1-(5,7-dimethoxy-2,2-dimethyl-2H-chromen-8-yl)butan-1-one (57) was produced by reducing malloapelta B in sodium borohydride environment (see scheme 6), 1-(5,7dimethoxy-2,2-dimethylchroman-8-yl)butan-1-one (58), 8-butyl-5,7-dimethoxy-2,2dimethylchroman (59) were produced by reducing malloapleta B in catalytic hydrogenation (see Scheme 6) The other compounds 1-(5,7-dimethoxy-2,2-dimethyl-2H-chromen-8-yl)-3-methoxy-1butene (60), 1-(5,7-dimethoxy-2,2-dimethyl-2H-chromen-8-yl)-3-hydroxy-1-butene (61), 1-(5,7dimethoxy-2,2-dimethyl-2H-chromen-8-yl)-3-methylpentan-1-one (62), and 2-(4-(5,7-dimethoxy2,2-dimethyl-2H-chromen-8-yl)-4-oxobutan-2-yl)malonate (63) were synthesized from malloapelta B by addition reaction (see Scheme 6) By applying this method we also obtained the same compounds The summary of synthesized compounds from malloapelta B by these methods is exhibited in Figure OR H3C CH3 H3C H CH3 O O O O O H3C H H3CO CH3 CH3 O H3CO O OCH3 OCH3 H3CO O H3CO CH3 R 49 CH3 50 CH2CH3 O 51 CH2CH2CH3 R= 52 CH(CH3)2 O H3CO H3CO OCH3 48 O CH3 CH3 O CH3 CH3 H R O OCH3 O CH3 O CH3 CH3 OCH2CH3 OCH3 CH3 O O O 55 54 56 O O H3CO O H3CO O NO2 OCH3 OCH3 OCH3 57 58 53 O H3CO O H3CO OCH3 O H3CO O O 59 OH CH3 H3CO OCH3 O- O O OCH3 60 OCH3 61 OCH3 62 Figure 6: Synthesized compounds from malloapelta B 118 O- O 63 O IV - STRUCTURES AND BIOLOGICAL ACTIVITIES OF SYNTHESIZED COMPOUNDS It is well-known that LPS or TNF induced NF-.B activation are related to septic shock, autoimmune disorders, and inflammatory diseases [27,28] It is also agreed that compounds containing , -unsaturated carbonyl moiety usually exhibit good inhibitory activity against these factors [26, 27] Interestingly, benzopyrans, with , -unsaturated carbonyl group, also display this characteristic [20, 21] Malloapleta B with , -unsaturated carbonyl motiety in side chain presented a potent NF-.B inhibitory activity (IC50 = 5.0 µM), and NFAT transcription factor inhibitory (IC50 = 2.48 µM) and cytotoxic activity against two human cancer cell lines (Hep-G2 and KB with IC50 = 0.49 µg/ml and 0.54 µg/ml, respectively) [20, 21] Therefore, malloapelta B were selected for studying the relationship between structure and biological activity In the structure of malloapelta B (see Figure 7) we proposed three positions A, B, C which seem to be active in organic reaction To investigate the relationship between structure and biological activity of this compound, we modified its structure by changing individual A, B, C position or both A and B, A and C, B and C to produce some derivatives Then the biological activity of the derivatives were retested by the same method applied for malloapelta B [18, 20, 21, 25] The relationship studies between structure and biological activity of the derivatives and malloapleta B were carried out by comparing their biological activity with that of malloapelta B Binh et al [22] modified the structure of malloapelta B by using cyclic voltammetry to oxidize the C position, in this method, a mechanism of electro organic oxidation of malloapelta B was proposed as shown in scheme Firstly, malloapelta B transferred one electron to convert into corresponding cation radical, which was further oxidized by LiClO4 then converted into 48 This compound was tested on Hep-G2 and RD cells As a result, 48 exhibited strongly cytotoxic activity on both tested cell lines with the IC50 values of 0.46 µg/ml and 0.33 µg/ml, respectively O A H3CO 2' 1' 4' 3' B 11 O 12 10 OCH3 C Figure 7: Three positions A, B, C in the structure of malloapelta B Comparing these results with those of malloapelta B, the IC50 values of both compounds were similar and that the oxidation of double bond at C-3/C4 (C position) did not affect to their cytotoxic activity The other method [25] to modify the C position (double bond at C-3/C4) of the structure of malloapelta B was applied by using nitration reaction (see scheme 3) to produce 53 In this method the hydrogen atom (H-3) of the C position on structure of malloapleta B was replaced by the NO2 group This compound also exhibited strongly cytotoxic activity on both tested cell lines Hep-G2 and RD with the IC50 values of 0.87 µg/ml and 0.62 µg/ml, respectively Comparing these resutls with those of malloapelta B, the IC50 values of this compound was slightly higher The observed result suggested that the addition of NO2 group into the position C in the structure of malloapelta B was not affect the cytotoxic activities The decreasing cytotoxic activity of this compound due to NO2 group obstructed the access into the C position of structure of malloapelta B [25] The B position on the structure of malloapelta B was also modified by an electro organic oxidation method to produce compound 49 (see scheme 2) [23] The B position was made partial changes by an addition reaction and Michael reaction with different reagents to produce 119 compounds 49-52, 54-57, 62-63 (see scheme 3,5,6) [24,25,26] The reduction of double bond (B position) and carbonyl group (A position) was attempted by catalytic hydrogenation of malloapelta B at 30 psi of H2 gas in the presence of 10% Pd/C resulted in the conversion of , unsaturated carbonyl to butyl yielded compound 59 (see scheme 6) However, by carrying out the same reaction at 15 psi of H2 gas in the presence of 10% Pd/C, this reaction reduced the double bond (B position) and saturation of 3,4 double bond (C position) in the pyran ring to yield compound 58 (see scheme 6) Compound 60 and 61 were produced by treating malloapelta B with lithium aluminum hydride The results are much complicated with the formation of isomerizied products 60 and 61 as showed in the scheme [26] Those compounds above were assayed for their inhibitory activity on TNFinduced, NF-.B using transfected Hela cell and the results are described in the literature [26] The authors concluded that only 59 showed the slightly decreased inhibitory activity The rest of compounds showed the NF- B inhibitory activity at nearly the same concentration of cell cytotoxicity Thus these compounds are considered to be inactive The results revealed that , -unsaturated carbonyl moiety and the C=C double bond plays an important role to the activity of malloapelta B According to the discussion above, mallotapelta B still showed the most interesting biological activities V - CONCLUDING REMARKS Numerous compounds have been isolated and identified from Mallotus apelta since the last two decades They were classified under the categories triterpenoids, steroids, flavonoids, cumarino-lignoids, cembrane diterpenoids, benzopyranoids and miscellaneous compounds Among them, benzopyranoids were known to be the most identified components from this plant Interestingly, the results of biological activity assay showed that malloapelta B, a major component of M apelta, exhibited considerable NF- B and NFAT transcription factor inhibitory and cytotoxic activities Consequently, great efforts have been made to modify 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