Chemical constituents of the plants from the genus Phyllanthus.

364

CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)

REVIEW Chemical Constituents of the Plants from the Genus Phyllanthus by Weiyan Qi a ), Lei Hua a ), and Kun Gao* a ) b ) a

) State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, P. R. China b ) School of Biotechnology and Chemical Engineering, Ningbo Institue of Technology, Zhejiang University, Ningbo 315100, P. R. China (phone: þ 86-931-8912592; fax: þ 86-931-8912582; e-mail: [email protected])

Contents 1. Intruduction 2. Chemical Constituents 2.1. Sesquiterpenes 2.2. Diterpenes 2.3. Triterpenoids 2.4. Lignans 2.5. Flavonoids 2.6. Tannins and Ellagitannins 2.7. Alkaloids 2.8. Sterols 2.9. Other Activities 3. Biological Activities 3.1. Cytotoxicity 3.2. Antioxidant Activity 3.3. Anti-Inflammatory and Anti-Allodynic Activities 3.4. Antiviral Activity 3.5. Hepatoprotective Activity 3.6. Antimicrobial Activity 3.7. Antimutagenic Activity 3.8. Antidiabetic Activity 3.9. Anti-Ulcer Activity 3.10. Others 4. Conclusions 1. Intruduction. – Phyllanthus, containing more than 700 species, is one of the largest genera of Euphoriaceae, and is widely distributed throughout South America, Asia, and Africa. Phyllanthus plants have been reported to contain terpenes, alkaloids, lignans, flavonoids, and tannins [1] [2]. Many of the isolates from the genus Phyllanthus exhibit various kinds of significant bioactivities. Some Phyllanthus species have long been used in traditional medicine to treat various kinds of diseases, including eye disease, jaundice, headache, eczema, warts, diarrhea, diabetes, and hepatitis in China 2014 Verlag Helvetica Chimica Acta AG, Zrich


365

[3]. Among them, the fruit of Phyllanthus emblica L. has shown many biological activities, including antibacterial, antioxidant, anti-inflammatory, antitumor, and hepatoprotective effects. The MeOH and H2O extracts of the fruits were found to significantly inhibit the reverse transcription of HIV. Phyllaemblicin B from P. emblica exhibited stronger anti-CVB3 activity in vitro than the positive control ribovirin [4]. Additionally, roots of P. acidus Skeels have frequently been used in the rehabilitation program for alcohol addicts in Thailand [5]. These significant biological features have prompted phytochemists to investigate the chemical constituents of Phyllanthus, which has led to the identification of several bioactive compounds. In this review, we compile the phytochemical progress and list the compounds isolated from the genus Phyllanthus over the past decades, including also the biological activities of compounds isolated in recent years. Many remarkable biological activities may serve as valuable informations for the design of new drug molecules. 2. Chemical Constituents. – In total ca. 327 chemical constituents have been isolated from the genus Phyllanthus, including sesquiterpenes, diterpenes, triterpenes, lignans, flavonoids, tannins, ellagitannins, phenols, and alkaloid, as well as others [4 – 118]. Their structures are shown below, and their names and the corresponding plant sources are collected in the Table. 2.1. Sesquiterpenes. So far, 30 sesquiterpenes, 1 – 30, have been isolated from the genus Phyllantus. They comprise bisabolane- and guaiane-type skeletons, 1 – 26 and 27 – 30, respectively. Compounds 1 – 5 and 10 – 16 are norbisabolanes, and they are the first norbisabolanes biogenetically synthesized by oxidative removal of the central methyl C-atom [6]. Generally, these bisabolane- and norbisabolane-type sesquiterpenes are highly oxygenated. Regarding the structural characteristics, C(1) and C(10) are always oxygenated by OH group, moreover, the OH group at C(10) is b-oriented, and the Me(13) is oxygenated to form COOH group. In addition, they have a spiro-acetal moiety at C(8). Compounds 5, 8, 10 – 18, and 20 – 26 were isolated in form of O-glycosides. Most of the glycosides possess a sugar moiety at C(13), except 5 and 8. Compounds 27 and 28, isolated from P. oxyphyllus in 2003, and englerins A and B (29 and 30, resp.), isolated from P. engleri in 2008, are guaiane-tpye sesquiterpenes with an O-bridge between C(7) and C(10). 2.2. Diterpenes. So far, only seven diterpenoids, 31 – 37 have been isolated. Considering of the limited number, Phyllanthus seems not to be a rich source of diterpenoids. Compounds 31 – 33 are cleistanthane-type diterpenoids and were isolated from P. oxyphyllus and P. engleri. The highly oxygenated pimarane diterpenes 34 and 35 were isolated from P. niruri. Compounds 36 and 37, isolated from P. fraternus and P. niruri, respectively, are monocyclic and acyclic diterpenoids, respectively. 2.3. Triterpenoids. Triterpenoids are a major group of the secondary metabolites of Phyllanthus. In total 59 triterpenoids, 38 – 96, were isolated from this genus. They mainly comprise pentacyclic triterpenes, including lupine- (i.e., 38 – 49), oleanane- (i.e., 50 – 72), and friedelane- (i.e., 73 – 80), as well as other types (i.e.,81 – 96). Compounds 68 – 72 were isolated in the form of O-glycosides, and the glucose moieties are all at C(3). The unusual dichapetalin-type triterpenoids 92 – 96 were the first reported with a

366



367

spiro-lactone side chain from the genus Phyllanthus. Until now, from ca. 20 species, the isolation of triterpenoids has been reported. Compounds of this class occurred mainly in P. flexuosus, P. niruri, P. polyphyllus, and P. muellerianus. 2.4. Lignans. Fifty-five lignans, 97 – 151, were reported, representing the majority among the secondary metabolites isolated from the genus Phyllanthus. They mainly comprise three lignan types, including arylnaphthalene (i.e., 97 – 130), dibenzyltyrolactone (i.e., 131 – 135), dibenzylbutane-types (i.e., 139 – 144), as well as other types, 145 – 151. Among them, arylnaphthalene-type compounds predominate, followed by those of dibenzylbutane type. Some of the arylnaphthalene-type lignans were isolated in the form of C(1)-O-glycosides, i.e., 103 – 105, 121 – 128. Plants of P. niruri, P. urinaria, P. myrtifolius, and P. virgatus are rich sources of these compounds. 2.5. Flavonoids. During the past years, ca. 45 flavonoids, 152 – 196, were reported, comprising flavanonol (i.e., 152), flavanone (i.e., 153 – 165), flavonol (i.e., 172 – 188), flavone (i.e., 189 – 191), flavan-3-ol (i.e., 166 – 171), and biflavonoid types (i.e., 192 – 196). Among them, flavonols and flavones constitute the main compounds. Twenty-two comounds, 158 – 165, 177 – 185, 187, 190 – 191, were isolated in form of O-glycosides. Additionally, compounds 186 – 188 represent the first known examples of flavonoid-8sulfonates from a natural source. Compounds of the flavonoid class occurred mainly in P. emblica, P. niruri, P. virgatus, and P. urinaria. 2.6. Tannins and Ellagitannins. So far, 33 compounds of this class, 197 – 229, have been reported. They all contain a sugar moiety, and, except 200 and 228, a galloyl group. Moreover, compounds 204 – 209, 211 – 214, 216, 218, and 220 – 222 have hexahydroxydiphenoyl (HHDP) groups at C(3) and C(6). They were mainly from P. emblica, P. amarus, P. urinaria, and P. myrtifolius. Geraniin (227) and corilagin (229) are widely distributed in the genus Phyllanthus. 2.7. Alkaloids. Seventeen alkaloids, 230 – 246, were isolated from this genus. They are mainly indolizidines (i.e., 231 – 240) and indole alkaloids (i.e., 244 and 245), and a new purine derivative, 230, and those with other C skeletons. Phyllanthus does not seem to be a rich source of alkaloids. 2.8. Sterols. Ten sterols, 247 – 256, were isolated from this genus. Except 256, all of them are of stigmasterol type, and compound 256 belongs to the ergostane family. Compound 255 was isolated as the glycoside of 253. 2.9. Others. Seventy-one compounds, 257 – 327, with other C-skeleton types have been reported. Most of them are phenol derivatives (i.e., 275 – 308 and 311).

368


Table 1. Chemical Constituents of the Genus Phyllanthus No.

Compound class and name

Plant source

Ref.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30

Sesquiterpenes Phyllaemblic acid Phyllaemblic acid methyl ester 1-O-Acetylphyllaemblic acid methyl ester 1,6-O-Diacetylphyllaemblic acid methyl ester Phyllaemblicin A Phyllaemblic acid B Phyllaemblic acid C Phyllaemblicin D Decinnamoylphyllanthocindiol Phyllaemblicin B Phyllaemblicin C 4’-Hydroxyphyllaemblicin B Phyllaemblicin E Phyllanthusol A Phyllanthusol B Phyllaemblicin F Phyllanthostatin 3 Dideacetylphyllanthostatin 3 Phyllanthocin Phyllanthoside Phyllanthostatin 1 Phyllanthostatin 4 Phyllanthostatin 5 Dideacetylphyllanthoside Phyllanthostatin 2 Phyllanthostatin 6 6,9-Epoxyguaian-5-ol 5-O-Acetyl-6,9-epoxyguaiane Englerin A Englerin B

P. emblica P. emblica P. emblica P. emblica P. emblica P. emblica P. emblica P. emblica P. acuminatus P. emblica P. emblica P. emblica P. emblica P. acidus P. acidus P. emblica P. acuminatus P. acuminatus P. brasiliensis P. acuminatus P. acuminatus P. acuminatus P. acuminatus P. acuminatus P. acuminatus P. acuminatus P. oxyphyllus P. oxyphyllus P. engleri P. engleri

[6] [6] [6] [6] [7] [8] [8] [8] [9] [7] [7] [4] [4] [5] [5] [4] [9] [9] [10] [9] [9] [9] [9] [9] [9] [9] [11] [11] [12] [12]

31 32 33 34 35 36 37

Diterpenes Cleistantha-8,11,13,15-tetraene-3,12-diol Cleistantha-8,11,13,15-tetraene-2,3,12-triol 19-Hydroxyspruceanol 19-O-b-d-glucopyranoside Orthosiphol G Orthosiphol I Phyllanterpenyl ester E-Phytol

P. oxyphyllus P. oxyphyllus P. reticulatus P. niruri P. niruri P. fraternus P. niruri

[11] [11] [13] [14] [14] [15] [16]

38

Triterpenes Lupeol

39 40 41

Lupeol acetate Lup-20(29)-ene-3b,24-diol Betulin

42

Glochidonol

43

Glochidiol

P. flexuosus P. watsonii P. urinaria P. flexuosus P. flexuosus P. reticulatus P. sellowianus P. flexuosus P. sellowianus

[17] [18] [19] [17] [20] [17] [20] [21] [22] [23] [22]


369

Table 1 (cont.) No.


44 45

Lup-20(29)-ene-1,3-dione Lup-20(29)-ene-1b,3b-diol

46 47

Lupenone Glochidone

48 49 50 51 52 53

Lupanyl acetate Lup-20(29)-ene-3b,15a-diol Olean-12-ene-3b,15a-diol Olean-12-ene-3b,24-diol Olean-12-ene-3b,15a,24-triol b-Amyrin

54 55 56 57 58 59

3a-Acetoxy-25-hydroxyolean-12-en-28-oic acid 12(13)-Dehydro-3a-acetoxyolean-28-oic acid Hederagenin Olean-18-en-3b-ol Oleana-9(11),12-dien-3b-ol Taraxerone

60

Taraxerol

61

Taraxeryl acetate

62 63

d-Amyrin acetate Oleana-11,13(18)-diene-3b,24-diol

64 65 66 67 68

71 72 73 74 75 76

Oleana-11,13(18)-dien-3b-ol Phyllenolide A Phyllenolide B Phyllenolide C 3’-O-Acetyl-3-O-a-l-arabinosyl-23-hydroxyolean-12-en-28-oic acid 4’-O-Acetyl-3-O-a-l-arabinosyl-23-hydroxyolean-12-en-28-oic acid 2’-O-Acetyl-3-O-a-l-arabinosyl-23-hydroxyolean-12-en-28-oic acid 3-O-a-l-Arabinosylhederagenin 3-O-a-l-Arabinosyloleanolic acid Friedelin Friedel-1-en-22b-ol 11b-Hydroxy-D: A-friedoolean-1-en-3-one Epifriedelinol

77 78 79

Trichadenic acid B 21a-Hydroxyfriedelan-3-one Friedelan-3-one

69 70

Plant source

Ref.

P. flexuosus P. flexuosus P. sellowianus P. flexuosus P. polyanthus P. watsonii P. flexuosus P. pulcher P. pulcher P. flexuosus P. flexuosus P. flexuosus P. flexuosus P. flexuosus P. emblica P. pulcher P. pulcher P. polyphyllus P. fraternus P. flexuosus P. reticulatus P. columnaris P. columnaris P. maderaspatensis P. reticulatus P. maderaspatensis P. polyanthus P. flexuosus P. maderaspatensis P. flexuosus P. myrtifolius P. myrtifolius P. myrtifolius P. polyphyllus

[23] [23] [22] [23] [24] [18] [23] [25] [25] [26] [17] [20] [20] [17] [20] [27] [28] [25] [25] [29] [30] [27] [31] [21] [32] [32] [33] [21] [33] [24] [20] [33] [27] [31] [34] [34] [34] [29]

P. polyphyllus

[29]

P. polyphyllus

[29]

P. polyphyllus P. polyphyllus P. muellerianus P. muellerianus P. reticulatus P. watsonii P. reticulatus P. flexuosus P. reticulatus P. muellerianus P. watsonii

[29] [29] [35] [35] [31] [18] [21] [36] [21] [37] [38] [18]

370


Table 1 (cont.) No.


Plant source

Ref.

80 81 82 83

Polpunonic acid 21a-Hydroxyfriedel-4(23)-en-3-one 29-Nor-3,4-secofriedelane Phyllanthol

84 85 86 87 88 89 90 91

[11] [37] [11] [24] [39] [40] [24] [41] [41] [41] [26] [24] [24] [42]

92 93 94 95 96

Phyllanthone Phyllanthenol Phyllantheol Phyllanthenone Ocotillol II (20S )-3b-Acetoxy-24-methylidenedammaran-20-ol (20S )-3a-Acetoxy-24-methylidenedammaran-20-ol (2Z,6Z,10Z,14E,18E,22E )-3,7,11,15,19,23-Hexamethyltetracosa2,6,10,14,18,22-hexaen-1-ol Acutissimatriterpene A Acutissimatriterpene B Acutissimatriterpene C Acutissimatriterpene D Acutissimatriterpene E

P. oxyphyllus P. reticulatus P. oxyphyllus P. polyanthus P. sellowianus P. polyanthus P. niruri P. niruri P. niruri P. flexuosus P. polyanthus P. polyanthus P. niruri P. acutissimus P. acutissimus P. acutissimus P. acutissimus P. acutissimus

[43] [43] [43] [43] [43]

97

Lignans Hypophyllanthin

98

Isolintetralin

99

Nirtetralin

100 101

Lintetralin Phyltetralin

102 103 104 105 106 107 108 109 110 111 112 113

Phyllamyricin F Phyllamyricoside A Phyllamyricoside B Phyllamyricoside C Phyllanthostatin A 4-Hydroxysecolintetralin Neonirtetralin Phyllamyricin A Phyllamyricin B Phyllanthusmin A Haplomyrtin Justicidin A

114

Diphyllin

115 116 117

Taiwanin C Phyllamyricin D Phyllamyricin E

P. virgatus P. amarus P. virgatus P. niruri P. niruri P. urinaria P. amarus P. niruri P. urinaria P. amarus P. niruri P. myrtifolius P. myrtifolius P. myrtifolius P. myrtifolius P. acuminatus P. niruri P. niruri P. myrtifolius P. myrtifolius P. oligospermus P. oligospermus P. oligospermus P. myrtifolius P. oligospermus P. polyphyllus P. acutissimus P. myrtifolius P. myrtifolius

[44] [45] [44] [46] [47] [48] [49] [50] [48] [49] [51] [52] [52] [52] [52] [53] [50] [54] [55] [55] [1] [1] [1] [55] [56] [1] [57] [43] [52] [52]


371

Table 1 (cont.) No.


Plant source

Ref.

118 119

Phyllamyricin C Justicidin B

120 121 122 123 124 125 126 127 128 129 130 131 132 133

[55] [55] [58] [58] [1] [1] [43] [59] [59] [59] [59] [13] [55] [60] [48] [61] [43] [43] [45]

134 135 136

Piscatorin Phyllanthusmin B Phyllanthusmin C Acutissimalignan A Cleistanthin A Cleistanthin A methyl ether Taxodiifoloside Cleistanthoside A Mananthoside I Retrojusticidin B Urinatetralin Acutissimalignan B Isogadian 3-(3,4-Dimethoxybenzyl)-4-[(7-methoxybenzo[1,3]dioxol-5-yl)methyl]dihydrofuran-2-one Dextrobursehernin Heliobuphthalmin lactone 5-Demethoxyniranthin

P. myrtifolius P. myrtifolius P. reticulatus P. reticulatus P. oligospermus P. oligospermus P. acutissimus P. taxodiifolius P. taxodiifolius P. taxodiifolius P. taxodiifolius P. reticulatus P. myrtifolius P. urinaria P. acutissimus P. acutissimus P. amarus

137 138 139

Secoisolariciresinol Linnanthin Niranthin

140 141

Secoisolariciresinol trimethyl ether Phyllanthin

142 143

[48] [48] [45] [48] [11] [62] [44] [45] [49] [50] [30] [48] [63] [50] [45]

144 145

Hydroxyniranthin 4-(3,4-Dimethoxyphenyl)-1-(7-methoxybenzo[1,3]dioxol-5-yl)2,3-bis(methoxymethyl)butan-1-ol Nirphyllin Virgatusin

P. urinaria P. urinaria P. amarus P. urinaria P. oxyphyllus P. niruri P. virgatus P. amarus P. niruri P. fraternus P. urinaria P. niruri P. niruri P. amarus

146 147

Urinaligran Pinoresinol

148 149 150 151

Sesamin-4-ol Virgatyne Phyllnirurin Hinokinin

P. niruri P. virgatus P. amarus P. urinaria P. urinaria P. oxyphyllus P. amarus P. niruri P. virgatus P. niruri P. virgatus P. niruri

[64] [44] [45] [48] [48] [11] [65] [66] [67] [64] [44] [46]

152 153 154

Flavonids Dihydrokaempferol Naringenin Eriodictyol

P. emblica P. emblica P. emblica

[68] [68] [68]

372


Table 1 (cont.) No.


Plant source

Ref.

155 156 157 158

P. niruri P. niruri P. sellowianus P. niruri

[69] [69] [70] [71]

159 160 161 162 163 164 165 166

8-(3-Methylbut-2-enyl)-2-phenylchroman-4-one 2-(4-Hydroxyphenyl)-8-(3-methylbut-2-enyl)chroman-4-one 7-Hydroxyflavanone 6,7,4’-Trihydroxy-8-(3-methylbut-2-enyl)flavanone 5-O-a-lrhamnopyranoside Eriodictyol 7-O-a-l-rhamnopyranoside Naringenin 7-O-b-d-glucopyranoside (S )-Eriodictyol 7-O-(6’’-O-p-coumaroyl)-b-d-glucopyranoside (S )-Eriodictyol 7-O-(6’’-O-galloyl)-b-d-glucopyranoside Eriodictyol 7-O-b-d-glucopyranoside Naringenin 7-O-(6’’-O-galloyl)-b-d-glucopyranoside Naringenin 7-O-(6’’-O-p-coumaroyl)-b-d-glucopyranoside ()-Epigallocatechin 3-O-gallate

167

()-Epigallocatechin

168 169 170 171

()-Epicatechin ()-Epicatechin 3-O-gallate ( )-Gallocatechin (þ)-Catechin

172 173

Kaempferol Quercetin

174 175 176 177 178 179 180

5,7-Dihydroxy-4’-methoxyflavonol Rhamnocitrin Kaempferol 7-methyl ether Kaempferol 3-O-a-l-rhamnopyranoside Quercetin 3-O-a-l-rhamnopyranoside Myricetin 3-O-a-l-rhamnopyranoside Astragalin

181 182

Quercetin 3-O-b-d-glucopyranoside Rutin

183 184 185 186 187 188 189 190 191 192 193 194 195 196

Quercetin 3-O-b-d-glucopyranosyl-(1 ! 6)-b-d-glucopyranoside Quercetin 3-O-b-d-glucopyranosyl-(1 ! 2)-b-d-xylopyranoside Kaempferol 4’-O-a-l-rhamnopyranoside Galangin 8-sulfonate Galangin 3-O-b-d-glucoside-8-sulfonate Kaempferol 8-sulfonate Niruriflavone Apigenin 7-O-(6’’-butyryl-b-glucopyranoside) Luteolin 4’-O-neohesperidoside Prodelphinidin A-1 Epicatechin-(4b ! 8)-gallocatechin Procyanidin B-1 Prodelphinidin B1 Prodelphinidin B2

P. niruri P. emblica P. emblica P. emblica P. emblica P. emblica P. emblica P. emblica P. niruri P. emblica P. niruri P. emblica P. emblica P. emblica P. emblica P. klotzschianus P. emblica P. sellowianus P. amarus P. virgatus P. urinaria P. urinaria P. emblica P. emblica P. emblica P. amarus P. virgatus P. urinaria P. virgatus P. urinaria P. virgatus P. niruri P. niruri P. virgatus P. virgatus P. virgatus P. niruri P. emblica P. emblica P. emblica P. emblica P. emblica P. emblica P. emblica

[72] [68] [68] [68] [68] [68] [68] [68] [73] [7] [73] [7] [7] [7] [7] [74] [68] [39] [65] [67] [75] [76] [68] [68] [68] [65] [67] [76] [67] [76] [67] [77] [72] [67] [67] [67] [78] [79] [79] [80] [7] [7] [81] [81]


373

Table 1 (cont.) No.


202 203 204 205 206 207

Tannins and Ellagitannins Phyllanemblinin D Phyllanemblinin E Phyllanemblinin F Pinocembrin 7-O-[4’’,6’’-( S )-hexahydroxydibenzoyl]-b-d-glucopyranoside Pinocembrin 7-O-[3’’-O-galloyl-4’’,6’’-( S )-hexahydroxydibenzoyl]-b-d-glucopyranoside Repandinin B Phyllanemblinin A Phyllanemblinin C Phyllanthusiin A Phyllanthusiin B Phyllanthusiin C

208 209 210 211

Phyllanthusiin D Virganin Euphormisin M2 Elaeocarpusin

212 213 214 215 216 217

Geraniinic acid B Amariinic acid B Phyllanthunin Acetonylgeraniin D Chebulanin Chebulagic acid

218 219 220 221 222 223 224 225 226 227

Mallotusinin Putranjivain A Phyllanthusiin G Repandusinic acid A Mallotinin Amariin Gemin D Phyllanemblinin B Amarulone Geraniin

228

Furosin

229

Corilagin

230 231

Alkaloids 3-(3-Methylbut-2-en-1-yl)isoguanine Norsecurinine

232

Securinine

197 198 199 200 201

Plant source

Ref.

P. emblica P. emblica P. emblica P. tenellus

[80] [80] [80] [82]

P. tenellus

[82]

P. urinaria P. emblica P. emblica P. flexuosus P. flexuosus P. flexuosus P. myrtifolius P. flexuosus P. virgatus P. virgatus P. myrtifolius P. amarus P. amarus P. amarus P. emblica P. urinaria P. emblica P. myrtifolius P. emblica P. emblica P. emblica P. urinaria P. urinaria P. urinaria P. amarus P. urinaria P. emblica P. amarus P. urinaria P. tenellus P. myrtifolius P. amarus P. sellowianus P. virgatus P. niruri P. emblica

[76] [80] [80] [83] [83] [83] [84] [83] [67] [67] [84] [85] [85] [85] [86] [76] [87] [84] [87] [87] [81] [88] [76] [76] [89] [90] [80] [91] [76] [82] [84] [85] [92] [67] [78] [80]

P. reticulatus P. niruri P. discoides P. niruri

[13] [93] [94] [93]

374


Table 1 (cont.) No.


Plant source

Ref.

233 234 235 236 237 238 239 240 241 242 243 244 245 246

Allosecurinine ent-Norsecurinine Viroallosecurinine Isobubbialine Epibubbialine 14,15-Dihydroallosecurinin-15b-ol Simplexine Phyllanthine (2E,4Z )-Deca-2,4-dienamide (2E,4E )-Octa-2,4-dienamide Phyllurine 1H-Indole-3-carboxaldehyde 1H-Indole-3-carboxylic acid Phyllanthimide

P. niruri P. niruri P. discoides P. amarus P. amarus P. discoides P. simplex P. simplex P. fraternus P. fraternus P. urinaria P. virgatus P. virgatus P. sellowianus

[93] [93] [94] [95] [95] [94] [96] [96] [97] [97] [98] [67] [44] [99]

247 248 249 250 251 252 253 254 255 256

Sterols Phyllanthosecosteryl ester Amarosterol-B Phyllanthosterol Amarosterol-A Fraternusterol Phyllanthostigmasterol b-Sitosterol Stigmasterol Daucosterol Campesterol

P. fraternus P. amarus P. fraternus P. amarus P. fraternus P. fraternus P. emblica P. corcovadensis P. emblica P. flexuosus

[100] [101] [100] [101] [100] [100] [86] [102] [86] [27]

257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279

Others Mucic acid dimethyl ester 2-O-gallate Mucic acid 6-methyl ester 2-O-gallate Mucic acid 1-methyl ester 2-O-gallate Mucic acid 2-O-gallate Mucic acid 1,4-lactone 2-O-gallate Mucic acid 1,4-lactone methyl ester 2-O-gallate Mucic acid 1,4-lactone 3-O-gallate Mucic acid 1,4-lactone 3,5-di-O-gallate Mucic acid 1,4-lactone 5-O-gallate Mucic acid 1,4-lactone methyl ester 5-O-gallate l-Malic acid 2-O-gallate 1,2,3,6-Tetra-O-galloyl-b-d-glucopyranoside 1,2,4,6-Tetra-O-galloyl-b-d-glucopyranoside 1,2,3,4,5-Penta-O-galloyl-b-d-glucopyranoside 1-O-Galloyl-b-d-glucopyranoside 1,6-Di-O-galloyl-b-d-glucopyranoside 1,4,6-Tri-O-galloyl-b-d-glucopyranoside 1,3,4,6-Tetra-O-galloyl-b-d-glucopyranoside 1-O-Galloyl-6-O-luteoyl-a-d-glucopyranoside Hovetrichoside A Carthamoside B5 Phyllester 4-O-Galloylquinic acid

P. emblica P. emblica P. emblica P. emblica P. emblica P. emblica P. emblica P. emblica P. emblica P. emblica P. emblica P. emblica P. emblica P. emblica P. virgatus P. virgatus P. virgatus P. virgatus P. niruri P. reticulatus P. reticulatus P. niruri P. amarus

[1] [1] [1] [1] [1] [1] [1] [1] [1] [1] [1] [68] [68] [68] [67] [67] [67] [67] [77] [13] [13] [47] [85]


375

Table 1 (cont.) No.


Plant source

Ref.

280

Gallic acid

281

Methyl gallate

282 283 284 285 286 287 288 289 290 291 292 293 294

[1] [67] [67] [75] [103] [57] [13] [76] [104] [76] [6] [70] [76] [105] [38] [38] [104]

P. urinaria

[104]

P. niruri P. emblica P. emblica

[105] [1] [68]

299 300 301 302 303 304

3-Ethylgallic acid 4-O-Methylgallic acid Isotachioside Protocatechuic acid 2,3,4,5,6-Pentahydroxybenzoic acid Gentisic acid 4-O-b-glucopyranoside 2-( Methoxycarbonyl)phenol 1-O-b-d-glucopyranoside Caffeic acid Syringin 2,3,5,6-Tetrahydroxybenzyl acetate Bis(2-ethyloctyl)phthalate Bis(2-ethylicosyl)phthalate (E )-3-(2,4’-Dihydroxy-3’-methoxy[1,1’-biphenyl]-4-yl)prop-2enoic acid Terephthalic acid mono{2-[(4-carboxyphenoxy)carbonyl]vinyl} ester Phyllangin Chebulic acid 2-( Methylbutyryl)phloroglucinol 1-O-b-d-apiofuranosyl-(1 ! 6)b-d-glucopyranoside Multifidol glucoside Trimethyl-3,4-dehydrochebulate Phyllanthusin F Debelalactone Brevifolincarboxylic acid Methyl brevifolincarboxylate

P. emblica P. virgatus P. virgatus P. urinaria P. emblica P. polyphyllus P. reticulatus P. urinaria P. urinaria P. urinaria P. emblica P. sellowianus P. urinaria P. niruri P. muellerianus P. muellerianus P. urinaria

305

Brevifolin

306 307 308 309 310 311 312 313 314

Potassium brevifolincarboxylate Isofraxidin Scopoletin Roseoside Byzantionoside B Niruriside 3’-Mono-O-methylellagic acid 4-O-a-l-rhamnopyranoside 3,3’,4’-Tri-O-methylellagic acid 4-O-b-d-glucopyranoside 3,3’,4’-Tri-O-methylellagic acid

315

Ellagic acid

316 317 318

4,4’-Di-O-methylellagic acid Phyllanthurinolactone Menisdaurilide

P. emblica P. urinaria P. urinaria P. debilis P. urinaria P. virgatus P. urinaria P. reticulatus P. virgatus P. niruri P. virgatus P. sellowianus P. sellowianus P. multiflorus P. multiflorus P. niruri P. acutissimus P. acutissimus P. acutissimus P. reticulatus P. urinaria P. reticulatus P. urinaria P. reticulatus P. urinaria P. polyphyllus

[68] [75] [106] [107] [76] [67] [75] [108] [67] [73] [67] [109] [110] [111] [111] [112] [43] [43] [43] [113] [114] [108] [114] [108] [115] [29]

295 296 297 298

376


Table 1 (cont.) No.


319

Aquilegiolid

320 321 322 323 324 325 326 327

Menisdaurin Turpenionoside A Turpenionoside B Tuberonic acid glucoside d-Glucose Levulose d-Galactose 5-( Hydroxymethyl)furfural

Plant source

Ref.

P. klotzschianus P. polyphyllus P. klotzschianus P. urinaria P. reticulatus P. reticulatus P. emblica P. sellowianus P. sellowianus P. sellowianus P. emblica

[116] [29] [116] [117] [13] [13] [68] [70] [70] [70] [118]

Additionally, ten mucic acid derivatives, 257 – 266, and three lactones, 317 – 319, were also reported. 3. Biological Activities. – 3.1. Cytotoxicity. In previous investigations, many plants belonging to the genus Phyllanthus have been shown to possess antitumor activities. In 2004, Gertsch et al. found that the CH2Cl2 , MeOH, and H2O extracts of P. reticulatus exhibited cytotoxicities against HeLa cells with IC50 values of 6, 18, and 26.5 mg/ml, respectively [119]. In addition, a 75% MeOH extract of P. amarus and the MeOH extract of P. polyphyllus showed cytotoxic activities against HepG2 and MCF-7 cell lines [120] [121]. The CH2Cl2 extract of the roots of P. pulcher displayed a strong cytotoxic activity against MCF-7, DU-145, and H460 cell lines. A further study of this plant revealed that compounds 42 and 54 exhibited moderate inhibitory activities against MCF-7, DU-145, and H-460 cell lines [25]. The cytotoxicities of the compunds isolated from P. emblica against cancer cells were determined in vitro. Phyllaemblicins B and C (10 and 11, resp.), exhibited significant inhibitory effects on B16F10, HeLa, and MK-1 cell proliferation with GI50 values ranging from 2.0 to 12.0 mg/ml. Other tested compounds showed inhibitory activities against the growth of the three tumor cell lines at a concentration less than 68 mg/ml [81]. In 2008, it was reported that compound 190 showed significant cytotoxicityies against four tumor cell lines with ED50 values in the range of 2.25 – 7.22 mm [79]. Triterpenes 69 and 72 showed moderate activities against the KB and BC cell lines, and triterpenes 92 and 93 exhibited activities against the P-388 cell line, whereas triperpene 96 showed significant activities against P-388, MCF-7, and Lu-1 cell lines [29] [43]. In 2000, Kittakoop and co-workers reported that sesquiterpenes 14 and 15 exhibited cytotoxicities against BC (EC50 4.2 and 4.0 mg/ml, resp.) and KB (EC50 14.6 and 8.9 mg/ ml, resp.) cell lines [5]. The cytotoxicity assay also revealed that sesquiterpene 29 showed significant cytotoxicity against the renal cancer cell line panel with the GI50 values ranging from 10 to 20 mm [12]. Four lignans, 124 – 127, isolated from P. taxodiifolius in 2006, and compounds 124 and 127 exhibited potent activities with GI50 values in the range of 10 7 – 10 9 m [59]. Phyllanthusmin A (111) also displayed significant cytotoxicity against KB and P-388 cell lines with IC50 values of 2.24 and


377

378



379

380



381

382


0.13 mg/ml, respectively [1]. In 2003, justickdin B (119) was reported to show moderate cytotoxicities against four tumor cell lines (IC50 values in the range of 0.2 – 4.7 mg/ml) [58]. Lignan 131 was also found to be active against all six cell lines tested [43]. Moreover, compounds 219 and 280 were tested for their cytotoxicities using MCF-7 cells, and showed IC50 values of 64.88 and 50.92 mg/ml, respectively [87]. 3.2. Antioxidant Activity. In 2007, seven ellagitannins, 202, 214 – 216, and 227 – 229, three flavonids, 176, 181, and 182, and five simple hydroxylated aromatic acids, 280, 285, 287, 290, and 303, were isolated from P. urinaria [76]. Antioxidant-activity studies on these compounds have been carried out using the 1,1-diphenyl-2-picryldydrozyl free radical (DPPH) method, and their structureactivity relationships have been discussed. Further, activities of ellagitannin 227 against DPPH radicals (IC50 0.92 and 1.27 mm at pH 4.5 and pH 7.9, resp.), hydroxyl redicals (IC50 0.11 mm by deoxyribose method, and 1.44 mm by electron spin resonce method), and superoxide radicals (IC50 2.65 mm) were determined. The inhibitory activities against xanthine oxidase (IC50 30.49 mm) were also measured [122]. Compounds 281, 300, and 304 were found to exhibit significant DPPH radical-scavenging activities with IC50 values of 9.8, 9.4 and 8.9 mm, respectively [75]. In addition, compounds 172, 173, 180, 182, and 227 from P. emblica showed strong antioxidant actvities in lipid peroxidation and DPPH systems [123]. In 2006, Shivanandappa reported that the extracts from leaves and fruits of P. niruri showed moderate antioxidant and strong radical-scavenging activities. Moreover, both H2O and MeOH extracts of P. niruri were effective antioxidants in vivo by their ability to inhibit CCl4-induced lipid peroxidation in the liver of rats [124]. By the DPPH and TBTS þ radical-scavenging activity method, the activities of compounds 173, 255, 280, 316, and 324, isolated from the fruit of P. emblica, were determined. All the compounds showed significant DPPH and TBTS þ radical scavenging activities [118]. Nitric oxide or reactive nitrogen species are responsible for altering the structural and functional behavior of many cellular components. Compounds 210, 217, 229, 247, and 252 from P. emblica exhibited significant NO scavenging activities with IC50 values


383

384



385

of 3.81 0.88, 5.99 0.35, 7.52 0.46, 28.97 1.57, and 36.23 1.94 mm, respectively [125]. 3.3. Anti-Inflammatory and Anti-Allodynic Activities. In traditional medicine, P. amarus has been used for the treatment of inflammatory diseases. Anti-inflammatory activity was determined by the carrageenan-induced mice paw edema method of Rapheal and Kuttan. The H2O and MeOH extracts (100, 250, and 500 mg/kg) produced an inhibition of 26, 33, 39%, and 29, 37, 42%, respectively, at 3 h [126]. In 2003, Calixto and co-workers reported that a hexane extract inhibited the allodynia induced by the intraplantar injection of complete Freunds adjuvant (CFA); the inhibitions observed were 76 7% (ipsilateral paw), 64 7% (contralateral paw), and 41 2% (edeema) [127]. In 2006, they found that lignans 99, 101, and 139 (30 nmol/paw) from P. amarus, similar to WEB2170, significantly inhibited PAF (platelet activating factor)-induced paw edema formation in mice [128]. In 2006, Tzeng et al. found that IC50 values for NO production from activated peritoneal macrophages by compounds 282, 105, 119, and 114 were 100, 25, 12.5, and 50 mm, respectively [57]. 3.4. Antiviral Activity. 3.4.1. Anti-HIV Activity. Notka et al. found that alcohol and aqueous extracts of P. amarus potently inhibited HIV-1 replication in HeLa CD4 þ cells (EC50 from 0.9 to 7.6 mg/ml). Geraniin (227) and corilagin (229) were the most

386


active (0.24 mg/ml) [129]. In 1996, niruriside (312) was isolated from the leaves of P. niruri L. by bioassay-guided fractionation for its ability to inhibit the binding of HIVREV protein to [ 33P]-labeled RRE RNA. Niruriside (312) showed specific inhibitory activity against the binding of REV protein to RRE RNA with an IC50 value of 3.3 mm [112]. In 1995, Lin and co-workers reported that phyllamyricin B (110) and retrojusticidin B (129) from P. myrtifolius had strong inhibitory effects on HIV-1 reverse transcriptase (IC50 3.5 and 5.5 mm, resp.) but much less activities on human DNA polymerase a (IC50 289 and 989 mm, resp.) [56]. Continuing with the chemical investigation of this plant material, six novel lignans were isolated. The glucoside 103 increased HIV-1 RT activity by 65% at 1.89 mm, and the activity almost reached the plateau (210% relative to control) at 18.9 mm [52]. In 2008, compounds 92 – 96, 123, 131, and 132 were also reported to exhibit moderate anti-HIV-1 activities by cell-based assays, while compound 115 was most active (88.2% inhibition at 200 mg/ml) [43]. 3.4.2. Anti-HBV Activity. Hepatitis B virus (HBV) is a hepatotropic virus and is known to be the major cause of chronic liver disease in humans. The P. amarus plant displayed potential for treating HBV. When P. amarus was administered to transgenic mice, hepatic HBsAg mRNA levels decreased. Further work revealed that P. amarus down-regulates HBV mRNA transcription by a specific mechanism involving interactions between HBV enhancer and C/EBP transcription factors [130] [131]. In 2003, 25 compounds were isolated from four Phyllanthus plants, including P. amarus, P.


387

388



389

multiflorus, P. tenellus and P. virgatus. Using an HBV-producing cell line and inhibition of the expression of the HBsAg and HBeAg as antiviral indicators, a study was conducted on these compounds. It was found that compounds 99, 139, 151, and 227, at the noncytotoxic concentration of 50 mm, suppressed effectively both HBsAg and HBeAg expression, with the inhibition from 32.1 to 74.3% [111]. Besides, EtOH extract of P. nanus also exhibited potent antiviral activity [132]. 3.4.3. Anti-HSV Activity. Herpes simplex virus (HSV) is a single large doublestranded DNA enveloped virus that is extremely widespread in the human population. It is responsible for a broad range of diseases, ranging from gingivostomatitis to keratoconjunctivitis, genital diseases, encephalitis, and also infections of newborn and immunocompromised patients. Different solvent extracts from P. urinaria showed antiHSV-1 and HSV-2 activities. The 50% inhibitory concentrations against HSV-2 infection of acetone, EtOH, and MeOH extracts were 4.3 0.5, 5.0 0.4 and 4.0 0.9 mg/ml, respectively. All three extracts showed no cytotoxic effects against Vero cells at a concentration of 10.0 mg/ml or below. Further studies on this plant revealed that compounds 227 and 274 exhibited anti-HSV activities. The 50% inhibitory concentration was 18.4 2.0 mm (against HSV-2 infection) and 19.2 4.0 mm (against HSV-1). [90] [133]. Additionally, the H2O extract from leaves and stems of P. orbicularis exhibited antiviral activities with EC50 values of 21.27 1.8, 25.7 7, and 65.8 8 mg/ml againt bovine herpesvirus type 1 (BHV-1), HSV-2, and adenovirus type 7 (Ad-7), respectively [134]. 3.4.4. Anti-CVB3 Activity. Coxsackie virus B3 (CVB3) is a member of the genus Enterovirus of the Picornaviridae family that contains a single-stranded, positive-sense RNA genome. In 2009, Zhang and co-workers reported that phyllaemblicin B (10), the main compound isolated from P. emblica, inhibited CVB3-mediated cytopathic effects on HeLa cells with an IC50 value of 7.75 0.15 mg/ml [135]. At the same time, three norsesquiterpenoids, 2, 10, and 11, from P. emblica were found to exhibit srong antiCVB3 activities with IC50 values of 21.8, 7.8, and 11.0 mg/ml, respectively [4]. 3.5. Hepatoprotective Activity. In 2008, Suru et al. found that the extracts of P. amarus could protect the liver against aflatoxin B1-induced hepatic damage and against EtOH-induced oxidative damage by possibly reducing the rate of lipid peroxidation and increasing the antioxidant defense mechanism in rats [136] [137]. Moreover, phyllanthin (141), a known principal constituent of this plant, exhibited hepatoprotective effect against EtOH-induced oxidative stress causing rat liver-cell damage through its antioxidant activity [138]. CCl4 induced a rise of the serum enzymes, GOT and GPT, well-known markers for hepatic injury. Harish and Shivanandappa reported that pretreatment of rats with the extracts of P. niruri markedly reduced CCl4-induced changes in the serum enzymes [124]. The hepatoprotective activities of the extracts were also demonstrated in vivo against paracetamol-induced liver damage [139]. P. rheedii has been used by Muthuvan tribes of Kerala for curing liver diseases. A study concluded that pretreatment with EtOH extract of P. rheedii protected the rat liver from hepatotoxicity of d-galactosamine, and showed a remarkable free-radical scavenging and choleretic activity [140]. P. urinaria and P. maderaspatensis extracts also exhibited remarkable hepatoprotective activities against acetaminophen-induced hepatotoxicity [141] [142]. In 2009, debelalactone (301), isolated from P. debilis, was

390


found to exhibit a significant antihepatotoxic activity aflatoxin B1-induced hepatic damage [107]. 3.6. Antimicrobial Activity. Justicidin B (119), which was found to occur in high amounts in P. reticulatus, inhibited the growth of the pathogenic fungi Aspergillus fumigatus, Aspergillus flavus, and Candida albicans [58]. The acetone, MeOH, and H2O extracts of P. parvulus and P. burchellii showed good inhibitory effects against bacteria [143]. In 2010, Chouhan and Singh reported that the antibacterial activity of a petroleum ether extract (PSPE) and of an EtOH extract (PSEE) was in the range of 7 – 20 mm (zone of inhibition) against the tested species of bacteria. PSEE was found to exhibit a significant activity against S. flexneri, and moderate activities against E. coli and V. chlorae [144]. 3.7. Antimutagenic Activity. In 2002, the extract of P. amarus was reported to possess an antimutagenic activity. The extract inhibited the mutagenicity produced and the activation of the mutagens. Inhibition of mutagenicity of 2-AAF and AFB1 may be mainly due to inhibition of their activation mediated by P-450 enzymes [145]. The H2O extract of P. orbicularis also showed a significant antimutagenic effect against the carvinogenic aromatic amines PhIP and 4-ABP [146]. 3.8. Antidiabetic Activity. Diabetes is one of the most prevalent chronic diseases in the world. P. sellowianus has been used in folk medicine as antidiabetic agent. The H2O extract was partitioned between CH2Cl2 and BuOH. At the dose of 200 mg/kg, the BuOH and H2O fractions significantly reduced the blood glucose levels (after 6 h from 359.7 14.6 to 295.5 20.1 mg/dl, and from 372.3 17.0 to 293.7 26.1 mg/dl, resp.) [147]. The petroleum ether and EtOH extracts of leaves of the P. reticulatus showed antidiabetic activities at the dose of 1000 mg/kg [148]. In 2009, it was reported that the H2O and MeOH extracts of P. simplex had therapeutic value in diabetes, and the H2O extract of the leaves and seeds of P. amarus lowered plasma glucose in normal mice in a dose-dependent manner [149] [150]. 3.9. Anti-Ulcer Activity. In 2008, Iacomini and co-workers found that the polysaccharide and another acidic heteroxylan from P. niruri possessed anti-ulcer activities, and they were able to reduce gastric lesions induced by EtOH (ED50 40.0 and 20.4 mg/kg, resp.) [151]. On the other hand, it was reported that the BuOH extract of the H2O-soluble fraction of the fruits of P. emblica exerts cytoprotective action on gastric ulcer formation predominatly by its antioxidant property [152]. 3.10. Others. The P. amarus H2O extract could inhibit CrVI-induced oxidative toxicity to MDA-MB-435S cells, metabolic activation of carcinogen, and cell-cycle regulators, and DNA repair [153 – 155]. Moreover, 75% MeOH extract of this plant reduced the toxic side-effects of cyclophosphamide (CTX) and did not interfer with the antitumor efficiency of CTX [156]. P. niruri is a medicinal plant widely distributed in Indonesia and is often used in folk medicine to treat epilepsy, malaria, hypertension, diarrhea, fever, and urinary calculus. Iizuka et al. reported that compound 304 isolated from the leaves of P. niruri L. inhibited norepinephrine (NE)-induced vasoconstrictions and was a potent inhibitor of platelet aggregation comparable to adenosine [157] [158]. Compound 156 from this plant exhibited nematicidal activity when tested against reniform nematode and rootknot nematode (LC50 3.3 and 14.5 ppm, resp.) [69]. The MeOH extract from the leaves of P. niruri L. showed oral activity against potassium oxonate- and uric acid-induced


391

hyperuricemia in rats. Further study of this plant revealed that compounds 141, 97, 101 showed significant reductions of 76.64, 64.47, 34.87%, respectively, in plasma uric acid level of hyperuricemic control animals, at 10 mg/kg [51]. In addition, compound 270 possessed antibabesial and antiplasmodial activities, and compounds 184 and 271 exhibited moderate activities [93]. Justicidin B (119) exhibited strong activities against Trypanosoma brucei rhodesiense and Trypanosoma cruzi (IC50 0.2 and 2.6 mg/ml, resp.) [58]. 4. Conclusions. – The genus Phyllanthus comprises ca. 800 species, and some of them have been used as traditional herbal medicines. This review revealed that Phyllanthus should be a rich source for natural product chemists to find more compounds with various types of skeletons and biological activities. Nevertheless, there are still many Phyllanthus species that have received no or only little attention. In the future, based on their chemical and biological diversity, the plants of Phyllanthus need further studies. This work was supported by the National Natural Science Foundation of China (Nos. 20972062 and 21172196)

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