Recent advances regarding constituents and bioactivities of plants from the genus Hypericum.

CHEMISTRY & BIODIVERSITY – Vol. 12 (2015)

309

REVIEW Recent Advances Regarding Constituents and Bioactivities of Plants from the Genus Hypericum by Jie Zhao* a ), Wei Liu a ), and Jin-Cai Wang b ) a

) School of Pharmacy, Xinxiang Medical University, Xinxiang 453003, P. R. China (phone: þ 86-373-3831879; e-mail: [email protected]) b ) First Affiliated Hospital, Xinxiang Medical University, Xinxiang 453003, P. R. China

Contents 1. Introduction 2. Chemical Constituents 2.1. Naphthodianthrones and Bianthraquinones 2.2. Phloroglucinols 2.2.1. Hyperforin Derivatives 2.2.2. Sampsoniones 2.2.3. Spirocyclic Acylphloroglucinols 2.2.4. Rottlerin-Type Compounds 2.2.5. Simple Phloroglucinol Derivatives 2.3. Xanthones 2.4. Benzophenones 2.5. Flavonoids 2.6. Chromones 2.7. Others 3. Biological Activities 3.1. Antidepressant Activity 3.2. Cytotoxic Activity 3.2.1. Cytotoxicity Induced by Phloroglucinol Derivatives 3.2.2. Cytotoxicity Induced by Xanthone Derivatives 3.2.3. Cytotoxicity Induced by Chromone Derivatives 3.2.4. Cytotoxicity Induced by Other Compounds 3.3. Antimicrobial Activity 3.4. Antioxidant Activity 4. Conclusions 1. Introduction. – Hypericum belongs to the family Hypericaceae (alternative name Clusiaceae) and is a genus of ca. 450 species [1]. Many of its species have been used as traditional medicinal plants in various parts of the world. The widespread interest in the use of Hypericum perforatum (St. Johns Wort (SJW)) in mild-to-moderate depression has prompted investigation of the bioactive metabolites from other species of this genus. SJW is the only herbal alternative to classic synthetic antidepressants in the 2015 Verlag Helvetica Chimica Acta AG, Zrich

310


therapy of depression. Numerous reports and several recent reviews have been published concerning these aspects [2]. In recent years, a large number of studies about Hypericum genus and its chemical constituents were performed worldwide because of their diverse activities [3 – 5]. Extracts from various Hypericum species were shown to possess antibacterial [6], antidepressant [7], antiviral [8], anti-inflammatory [9], and antioxidant activities [10]. In 2007, Xiao and Mu reviewed the secondary metabolites of Hypericum spp. and compiled the biological activities up to the beginning of 2005 [11]. Since then, a remarkable progress has been achieved in exploring metabolites and bioactivities of active compounds from Hypericum species. In this article, we provide an overview of the advances on Hypericum species during the past few decades. The names of the isolated compounds, and their sources, and corresponding references are presented in the Table. This review is intended to fully enumerate the constituents, including their bioactivities, and, thus, to provide a reference compilation for further research on this genus. 2. Chemical Constituents. – The known chemical constituents of Hypericum, 1 – 371, include phloroglucinols, xanthones, flavonoids, and others. As can be seen, phloroglucinols and xanthones are the predominant constituents of the genus Hypericum. 2.1. Naphthodianthrones and Bianthraquinones, 1 – 12. One of the most interesting biologically active substances of H. perforatum is hypericin (1). It was established that hypericin is 1,3,4,6,8,13-hexahydroxy-10,11-dimethylphenanthro[1,10,9,8-opqra]perylene-7,14-dione, and belongs to a class of colored (or pigmented) chemical substances that show photosensitizing activity [12]. A more detailed study of H. perforatum led to the detection and isolation of hypericin (1) and pseudohypericin (2). Protohypericin (3) and hypericodehydrodianthrone (5) were isolated from H. montanum, and protopseudohypericin (4), pseudohypericodehydrodianthrone (6), and cyclopseudohypericin (7) from H. perforatum [12]. It is well-known that light induces the oxidation of protopigments 3 and 4 to 1 and 2, respectively [12]. Four new bianthraquinone glycosides, 8 – 11, have been isolated from H. perforatum [13]. Later, a new bianthraquinone glycoside, 12, was isolated from H. sampsonii [14]. The aglycone of these five glycosides is skyrin. Compounds 8 and 11, and 9 and 12 are the two respective atropisomeric forms. 2.2. Phloroglucinols. A large number of differently substituted and structurally diverse phloroglucinols were reported to occur in H. perforatum. We, herein, classified 170 analogs of phloroglucinol in five subclasses, i.e., hyperforin derivatives, sampsoniones, spirocyclic acylphloroglucinol derivatives, rottlerin-type compounds, and simple phloroglucinol derivatives. 2.2.1. Hyperforin Derivatives, 13 – 58. Hyperforin (13), a bicyclic polyprenylated acylphloroglucinol derivative, is the main active principle of H. perforatum extract responsible for its antidepressive activity [15]. Adhyperforin (14), as 13, is a potent inhibitor of the uptake of dopamine, serotonin, and noradrenaline [16]. Two new prenylated phloroglucinol derivatives, furoadhyperforin isomers A and B (15 and 20, resp.), as well as eight known compounds, furohyperforin isomer 1 (16), 27epifurohyperforin isomer 1 (21), furohyperforin (26), 33-deoxy-33-hydroperoxyfurohyperforin (27), furohyperforin isomer 2 (28), hyperibone J (32), 8-hydroxyhyperforin-8,1-hemiacetal (31), and pyrano[7,28-b]hyperforin (34), were isolated from the


311

Table. Chemical Constituents of Plants from the Genus Hypericum Compound

Compound class and name

Source

Ref.

1 2 3 4 5 6 7 8 9 10 11 12

Naphthodianthrones and bianthraquinones Hypericin Pseudohypericin Protohypericin Protopseudohypericin Hypericode hydrodianthrone Pseudohypericode hydrodianthrone Cyclopseudohypericin (þ)-( S )-Skyrin 6-O-b-d-glucopyranoside (þ)-( S )-Skyrin 6-O-b-d-xylopyranoside (þ)-( S )-Skyrin 6-O-a-l-arabinofuranoside ()-( R)-Skyrin 6-O-b-d-glucopyranoside ()-( R)-Skyrin 6-O-b-d-xylopyranoside

H. perforatum H. perforatum H. montanum H. perforatum H. perforatum H. perforatum H. perforatum H. perforatum H. perforatum H. perforatum H. perforatum H. sampsonii

[12] [12] [12] [12] [12] [12] [12] [13] [13] [13] [13] [14]

13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46

Phloroglucinols Hyperforin derivatives Hyperforin Adhyperforin Furoadhyperforin isomer A Furohyperforin isomer 1 Hyperibone A Hyperibone C Hyperibone B Furoadhyperforin isomer B 27-Epifurohyperforin isomer 1 Hyperibone D Hyperibone E Hyperibone F Hyperibone G Furohyperforin 33-Deoxy-33-hydroperoxyfurohyperforin Furohyperforin isomer 2 Hyperibone H Hyperibone I 8-Hydroxyhyperforin-8,1-hemiacetal Hyperibone J Oxepahyperforin Pyrano[7,28-b]hyperforin Papuaforin A Papuaforin C Papuaforin D Papuaforin E Papuaforin B Hyperpapuanone Hyperibone L-a Hyperibone L-b 7-Epiclusianone Ialibinone A Ialibinone B Ialibinone C

H. perforatum H. perforatum H. perforatum H. perforatum H. scabrum H. scabrum H. scabrum H. perforatum H. perforatum H. scabrum H. scabrum H. scabrum H. scabrum H. perforatum H. perforatum H. perforatum H. scabrum H. scabrum H. perforatum H. scabrum H. perforatum H. perforatum H. papuanum H. papuanum H. papuanum H. papuanum H. papuanum H. papuanum H. scabrum H. scabrum H. sampsonii H. papuanum H. papuanum H. papuanum

[15] [16] [17] [17] [18] [18] [18] [17] [17] [18] [18] [18] [18] [17] [17] [17] [18] [18] [17] [19] [18] [17] [20] [20] [20] [20] [20] [20] [19] [19] [21] [22] [22] [22]

312


Table (cont.) Compound


Source

Ref.

47 48 49 50 51 52 53 54 55

H. papuanum H. papuanum H. papuanum H. papuanum H. papuanum H. papuanum H. papuanum H. papuanum H. perforatum

[22] [22] [23] [23] [23] [23] [23] [23] [24]

H. perforatum

[24]

57 58

Ialibinone D Ialibinone E Enaimeone A Enaimeone B Enaimeone C 1’-Hydroxyialibinone A 1’-Hydroxyialibinone B 1’-Hydroxyialibinone D Methyl (1S,3R,4R )-4-methyl-1,5-bis(3-methylbut-2-en-1-yl)-4-(4-methylpent-3-en-1-yl)-3-(2methylpropanoyl)-2-oxocyclohexanecarboxylate (2R,3R,6R )-3-Methyl-4,6-bis(3-methylbut-2-en1-yl)-3-(4-methylpent-3-en-1-yl)-2-(2-methylpropanoyl)cyclohexanone Prolifenone A Prolifenone B

H. prolificum H. prolificum

[25] [25]

59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87

Sampsoniones Sampsonione A Sampsonione B Sampsonione C Sampsonione D Sampsonione E Hypersampsone A Hypersampsone D Hypersampsone B Hypersampsone C Hypersampsone E Sampsonione F Sampsonione G Sampsonione H Sampsonione I Sampsonione J Sampsonione K Sampsonione L Sampsonione M Sampsonione N Sampsonione O Otogirinin D Sampsonione P Otogirinin E Sampsonione Q Otogirinin A Otogirinin B Otogirinin C Sinaicinone Hypersampsone F

H. sampsonii H. sampsonii H. sampsonii H. sampsonii H. sampsonii H. sampsonii H. sampsonii H. sampsonii H. sampsonii H. sampsonii H. sampsonii H. sampsonii H. sampsonii H. sampsonii H. sampsonii H. sampsonii H. sampsonii H. sampsonii H. sampsonii H. sampsonii H. erectum H. sampsonii H. erectum H. sampsonii H. erectum H. erectum H. erectum H. sinaicum H. sampsonii

[26] [26] [27] [27] [27] [21] [21] [21] [21] [21] [27] [27] [27] [28] [28] [29] [29] [29] [30] [30] [31] [30] [31] [30] [31] [31] [31] [32] [21]

88

Spirocyclic phloroglucinols Tomoeone A

H. ascyron

[33]

56


313



Source

Ref.

89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106

Tomoeone C Tomoeone E Tomoeone G Tomoeone B Tomoeone D Tomoeone F Tomoeone H Hyperbeanol A Hyperbeanol B Hyperbeanol C Hyperbeanol D Chipericumin C Chipericumin D Chipericumin A Chipericumin B Hypercalin B Hyperielliptone HA Hyperielliptone HB

H. ascyron H. ascyron H. ascyron H. ascyron H. ascyron H. ascyron H. ascyron H. beanii H. beanii H. beanii H. beanii H. chinense H. chinense H. chinense H. chinense H. beanii H. geminiflorum H. geminiflorum

[33] [33] [33] [33] [33] [33] [33] [34] [34] [34] [34] [35] [35] [35] [35] [34] [36] [36]

107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135

Rottlerin-type compounds Sarothralin Sarothralen A Saroaspidin A Saroaspidin B Saroaspidin C Sarothralin G Japonicine C Uliginosin A Japonicine A Albaspidin P-P Albaspidin A-A Drummondin E Drummondin F Hyperbrasilol C Sarothralen B Drummondin A Drummondin B Drummondin C Drummondin D Hyperbrasilol B Uliginosin B Sarothralen C Japonicine B Isodrummondin D Isohyperbrasilol B Isouliginosin B Hyperbrasilol A Sarothralen D Japonicine D

H. japonicum H. japonicum H. japonicum H. japonicum H. japonicum H. japonicum H. japonicum H. uliginosum H. japonicum H. drummondii H. drummondii H. drummondii H. drummondii H. brasiliense H. japonicum H. drummondii H. drummondii H. drummondii H. drummondii H. brasiliense H. uliginosum H. japonicum H. japonicum H. drummondii H. brasiliense H. brasiliense H. brasiliense H. japonicum H. japonicum

[37] [38] [39] [39] [39] [40] [41] [42] [41] [43] [43] [44] [44] [45] [37] [46] [46] [46] [43] [44] [42] [39] [40] [47] [44] [43] [43] [39] [40]

314


Table (cont.) Compound 136 137 138 139 140

141 142 143 144 145 146 147 148 149 150 151

152

153

154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172

Compound class and name Simple phloroglucinol derivatives 3-Geranyl-1-(2-methylpropanoyl)-phloroglucinol 3-Geranyl-1-(2-methylbutanoyl)-phloroglucinol 1-(2,4-Dihydroxy-6-methoxy-3-methylphenyl)2-methylpropan-1-one 1-(2,4-Dihydroxy-6-methoxy-3-methylphenyl)2-methylbutan-1-one 1-{3-[(3,3-Dimethyloxiran-2-yl)methyl]-2,4,6trihydroxy-5-(3-methylbut-2-en-1-yl)phenyl}2-methylbutan-1-one Olympicin A Olympicin B Olympicin C Olympicin D Olympicin E 3-Geranyl-1-(3-methylbutanoyl)phloroglucinol Hyperjovinol A 1-(4-{[(2E )-3,7-Dimethylocta-2,6-dien-1-yl]oxy}2,6-dihydroxyphenyl)-2-methylpropan-1-one 4-Geranyloxy-1-(2-methylbutanoyl)phloroglucinol Hyperjovinol B 1-[3,4-Dihydro-5,7-dihydroxy-2-methyl-2(4-methylpent-3-en-1-yl)-2H-1-benzopyran-6-yl]2-methylpropan-1-one 1-[3,4-Dihydro-5,7-dihydroxy-2-methyl-2(4-methyl-pent-3-en-1-yl)-2H-1-benzopyran-8-yl]2-methylpropan-1-one 1-[3,4-Dihydro-5,7-dihydroxy-2-methyl-2(4-methylpent-3-en-1-yl)-2H-1-benzopyran-8-yl]2-methylbutan-1-one Hypercalyxone A Hypercalyxone B Prolificin A Hyperguinone A Hyperguinone B Petiolin A Petiolin B Petiolin J Petiolin C Petiolin L Petiolin M Yojironin C Yojironin E Yojironin F Yojironin G Yojironin H Yojironin D Yojironin I Petiolin D

Source

Ref.

H. empetrifolium H. empetrifolium H. beanii

[48] [48] [49]

H. beanii

[49]

H. foliosum

[50]

H. olympicum H. olympicum H. olympicum H. olympicum H. olympicum H. styphelioides H. jovis H. jovis

[51] [51] [51] [51] [51] [52] [53] [53]

H. jovis H. jovis H. jovis

[53] [53] [53]

H. amblyocalyx

[54]

H. amblyocalyx

[54]

H. amblyocalyx H. amblyocalyx H. prolificum H. papuanum H. papuanum H. pseudopetiolatum H. pseudopetiolatum H. pseudopetiolatum H. pseudopetiolatum H. pseudopetiolatum H. pseudopetiolatum H. yojiroanum H. yojiroanum H. yojiroanum H. yojiroanum H. yojiroanum H. yojiroanum H. yojiroanum H. pseudopetiolatum

[54] [54] [25] [23] [23] [55] [55] [56] [55] [56] [56] [57] [57] [58] [58] [58] [58] [58] [59]


315



Source

Ref.

173 174 175 176 177 178 179 180 181 182

Petiolin K Furonewguinone A Furonewguinone B Erectquione A Erectquione B Erectquione C Hypercalin A Hypercalin B Hypercalin C Elliptophenone A

H. pseudopetiolatum H. papuanum H. papuanum H. erectum H. erectum H. erectum H. calycinum H. calycinum H. calycinum H. ellipticum

[56] [24] [24] [60] [60] [60] [61] [61] [61] [62]

H. ellipticum H. ellipticum

[62] [62]

H. ellipticum H. ellipticum H. chinense H. chinense H. chinense H. chinense H. chinense H. chinense H. chinense H. chinense H. chinense H. chinense H. chinense H. chinense H. chinense H. chinense H. chinense H. chinense H. chinense H. chinense H. chinense

[62] [62] [63] [63] [63] [63] [63] [63] [63] [63] [64] [64] [64] [64] [64] [64] [64] [64] [64] [64] [65]

H. chinense H. chinense H. chinense H. chinense H. chinense H. chinense H. chinense H. chinense H. chinense H. chinense H. chinense H. chinense H. chinense

[65] [65] [65] [65] [65] [65] [65] [65] [65] [65] [65] [65] [65]

183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218

Xanthones Elliptoxanthone A 2,6,8-Trihydroxy-1-(3-methylbut-2-en-1-yl)9H-xanthen-9-one 1,6-Dihydroxy-4-methoxy-9H-xanthen-9-one 1,4,5-Trihydroxy-9H-xanthen-9-one 2-Hydroxy-5-methoxy-9H-xanthen-9-one 1,2,5-Trihydroxy-9H-xanthen-9-one 1,3-Dihydroxy-5-methoxy-9H-xanthen-9-one 3,5-Dihydroxy-1-methoxy-9H-xanthen-9-one 4-Hydroxy-2,3-dimethoxy-9H-xanthen-9-one 3,5,6-Trihydroxy-1-methoxy-9H-xanthen-9-one 3,6-Dihydroxy-1,7-dimethoxy-9H-xanthen-9-one 3,7-Dihydroxy-1-methoxy-9H-xanthen-9-one 4,6-Dihydroxy-2,3-dimethoxy-9H-xanthen-9-one 2,6-Dihydroxy-3,4-dimethoxy-9H-xanthen-9-one 6-Hydroxy-2,3,4-trimethoxy-9H-xanthen-9-one 3,6-Dihydroxy-1,2-dimethoxy-9H-xanthen-9-one 4,7-Dihydroxy-2,3-dimethoxy-9H-xanthen-9-one 3,7-Dihydroxy-2,4-dimethoxy-9H-xanthen-9-one 3-Hydroxy-2-methoxy-9H-xanthen-9-one 1,5-Dihydroxy-3-methoxy-9H-xanthen-9-one 3,4-Dihydroxy-2-methoxy-9H-xanthen-9-one 1,5,6-Trihydroxy-3-methoxy-9H-xanthen-9-one 1,3,7-Trihydroxy-2-(2-hydroxy-3-methylbut3-en-1-yl)-9H-xanthen-9-one 1,3,7-Trihydroxy-5-methoxy-9H-xanthen-9-one 1,7-Dihydroxy-5,6-dimethoxy-9H-xanthen-9-one 4,5-Dihydroxy-2,3-dimethoxy-9H-xanthen-9-one 1,3-Dihydroxy-2,4-dimethoxy-9H-xanthen-9-one 2-Hydroxy-9H-xanthen-9-one 2-Hydroxy-1-methoxy-9H-xanthen-9-one 1,7-Dihydroxy-9H-xanthen-9-one 2,5-Dihydroxy-9H-xanthen-9-one 2,7-Dihydroxy-9H-xanthen-9-one 1,3-Dihydroxy-2-methoxy-9H-xanthen-9-one 2,5-Dihydroxy-1-methoxy-9H-xanthen-9-one 3-Hydroxy-2,4-dimethoxy-9H-xanthen-9-one 1,3,5,6-Tetrahydroxy-9H-xanthen-9-one

316




Source

Ref.

219 220 221 222 223 224 225 226 227 228

1,3,5-Trihydroxy-6-methoxy-9H-xanthen-9-one 1,3,6-Trihydroxy-5-methoxy-9H-xanthen-9-one 1,3,6,7-Tetrahydroxy-9 H-xanthen-9-one 1,5-Dihydroxy-6,7-dimethoxy-9H-xanthen-9-one 3,8-Dihydroxy-1,2-dimethoxy-9H-xanthen-9-one 3,5-Dihydroxy-1,2-dimethoxy-9H-xanthen-9-one 1,3,5-Trihydroxy-6,7-dimethoxy-9H-xanthen-9-one 1,3,7-Trihydroxy-5,6-dimethoxy-9H-xanthen-9-one 1,7-Dihydroxy-6-methoxy-9H-xanthen-9-one 1,3,7-Trihydroxy-2-(3-methylbut-2-en-1-yl)9H-xanthen-9-one 2,3,6,8-Tetrahydroxy-1-(3-methylbut-2-en-1-yl)9H-xanthen-9-one 1,3,7-Trihydroxy-9H-xanthen-9-one 1,7-Dihydroxy-4-methoxy-9H-xanthen-9-one 2,5-Dihydroxy-9H-xanthen-9-one 1,3-Dihydroxy-6-methoxy-9H-xanthen-9-one 3,6,7-Trihydroxy-1-methoxy-9H-xanthen-9-one 1,2,5-Trihydroxy-9H-xanthen-9-one 1,5-Dihydroxy-2-methoxy-9H-xanthen-9-one 1,3,5-Trihydroxy-6-methoxy-9H-xanthen-9-one 1-Hydroxy-9H-xanthen-9-one 1-Hydroxy-5,6,7-trimethoxy-9H-xanthen-9-one 1-Hydroxy-6,7-dimethoxy-9H-xanthen-9-one 1,3,6,7-Tetrahydroxy-2-(3-methylbut-2-en-1-yl)9H-xanthen-9-one 1,3,5-Trihydroxy-9H-xanthen-9-one 1,3,5-Trimethoxy-9H-xanthen-9-one 2,6,8-Trihydroxy-3-methoxy-1-(3-methylbut-2-en1-yl)-9H-xanthen-9-one 2-Hydroxy-5-methoxy-9H-xanthen-9-one 1,3,5,6-Tetrahydroxy-2-(3-methylbut-2-en-1-yl)9H-xanthen-9-one g-Mangostin 5-Hydroxy-2-methoxy-9H-xanthen-9-one 2-Hydroxy-3-methoxy-9H-xanthen-9-one 6,7-Dihydroxy-1,3-dimethoxy-9H-xanthen-9-one 4-Hydroxy-1,2-dimethoxy-9H-xanthen-9-one 1,5,6-Trihydroxy-3-methoxyxanthone 3,8-Dihydroxy-1,2-dimethoxy-9H-xanthen-9-one 1,3,8-Trihydroxy-2-methoxy-9H-xanthen-9-one 1,3,8-Trihydroxy-4-methoxy-9H-xanthen-9-one 1,5-Dihydroxy-6-methoxy-9H-xanthen-9-one 2,3-Dimethoxy-9H-xanthen-9-one 1,8-Dihydroxy-3-methoxy-9H-xanthen-9-one 2,3,4-Trihydroxy-9H-xanthen-9-one 7-Hydroxy-2,3,4-trimethoxy-9H-xanthen-9-one 3,6,7-Trihydroxy-1-methoxy-9H-xanthen-9-one 1,3,5,6-Tetrahydroxy-4-(3-methylbut-2-en-1-yl)9H-xanthen-9-one

H. chinense H. chinense H. chinense H. chinense H. chinense H. chinense H. chinense H. chinense H. chinense H. chinense

[65] [65] [65] [65] [65] [65] [65] [65] [65] [65]

H. scabrum

[20]

H. scabrum H. scabrum H. beanii H. beanii H. beanii H. beanii H. beanii H. beanii H. beanii H. perforatum H. perforatum H. perforatum

[20] [20] [34] [34] [34] [34] [34] [34] [34] [66] [66] [66]

H. perforatum H. perforatum H. perforatum

[66] [66] [66]

H. japonicum H. androsaemum

[67] [68]

H. androsaemum H. hookerianum H. hookerianum H. geminiflorum H. geminiflorum H. geminiflorum H. geminiflorum H. geminiflorum H. geminiflorum H. geminiflorum H. geminiflorum H. geminiflorum H. ericoides H. ericoides H. roeperianum H. japonicum

[68] [69] [70] [70] [71] [71] [71] [71] [71] [36] [36] [36] [36] [72] [72] [69] [73]

229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262


317



Source

Ref.

263 264 265

H. japonicum H. henryi H. sampsonii

[73] [73] [74]

H. sampsonii

[74]

H. japonicum

[73]

H. patulum H. patulum H. patulum H. styphelioides H. styphelioides

[75] [75] [75] [52] [52]

H. geminiflorum H. scabrum H. scabrum H. scabrum H. scabrum H. scabrum H. scabrum H. scabrum H. ellipticum H. perforatum H. perforatum H. japonicum H. roeperianum H. japonicum H. japonicum H. androsaemum H. japonicum

[36] [20] [20] [20] [20] [20] [20] [20] [62] [66] [66] [69] [69] [73] [67] [68] [73]

H. chinense

[65]

291 292 293 294 295

1,5,6-Trihydroxy-9H-xanthen-9-one 1,5-Dihydroxy-4-methoxy-9H-xanthen-9-one Potassium 1,3-dihydroxy-5-methoxy-9-oxo9H-xanthene-4-sulfonate Potassium 5-(b-d-glucopyranosyloxy)1,3-dihy-droxy-9-oxo-9H-xanthene-4-sulfonate 4,8-Dihydroxy-9-oxo-9H-xanthen-3-yl b-dglucopyranoside Patuloside A Patuloside B Paxanthonin 5-O-Demethylpaxanthonin 2-[(1S,4S )-2,2-Dimethyl-4-(prop-1-en-2-yl)cyclopentyl]-1,3,5-trihydroxy-9H-xanthen-9-one 10H-[1,3]Dioxolo[4,5-b]xanthen-10-one Hyperxanthone A Hyperxanthone B Hyperxanthone C Hyperxanthone D Hyperxanthone F Hyperxanthone E Toxyloxanthone B Elliptoxanthone B 3-O-Methylpaxanthone Paxanthone Isojacareubin 5-O-Methylisojacareubin 6-Deoxyisojacareubin 1,6-Dihydroxyisojacereubin 5-O-b-d-glucoside Cudraxanthone K 5,9,10-Trihydroxy-1,2,2-trimethyl-1,2-dihydro6H-furo[2,3-c]xanthen-6-one 2,3-Dihydro-4,7-dihydroxy-2-(1-hydroxy-1methylethyl)-5H-furo[3,2-b]xanthen-5-one 2-Deprenylrheediaxanthone B 5-O-Methyl-2-deprenylrheediaxanthone B Calycinoxanthone D Roeperanone Chinexanthone A

H. roeperianum H. roeperianum H. roeperianum H. roeperianum H. chinense

[69] [69] [69] [69] [63]

296 297 298 299 300 301 302 303 304

Xanthonolignoids 2-O-Demethylkielcorin Kielcorin Subalatin 5’-Demethoxycadensin G Cadensin G Cadensin D Cadensin A Hyperielliptone HC Hyperielliptone HD

H. chinense H. chinense H. chinense H. chinense H. chinense H. geminiflorum H. japonicum H. geminiflorum H. geminiflorum

[63] [63] [63] [63] [63] [36] [73] [36] [36]

266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290

318




Source

Ref.

305 306 307 308

Gemixanthone A Bijaponicaxanthone Jacarelhyperol A Jacarelhyperol B

H. geminiflorum H. japonicum H. japonicum H. japonicum

[71] [73] [76] [76]

H. thasium

[77]

H. thasium

[77]

H. thasium

[77]

H. thasium

[77]

H. thasium H. annulatum H. annulatum H. patulum H. pseudopetiolatum H. pseudopetiolatum H. pseudopetiolatum H. pseudopetiolatum H. elegans H. elegans H. elegans H. styphelioides H. carinatum H. carinatum H. sampsonii

[77] [78] [78] [79] [80] [80] [80] [80] [81] [81] [81] [52] [82] [82] [14]

H. sampsonii

[14]

H. erectum H. erectum

[31] [31]

H. thasium H. sikokumontanum H. sikokumontanum H. sikokumontanum H. thasium H. sikokumontanum H. sikokumontanum H. thasium H. japonicum

[77] [83] [83] [83] [77] [83] [83] [77] [84]

H. japonicum H. japonicum H. japonicum H. japonicum H. japonicum

[84] [84] [84] [84] [84]

309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344

Benzophenones 2-(3,5-Dihydroxybenzoyl)-3,5-dihydroxyphenyl b-d-xylopyranoside 2-(3,5-Dihydroxybenzoyl)-3-hydroxy-5methoxyphenyl b-d-xylopyranoside 2-(3,5-Dihydroxybenzoyl)-3,5-dihydroxyphenyl 4-O-acetyl-b-d-xylopyranoside 2-(3,5-Dihydroxybenzoyl)-3,5-dihydroxyphenyl 3-O-acetyl-a-l-arabinopyranoside Garcimangosone D Annulatophenonoside Acetylannulatophenonoside Paglucinol Petiolin F Petiolin G Petiolin H Petiolin I Elegaphenonoside Hypericophenonoside Neoannulatophenonoside 4-Benzoyl-2,6-dihydroxyphenyl b-d-glucopyranoside Cariphenone A Cariphenone B (2,6-Dihydroxy-4-{[(2E)-7-hydroxy-3,7-dimethyloct2-en-1-yl]oxy}phenyl)(phenyl)-methanone (2,6-Dihydroxy-4-{[(2E)-5-hydroxy-3,7-dimethylocta-2,7-dien-1-yl]oxy}phenyl)-(phenyl)methanone Otogirinin F Otogirinin G Flavonoids Quercetin Hyperin Rutin Quercitrin Isoquercetin Avicularin Quercetin 3-O-(2-acetyl)-b-d-galactoside Quercetin-7-O-a-l-rhamnoside Quercetin 3-O-a-l-rhamnosyl-(1 ! 2)O-a-l-rhamnoside Kaempferol Kaempferol-3-O-b-d-glucoside Kaempferol-7-O-a-l-rhamnoside (2R,3R )-Dihydroquercetin 3,7-O-a-l-dirhamnoside (2R,3R )-Dihydroquercetin 7-O-a-l-rhamnoside


319



Source

Ref.

345 346

(2R,3R )-Dihydroquercetin 2,3-trans-Dihydro-3,5,4’-trihydroxyfavonol 7-O-a-l-rhamnoside 2-(3,4-Dihydroxyphenyl)-5-hydroxy3-methoxy-8,8-dimethyl-4H,8Hbenzo[1,2-b:3,4-b’]dipyran-4-one 3,8’’-Biapigenin

H. japonicum H. japonicum

[84] [84]

H. japonicum

[84]

H. thasium

[77]

H. sikokumontanum H. sikokumontanum H. sikokumontanum H. sikokumontanum H. sikokumontanum H. sikokumontanum H. sikokumontanum H. japonicum

[83] [83] [83] [83] [83] [83] [83] [84]

H. japonicum

[84]

H. yojiroanum H. yojiroanum H. chinense H. chinense H. chinense H. chinense H. chinense H. chinense H. chinense H. chinense H. chinense H. chinense H. chinense H. chinense

[57] [57] [85] [85] [85] [86] [86] [86] [86] [87] [88] [88] [88] [88]

347

348 349 350 351 352 353 354 355 356 357

358 359 360 361 362 363 364 365 366 367 368 369 370 371

Chromones Takanechromone A Takanechromone B Takanechromone C Takanechromanone A Takanechromanone B 5,7-Dihydroxy-3-methyl-4H-1-benzopyran-4-one 3-Ethyl-5,7-dihydroxy-4H-1-benzopyran-4-one 8-(b-d-Glucopyranosyloxy)-5,7-dihydroxy2-(1-methylethyl)-4H-1-benzopyran-4-one 8-(b-d-Glucopyranosyloxy)-5,7-dihydroxy2-(1-methylpropyl)-4H-1-benzopyran-4-one Others Yojironin A Yojironin B Biyoulactone A Biyoulactone B Biyoulactone C Hyperolactone A Hyperolactone B Hyperolactone C Hyperolactone D Biyouyanagin A Biyouyanagin B Biyouyanagiol 5,6-Dihydrohyperolactone D 4-Hydroxyhyperolactone D

aerial parts of H. perforatum. The orientations of HC(28) in the pairs of 15/16 and 20/ 21 were a and b, respectively[17]. Tanaka et al. isolated nine new polyprenylated benzoylphloroglucinol derivatives, hyperibones A – I (17 – 19, 22 – 25, 29, and 30, resp.); hyperibone J (32), and hyperibone L-a and hyperibone L-b (41 and 42, resp.) were isolated from the aerial parts of the Uzbekistan medicinal plant H. scabrum [18] [19]. Winkelmann et al. isolated 19 acylphloroglucinol derivatives, papuaforins A – E (35 – 39, resp.), hyperpapuanone (40), ialibinones A – E (44 – 48, resp.), enaimeones A – C (49 – 51, resp.), 1’-hydroxyialibinones A, B, and D (52 – 54, resp.), and hyperguinones A and B (157 and 158, resp.) from the petroleum-ether (PE) extract of the aerial parts of H. papuanum. Hyperpapuanone (40) had a bicyclo[3.3.1]non-3-ene ring

320


system, and the bicyclic ring system of 49 – 51 can be considered as a partial structure of the ialibinones [20] [22] [23]. Three new analogs of hyperforin (13), pyrano[7,28-b]hyperforin (34), and methyl (1S,3R,4R)-4-methyl-1,5-bis(3-methylbut-2-en-1-yl)-4-(4-methylpent-3-en-1-yl)-3-(2methylpropanoyl)-2-oxocyclohexanecarboxylate (55), together with (2R,3R,6R)-3methyl-4,6-bis(3-methylbut-2-en-1-yl)-3-(4-methylpent-3-en-1-yl)-2-(2-methylpropanoyl)cyclohexanone (56), were isolated from the aerial parts of H. perforatum [24]. Prolifenones A and B (57 and 58, resp.) were isolated from the hexane extract of the aerial parts of H. prolificum [25]. 2.2.2. Sampsoniones, 59 – 87. Sampsonione derivatives were mainly isolated from H. sampsonii, as well as from other species such as H. erectum and H. sinaicum. Hu et al., who carried out a detailed investigation of the EtOH extract of the aerial parts of H. sampsonii, isolated sampsoniones A – M (59 – 63 and 69 – 76, resp.), which form a unique family of related polyprenylated benzoylphloroglucinols possessing a novel tetracyclic skeleton with a homoadamantyl-like core formed by complex cyclizations of prenyl substituents [26 – 29]. Sampsonione I (72) was the first


321

polyprenylated benzoylphloroglucinol with a novel rigid-caged tetracyclo[7.3.1.13,11.03,8 ]tetradecane-2,12,14-trione skeleton. Later, hypersampsones A – F (64 – 68, and 87, resp.) and sampsoniones N – Q (77, 78, 80, and 82, resp.) were isolated from the same plant [21] [30]. Otogirinins A – E (83 – 85, 79, and 81, resp.), were found in the MeOH extract of Hyperici erecti herba (H. erectum Thunb.) [31]. Sinaicinone (86), isolated from the aerial parts of H. sinaicum, was a complex adamantanyl derivative with a unique skeleton and O-bearing side chains [32]. 2.2.3. Spirocyclic Acylphloroglucinols, 88 – 106. Spirocyclic acylphloroglucinols are all derivatives which possess an unusual 6,6,5-spirocyclic skeleton with geminal isoprenyl groups and a monoterpene moiety, and they are stereoisomers of each other that differ only at the relative configuration, at C(4) and C(13).

322


Tomoeones A – H (88 – 95, resp.) were isolated from leaves of H. ascyron [33]. The phytochemical investigation of the MeOH extract of H. beanii led to the isolation of four new acylphloroglucinols, hyperbeanols A – D (96 – 99, resp.) [34]. Two new tetracyclic prenylated acylphloroglucinols, chipericumins A and B (102 and 103, resp.), together with two new tricyclic prenylated acylphloroglucinols, chipericumins C and D (100 and 101, resp.), were isolated from the roots of H. chinense [35]. A new phloroglucinol, hyperielliptone HA (105), and a new spirophloroglucinol with an unprecedented skeleton, hyperielliptone HB (106), were isolated from the heartwood of H. geminiflorum. Compounds 105 and 106 were obtained as tautomeric pairs [36]. 2.2.4. Rottlerin-Type Compounds, 107 – 135. The basic chemical structure of rottlerin-type compounds contains two rings, a filicinic acid moiety (A ring) and a phloroglucinol moiety (B ring), bridged by a CH2 group. Nine new antimicrobial rottlerin-type compounds, i.e., sarothralin (107), sarothralens A – D (108, 121, 128, and 134, resp.), saroaspidins A – C (109 – 111, resp.), and sarothralin G (112), were isolated from the Et2O extracts of H. japonicum [37 – 40]. Four new acylphloroglucinol derivatives, japonicins A – D (115, 129, 113, and 135, resp.), were identified in the medicinal plant H. japonicum [41]. Antibiotic phloroglucinols, uliginosins A and B (114 and 127, resp.) were isolated from H. uliginosum [42]. Four new phloroglucinols, hyperbrasilols A – C (133, 126, and 120,


323

resp.) and isohyperbrasilol B (131), and one known phloroglucinol, isouliginosin B (132), were isolated from a PE extract of leaves and flowers of H. brasiliense [43] [44]. Seven new filicinic acid derivatives, drummondins A – F (122 – 125, 118, and 119, resp.) and isodrummondin D (130), and two known compounds, albaspidin P-P and A-A (116 and 117, resp.), were isolated from the hexane extract of stems and leaves of H. drummondii [45 – 47].

324



325

2.2.5. Simple Phloroglucinol Derivatives, 136 – 182. The simple acylphloroglucinols described in this Sect. have a prenyl/geranyl moiety or a pyran/furan ring skeleton, and contain isovaleryl, methylbutyryl, isobutyryl, acetyl, and benzoyl substituents. The monomeric acylphloroglucinol derivatives with methylbutyryl or isobutyryl substituents, 3-geranyl-1-(2-methylpropanoyl)phloroglucinol (136) and 3-geranyl-1-(2methylbutanoyl)phloroglucinol (137), respectively, were isolated from H. empetrifolium [48]. 1-(2,4-Dihydroxy-6-methoxy-3-methylphenyl)-2-methylpropan-1-one (138) was isolated from the CH2Cl2 extract of the aerial parts of H. beanii, together with a minor related acylphloroglucinol, 1-(2,4-dihydroxy-6-methoxy-3-methylphenyl)-2methylbutan-1-one (139), as a 5 : 2 mixture [49]. 1-{3-[(3,3-Dimethyloxiran-2-yl)methyl]-2,4,6-trihydroxy-5-(3-methylbut-2-en-1-yl)phenyl}-2-methylbutan-1-one (140), a new bioactive acylphloroglucinol with an epoxide moiety, was isolated from H. foliosum [50]. New acylphloroglucinols with O-geranyl substituents, olympicins A – E

326


(141 – 145, resp.), were isolated and characterized from the aerial parts of the plant H. olympicum [51]. 3-Geranyl-1-(3-methylbutanoyl)phloroglucinol (146) was isolated from H. styphelioides [52]. Two new, hyperjovinols A and B (147 and 150, resp.), and three known phloroglucinol derivatives were isolated from the CH2Cl2 extract of the Greek endemic plant H. jovis [53]. Two new bicyclic acylphloroglucinol derivatives, hypercalyxones A and B (154 and 155, resp.), were isolated from the PE extract of the aerial parts of H. amblyocalyx, together with two additional derivatives, 152 and 153, previously only known as semisynthetic products [54]. The bicyclic compounds 157 and 158 were isolated from H. papuanum, together with the corresponding tautomers, and were named hyperguinones A and B, respectively [23]. Tanaka et al. isolated eight prenylated acylphloroglucinols, petiolins A – D (159, 160, 162, and 172, resp.) and petiolins J – M (161, 173, 163, and 164, resp.), from the aerial parts of H. pseudopetiolatum [55] [56] [59]. Yojironins C – I (165 – 171, resp.) were identified in the whole plants of H. yojiroanum [57] [58]. The prenylated phloroglucinol derivatives, hyperguinones A and B (157 and 158, resp.), and petiolins A and B (159 and 160, resp.) possess a chromane skeleton, and 162 – 169, 172, and 173 contain a dihydrofuran ring. Petiolins D and K (172 and 173, resp.) are prenylated acylphloroglucinols with a citran skeleton. Three polyprenylated phloroglucinol derivatives, erectquiones A – C (176 – 178, resp.), were isolated from H. erectum [60]. Hypercalins A – C (179 – 181, resp.) were obtained from the crude PE extract of the aerial parts of H. calycinum [61].


327

2.3. Xanthones, 183 – 308. The genus Hypericum is a rich source of xanthones. Two xanthones, elliptoxanthones A and B (183 and 281, resp.), were isolated from the aerial parts of H. ellipticum, together with three known xanthones, 184 – 186 [62]. In the course of their search for xanthones in Hypericum species, Tanaka et al. isolates 14 new xanthones, 193 – 200, 205 – 209, and 290, a new xanthonolignoid, 2-Odemethylkielcorin (296), and a new phenylxanthone, chinexanthone A (295), together with four known xanthonolignoids, kielcorin (297), subalatin (298), 5’-demethoxycadensin G (299), cadensin G (300), and 31 known xanthones, 187 – 194, 201 – 204, and 210 – 228, from H. chinense [63 – 65]. Six new xanthones, hyperxanthones A – F (274 – 279, resp.), and six known xanthones, 212, 229 – 232, and 280, were obtained from the aerial parts of H. scabrum [20]. Lin and co-workers isolated three new xanthones, 6,7-

328


dihydroxy-1,3-dimethoxy-9H-xanthen-9-one (250), 4-hydroxy-1,2-dimethoxy-9Hxanthen-9-one (251), and gemixanthone A (305), two new xanthonolignoids, hyperielliptones HC and HD (303 and 304, resp.), and the known xanthones 1,3,8trihydroxy-2-methoxy-9H-xanthen-9-one (254), 1,3,8-trihydroxy-4-methoxy-9H-xanthen-9-one (255), 1,7-dihydroxy-9H-xanthen-9-one (212), 1,5-dihydroxy-6-methoxy-9Hxanthen-9-one (256), 10H-[1,3]dioxolo[4,5-b]xanthen-10-one (273), 1-hydroxy-9Hxanthen-9-one (238), 2,3-dimethoxy-9H-xanthen-9-one (257), cadensin D (301), and 1,8-dihydroxy-3-methoxy-9H-xanthen-9-one (258) from the heartwood and root of H.


329

geminiflorum [36] [71]. Seven known xanthones, 233 – 238, and calycinoxanthone D (293), were isolated from the aerial parts of H. beanii [34]. Potassium 1,3-dihydroxy-5methoxy-9-oxo-9H-xanthene-4-sulfonate (265) and potassium 1,3-dihydroxy-5-O-b-dglycopyranosylxanthone-4-sulfonate (266) were obtained from H. sampsonii as the first sulfonated xanthonoids [74]. Five xanthones, 2,3,6,8-tetrahydroxy-1-(3-methylbut-2-

330


en-1-yl)-9H-xanthen-9-one (229), g-mangostin (247), 1,3,5,6-tetrahydroxy-2-(3-methylbut-2-en-1-yl)-9H-xanthen-9-one (246), 1,7-dihydroxy-9H-xanthen-9-one (212), and cudraxanthone K (288), were isolated from cell cultures of H. androsaemum [68]. Two new xanthone derivatives, 1-hydroxy-5,6,7-trimethoxy-9H-xanthen-9-one (239) and 3O-methylpaxanthone (282), were isolated from the callus of H. perforatum, together with the known compounds paxanthone (283), cadensin G (300), 1-hydroxy-6,7dimethoxy-9H-xanthen-9-one (240), 1,3,6,7-tetrahydroxy-9H-xanthen-9-one (221), 1,3,5,6-tetrahydroxy-9H-xanthen-9-one (218), 1,3,5-trihydroxy-9H-xanthen-9-one (242), 1,3,5-trimethoxy-9H-xanthen-9-one (243), and 2,6,8-trihydroxy-3-methoxy-1(3-methylbut-2-en-1-yl)-9H-xanthen-9-one (244) [66]. Two new xanthone glycosides, patulosides A and B (268 and 269, resp.), were isolated from cell suspension cultures of H. patulum [75]. A new xanthone, 2-[(1S,4S)-2,2-dimethyl-4-(prop-1-en-2-yl)cyclopentyl]-1,3,5-trihydroxy-9H-xanthen-9-one (272), and the known compound 5-Odemethylpaxanthonin (271) were isolated from the leaves of H. styphelioides [52]. Four new xanthones were identified in the roots of H. roeperianum, and their structures were established by a combination of spectroscopic and chemical methods as 5-O-methyl-2deprenylrheediaxanthone B (292), 5-O-methylisojacareubin (285), 5-O-demethylpaxanthonin (271), and roeperanone (294). In addition, 2-hydroxy-9H-xanthen-9-one (210), 5-hydroxy-2-methoxy-9H-xanthen-9-one (248), 1,5-dihydroxy-2-methoxy-9Hxanthen-9-one (236), 2-deprenylrheediaxanthone B (291), isojacareubin (284), and calycinoxanthone D (293) were isolated and characterized [69]. From the aerial parts of H. japonicum, a new xanthone glycoside, 4,8-dihydroxy-9-oxo-9H-xanthen-3-yl b-d-


331

332


glucopyranoside (267), a novel dimeric xanthone, bijaponicaxanthone (306), a prenylated xanthone, 1,3,5,6-tetrahydroxy-4-(3-methylbut-2-en-1-yl)-9H-xanthen-9one (262), two new xanthones, 1,6-dihydroxyisojacereubin-5-O-b-d-glucoside (287) and 3,6,7-trihydroxy-1-methoxy-9H-xanthen-9-one (261), and two new bisxanthones,


333

jacarelhyperols A and B (307 and 308, resp.), were isolated, together with the four known xanthones, 1,5,6-trihydroxy-9H-xanthen-9-one (263), isojacareubin (284), 6deoxyisojacareubin (286), and 5,9,10-trihydroxy-1,2,2-trimethyl-1,2-dihydro-6H-furo[2,3-c]xanthen-6-one (289) [67] [73] [76]. Five known xanthones, kielcorin (297), cadensin A (302), 1,7-dihydroxy-9H-xanthen-9-one (212), 1,5-dihydroxy-4-methoxy9H-xanthen-9-one (264), and 1,2,5-trihydroxy-9H-xanthen-9-one (235), were also found in the CH2Cl2 extract of the stems and leaves of H. henryi [73]. H. ericoides contains 2,3,4-trihydroxy-9H-xanthen-9-one (259), 1,7-dihydroxy-9H-xanthen-9-one (212), 2-hydroxy-9H-xanthen-9-one (210), and a new compound identified as 7hydroxy-2,3,4-trimethoxy-9H-xanthen-9-one (260) by spectroscopic evidence [72]. 2.4. Benzophenones, 309 – 330. A phytochemical investigation of the AcOEt extract of H. thasium led to the isolation of four benzophenone derivatives, 2-(3,5dihydroxybenzoyl)-3,5-dihydroxyphenyl b-d-xylopyranoside (309), 2-(3,5-dihydroxybenzoyl)-3-hydroxy-5-methoxyphenyl b-d-xylopyranoside (310), 2-(3,5-dihydroxybenzoyl)-3,5-dihydroxyphenyl 4-O-acetyl-b-d-xylopyranoside (311), 2-(3,5-dihydroxy-

334


benzoyl)-3,5-dihydroxyphenyl 3-O-acetyl-a-l-arabinopyranoside (312), and the known benzophenone derivative 313 [77]. Two benzophenone O-arabinosides, annulatophenonoside (314) and acetylannulatophenonoside (315), were obtained from the MeOH extract of the herb of H. annulatum [78]. Paglucinol ({3-[(1S,4S)2,2-dimethyl-4-(1-methylethenyl)cyclopentyl]-2,4,6-trihydroxyphenyl}(phenyl)methan-


335

one; 316), was isolated from cell suspension cultures of H. patulum [79]. Four new benzophenone O-rhamnosides, petiolins F – I (317 – 320, resp.), were isolated from the aerial parts of H. pseudopetiolatum [80]. Elegaphenonoside (321), a new benzophenone O-rhamnoside, together with two known benzophenone O-glycosides, i.e., hypericophenonoside (322) and neoannulatophenonoside (323), were isolated from the aerial parts of H. elegans [81]. Two new benzophenones, cariphenones A and B (325 and 326, resp.), were isolated from the leaves of H. carinatum [82]. Two new

336


benzophenones, (2,6-dihydroxy-4-{[(2E)-7-hydroxy-3,7-dimethyloct-2-en-1-yl]oxy}phenyl)(phenyl)methanone (327) and (2,6-dihydroxy-4-{[(2E)-5-hydroxy-3,7-dimethylocta-2,7-dien-1-yl]oxy}phenyl)(phenyl)methanone (328), were obtained from the anti-HBV-active fraction of the whole herbs of H. sampsonii [14]. Otogirinins F and G (329 and 330, resp.) were isolated from the AcOEt-soluble fraction of the MeOH extract of H. erectum [31]. 2.5. Flavonoids, 331 – 348. Flavonoids (2 – 4%) are distributed widely in the genus Hypericum. The flavonol aglycones identified so far include quercetin (331) and kaempferol (340). Hyperin (332) and rutin (333) usually dominate among the glycosides of H. perforatum, followed by quercitrin (334) and isoquercitrin (335). Two new flavonoids, 2-(3,4-dihydroxyphenyl)-5-hydroxy-3-methoxy-8,8-dimethyl-4H,8Hbenzo[1,2-b:3,4-b’]dipyran-4-one (347) and (2R,3R)-dihydroquercetin 3,7-O-a-l-dirhamnoside (343), were isolated, together with nine known flavonoids, 331, 333, 339 – 342, and 344 – 346, from the aerial parts of H. japonicum [84]. 2.6. Chromones, 349 – 357. From the aerial parts of H. japonicum, two novel chromoneglycosides, 8-(b-d-glucopyranosyloxy)-5,7-dihydroxy-2-(1-methylethyl)-4H-


337

1-benzopyran-4-one (356) and 8-(b-d-glucopyranosyloxy)-5,7-dihydroxy-2-(1-methylpropyl)-4H-1-benzopyran-4-one (357), were isolated [84]. Three chromone glucosides, takanechromones A – C (349 – 351, resp.), and two chromanone glucosides, named takanechromanones A and B (352 and 353, resp.), together with four known chromones, 354 – 357, were obtained from the MeOH extracts of H. sikokumontanum [83].

338


2.7. Others, 358 – 371. Two new meroterpenoids, yojironins A and B (358 and 359, resp.), were isolated from whole plants of H. yojiroanum [57]. Three novel pentacyclic meroterpenoids with a unique dilactone structure containing CC bonded bi- and tricyclic g-lactone moieties, biyoulactones A – C (360 – 362, resp.), were obtained from the roots of H. chinense, and their structures were elucidated on the basis of spectroscopic data [85]. Four novel spiro compounds, hyperolactones A – D (363 – 366, resp.), were isolated from stems and leaves of H. chinense. Hyperolactones have a common spiro-lactone structure with a 2-alkyl- or 2-aryl-9-methyl-9-vinyl-1,7-dioxaspiro[4.4]non-2-ene-4,6-dione skeleton [86]. A structurally unique hydrophobic compound, biyouyanagin A (367), was isolated from the MeOH extract of the leaves of H. chinense [87]. Three new spiro-lactone-related derivatives, biyouyanagin B (368), 5,6dihydrohyperolactone D (370), and 4-hydroxyhyperolactone D (371), together with biyouyanagiol (369), an acylphloroglucinol-related compound with a unique cyclopenta-1,3-dione moiety, were isolated from H. chinense. Biyouyanagin A (367) was considered to be a stereoisomer of biyouyanagin B (368) [88].


339

Other constituents of the genus Hypericum are phenols (caffeic, chlorogenic, pcoumaric, ferulic, p-hydroxybenzoic, and vanillic acids), acids (isovalerianic, nicotinic, myristic, palmitic, stearic acids), carotenoids, choline, nicotinamide, pectin, b-sitosterol, straight-chain saturated hydrocarbons (C16 and C30) and alcohols (C24 , C26 and C28 ), and volatile oils (a- and b-pinene, a-terpineol, geraniol, traces of myrcene and limonene (monoterpenes), and caryophyllene and humulene (sesquiterpenes)) [2] [89]. 3. Biological Activities. – 3.1. Antidepressant Activity. Extracts of H. perforatum are widely used for the treatment of depressive disorders and are unspecific inhibitors of the neuronal uptake of several neurotransmitters. Initially, attention was focused on hypericin (1) as the major constituent of SJW, assumed to be responsible for the herbs antidepressant effects by inhibiting the enzyme monoaminooxidase (MAO). Other mechanisms of antidepressant activities are inhibition of dopamine b-hydroxylase in vitro, inhibition of synaptic uptake of serotonin and dopamine, inhibition of catechol Omethyl transferase in vitro, suppression of interlukin-6 in blood samples in vivo, and modulation of expression of serotonin receptors. The antidepressant activity of 1 is attributed to its inhibition of neuronal uptake of serotonin, norepinephrine, and

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dopamine. Like many other antidepressants, it also inhibits g-aminobutyric acid (GABA) and a-glutamate uptake [90]. However, several studies indicated that the phloroglucinol derivative hyperforin (13), and also flavone derivatives, e.g., rutin (333), participate in the antidepressant efficacy [12]. Hyperforin (13) is not only the major lipophilic chemical constituent of the medicinal plant H. perforatum, but also a potent uptake inhibitor of serotonin (5-HT), dopamine (DA), noradrenaline (NA), GABA, and l-glutamate with IC50 values in the range of 0.05 – 0.10 mg ml 1 (5-HT, NA, DA, and GABA) and ca. 0.5 mg ml 1 (l-glutamate) in synaptosomal preparations [90]. The role of the flavonol glycosides in the treatment of depression using SJW extracts is still under discussion, but an experiment demonstrated that SJW extracts without rutin (333) are less effective. Quercetin (331), as the active principle of H. hircinum extracts, showed a selective inhibitory activity against MAO-A, with an IC50 value of 0.010 mm [91]. Rutin (333) is essential for the antidepressant activity of H. perforatum extracts in the forced swimming test (FST) [92]. It was suggested that flavonoid derivatives might be responsible for the inhibitory effect on MAO [93]. A cyclohexane extract of H. polyanthemum and its main phloroglucinol derivative, uliginosin B (126), present antidepressant-like activity in the rodent FST [94]. 3.2. Cytotoxic Activity. 3.2.1. Cytotoxicity Induced by Phloroglucinol Derivatives. Hyperibone J (32), a hyperforin analog, showed moderate cytotoxicity against breast and lung tumor cells (IC50 values of 17.8 and > 20 mg ml 1, resp.) [19].


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New prenylated acylphloroglucinol derivatives, papuaforins A and C – E (36 – 38, resp.), hyperpapuanone (40), ialibinones A, B, and D (44, 45, and 47, resp.), and 1’hydroxyialibinones A, B, and D (52 – 54, resp.) from H. papuanum, were found to be moderately cytotoxic against KB cells (ATCC CCL 17). The IC50 values were 7.5 0.47 (35), 4.9 0.59 (36), 6.6 1.2 (37), 5.6 0.57 (38), 3.2 1.1 (40), 8.0 2.1 (44), 7.3 1.9 (45), 6.6 1.9 (47), 25.3 1.4 (52), > 40 (53), and 32.5 3.2 mg ml 1 (54). Hence, the hydroxylation of the ialibinones reduces the cytotoxicity remarkably [23]. Complex polyprenylated benzoylphloroglucinol derivatives from H. sampsonii, sampsoniones A and I (59 and 72, resp.), were found to be active against P388 cancer cell line (IC50 values of 13 and 6.9 mg ml 1, resp.) [27].


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Phloroglucinol derivatives tomoeones A – H (88 – 95, resp.), from H. ascyron were evaluated for their cytotoxic activities against human tumor cell lines, including multidrug-resistant (MDR) cancer cell lines. Tomoeone F (94) demonstrated significant cytotoxicity against KB cells with an IC50 value of 6.2 mm. Compound 94 was also cytotoxic against MDR cancer cell lines (KB-C2 and K562/Adr) and was more potent than doxorubicin [33]. Spirocyclic acylphloroglucinols, hyperbeanols A – D (96 – 99), from H. beanii were also evaluated against the cancer cell lines SK-BR-3, HL-60, SMMC-7721, PANC-1, MCF-7, and K562. Only 97 and 99 exhibited modest cytotoxicities against K562 cells with IC50 values of 16.9 and 20.7 mm, respectively [34]. The four acylphloroglucinol derivatives, hypercalyxones A and B (154 and 155, resp.), 1-[3,4-dihydro-5,7-dihydroxy-2-methyl-2-(4-methylpent-3-en-1-yl)-2H-1-benzopyran-8-yl]-2-methylpropan-1-one (152), and 1-[3,4-dihydro-5,7-dihydroxy-2-methyl-2-(4-methylpent-3-en-1-yl)-2H-1-benzopyran-8-yl]-2-methylbutan-1-one (153) from H. amblyocalyx, were tested for their cytotoxic potentials against KB, Caco-2, myosarcoma, and Jurkat T cells. Against KB cells, the new compounds 154 and 155 provided IC50 values of 6.5 0.78 and 7.0 0.63 mg ml 1, respectively. Compounds 152 and 153 showed similar activities (IC50 values of 8.5 0.38 and 6.2 0.72 mg ml 1, resp.). Very similar results were obtained by the cytotoxicity assays using Jurkat T and Caco-2 cells. All compounds were inactive against myosarcoma cells up to a concentration of 20 mg ml 1 [54]. Petiolins A – C (159, 160, and 162, resp.) from H. pseudopetiolatum, exhibited cytotoxicities against L1210 cells (IC50 values of 2.5, > 10, and 3.3 mg ml 1, resp.) and KB cells (IC50 values of 4.8, 9.6, and 4.9 mg ml 1, resp.) in vitro [56]. Yojironin E (166) showed cytotoxicity against P388 cells (IC50 3.7 mg ml 1) and KB cells (IC50 5.0 mg ml 1) in vitro [58]. A new meroterpenoid, yojironin A (358), showed cytotoxicity against L1210 cells (IC50 4.1 mg ml 1) and KB cells (IC50 6.8 mg ml 1) in vitro [57]. 3.2.2. Cytotoxicity Induced by Xanthone Derivatives. Elliptoxanthone A (183), 2,6,8-trihydroxy-1-(3-methylbut-2-en-1-yl)-9H-xanthen-9-one (184), 1,6-dihydroxy-4methoxy-9H-xanthen-9-one (185), and 1,4,5-trihydroxy-9H-xanthen-9-one (186) from H. ellipticum were evaluated for their cytotoxicities using three human colon cancer cell lines (HT-29, HCT-116, and Caco-2) and a normal human colon cell line (CCD18Co). Compounds 183 and 184 showed weaker activities (IC50 84 – 104 mg ml 1) than the two non-prenylated xanthone derivatives 185 and 186 (IC50 71 – 95 mg ml 1) [62]. The xanthones, including xanthonolignoids, 296 – 300, a phenyl xanthone (295), prenylated xanthones, 4,7-dihydroxy-2-(1-hydroxy-1-methylethyl)-2,3-dihydro-5H-furo[3,2-b]xanthen-5-one (290) and 1,3,7-trihydroxy-2-(2-hydroxy-3-methylbut-3-en-1yl)-9H-xanthen-9-one (205), and simple xanthones 187 – 228, isolated from H. chinense, were examined for their cytotoxic activities against a panel of human cancer cell lines (KB, K562, MCF7, and COLO205), as well as MDR human cancer cell lines including KBC2 and K562/Adr. Among the evaluated xanthonolignoids, kielcorin (297) demonstrated relatively potent cytotoxicity against KB cells with an IC50 value of 8.1 mg ml 1. It also showed about threefold reversal effect of colchicine resistance against colchicine-resistant KB (KB-C2) cells (6.5 mg ml 1), as compared with its cytotoxicity (IC50 18.4 mg ml 1) against KB-C2 cells. 2-O-Demethylkielcorin (296) displayed a relatively potent cytotoxicity (15.8 mg ml 1) against COLO205 cells. The

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prenylated xanthone possessing a dihydrofuran ring (290) showed relatively potent cytotoxicities against KB and MCF-7 cell lines (IC50 values of 9.1 and 9.8 mg ml 1, resp.). Among the evaluated simple xanthones, 2-hydroxy-1-methoxy-9H-xanthen-9one (211) showed a significant cytotoxicity against MCF-7 cells with an IC50 value of 4.0 mg ml 1, and relatively potent cytotoxicities against KB, K562, and COLO205 cell lines with IC50 values ranging from 14.0 to 21.6 mg ml 1. Compounds 189, 201, 202, 210, 212, 213, and 273 also exhibited relatively potent-to-moderate cytotoxicities against both KB and its MDR cancer cells (KB-C2) with IC50 values in the range of 12.3 – 25.4 mg ml 1 [63]. Potassium 1,3-dihydroxy-5-methoxy-9-oxo-9H-xanthene-4-sulfonate (265) and potassium 1,3-dihydroxy-5-O-b-d-glucopyranosylxanthone-4-sulfonate (266) exhibited significant cytotoxicities against P388 cancer cell line (ED50 values of 3.46 and 15.69 mmol l 1, resp.) [74]. Hyperxanthones C and E (276 and 279, resp.), 212, 218, 230, and 231 from H. scabrum showed moderate activityies against A549 and MCF-7 cancer cell lines (IC50 values ranging from 8.5 to 19.5 mg ml 1) [20]. 3.2.3. Cytotoxicity Induced by Chromone Derivatives. Chromone glucosides, takanechromones A – C (349 – 351), chromanone glucosides, takanechromanones A and B (352 and 353, resp.), 5,7-dihydroxy-3-methyl-4H-1-benzopyran-4-one (354), and 3-ethyl-5,7-dihydroxy-4H-1-benzopyran-4-one (355) from H. sikokumontanum, were evaluated against human cancer cell lines. Compounds 352 and 353 showed cytotoxicities against MDR cancer cell lines, especially against K562/Adr, which were comparable to those of doxorubicin [83]. 3.2.4. Cytotoxicity Induced by Other Compounds. Biyouyanagiol (369), 4-hydroxyhyperolactone D (371), hyperolactone A (363), hyperolactone C (365), hyperolactone D (366), and biyouyanagin A (367) from H. chinense were evaluated for their cytotoxicities against human tumor cell lines, including MDR cancer cell lines (KB cells (KB-C2), MCF-7, COLO205, and K-562). Biyouyanagin A (367) displayed moderate cytotoxicity against all tested cell lines with IC50 values ranging from 16.6 to 38.8 mg ml 1. Its cytotoxicity against KB-C2 was enhanced in the presence of colchicine; colchicine itself had no effect on the growth of KB-C2 cells at this concentration. A similar trend against MDR cancer cell lines was also observed for 363, 365, 366, and 371, suggesting that the spiro-lactone moiety could play an important role in this activity. Since these compounds are more sensitive to K562/Adr MDR cancer cells, and their cytotoxicities against KB-C2 were enhanced by colchicine, they might have some effect on the P-glycoprotein (P-gp) function of KB-C2 cells. 3.3. Antimicrobial Activity. Hyperforin (13), an acylphloroglucinol, shows exceptional antibacterial activities against penicillin-resistant Staphylococcus aureus (PRSA) and methicillin-resistant S. aureus (MRSA), with minimum inhibitory concentration (MIC) values ranging from 0.1 to 1 mg ml 1 [95]. Of the polyprenylated benzoylphloroglucinol derivatives, hyperibones A – I (17 – 19, 22 – 25, 29, and 30, resp.), were isolated from H. scabrum, 17, 19, and 22 exhibited mild in vitro antibacterial activities against MRSA and methicillin-sensitive S. aureus (MSSA) by the disc-diffusion test [19]. Dried aerial parts of H. papuanum are traditionally used as a remedy for sores and wounds due to their antibacterial activity. Phloroglucinol derivatives, ialibinones A – E


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(44 – 48, resp.), from H. papuanum, were evaluated for their antibacterial potentials against Bacillus cereus, Staphylococcus epidermidis, and Micrococcus luteus. Ialibinones C and D (46 and 47, resp.) showed stronger activities than ialibinones A and B (44 and 45, resp.) against B. cereus and S. epidermidis, but almost identical effects against M. luteus (MIC values ranging from 16 to 64 mg ml 1). The results indicate that the 1-methylvinyl group at C(3) plays a crucial role for the antibacterial activity. Further phloroglucinol derivatives from this plant are hyperpapuanone (40), 1’hydroxyialibinones A, B, and D (52, 53, and 54, resp.), and enaimeones A – C (49 – 51, resp.). Compounds 52, 53, and 54 exhibited identical or slightly reduced antibacterial acivities compared with 44, 45, and 47, whereas hyperpapuanone (40) showed moderately potent antibacterial activity against M. luteus, S. epidermis, and B. cereus [22] [23]. 7-Epiclusianone (43), isolated from the roots of H. sampsonii, showed promising activity with a MIC value of 7.3 mm against the NorA overexpressing MDR S. aureus strain SA-1199B; the MIC value of the positive control antibiotic norfloxacin 100 mm [21]. Filicinic acid derivatives, drummondins A – F (122 – 125, 118, and 119, resp.), isodrummondin D (130), and two known compounds, albaspidins A-A and P-P (117 and 116, resp.), from H. drummondii, possessed strong antibiotic activities against the Gram-positive bacteria S. aureus and Bacillus subtilis, and the acid-fast bacterium Mycobacterium smegmatis (MIC values ranging from 0.2 to 6.25 mg ml 1). For all three tested strains, the activities of 122, 123, 125, and 115 were equivalent to or higher than those exhibited by streptomycin. The linear chromene 125 was as active as the angular chromene 130. Both C-prenylated and O-prenylated compounds, 119 and 118, respectively, were active [46] [47]. Hyperbrasilols A – C (133, 126, and 120, resp.), isohyperbrasilol B (131), japonicine A (115), uliginosin A (114), and isouliginosin B (132), obtained from a PE extract of the leaves and flowers of H. brasiliense, were inhibitory to B. subtilis in a bioautography assay on silica-gel glass-backed plates. The most active compounds, 120 and 131, were antibacterial at 0.16 mg ml 1 [43] [44]. The new antibacterial acylphloroglucinols, olympicins A – E (141 – 145, resp.), were evaluated against a panel of MRSA and MDR strains of S. aureus. Compound 141 exhibited MIC values in the range of 0.5 – 1 mg l 1 against the tested S. aureus strains. Compounds 142 – 145 were also shown to be active, with MIC values ranging from 64 to 128 mg l 1 [51]. The four acylphloroglucinol derivatives, hypercalyxones A and B (154 and 155, resp.), 1-[3,4-dihydro-5,7-dihydroxy-2-methyl-2-(4-methylpent-3-en-1-yl)-2H-1-benzopyran-8-yl]-2-methylpropan-1-one (152), and 1-[3,4-dihydro-5,7-dihydroxy-2-methyl-2(4-methylpent-3-en-1-yl)-2H-1-benzopyran-8-yl]-2-methylbutan-1-one (153), from H. amblyocalyx, were active against B. cereus, S. aureus, S. epidermidis, and M. luteus. In particular, the antibacterial activities of 152 and 153 against S. epidermidis and M. luteus were equivalent to or higher than those displayed by chloramphenicol. Since 152 and 153 were significantly more active than 154 and 155, it can be concluded that the prenyl side chain at C(3) decreases the antibacterial activity. Furthermore, compounds with a 2methylpropanoyl side chain, i.e., 154 and 152, displayed stronger activities than the corresponding ones with a 2-methylbutanoyl residue, i.e., 155 and 153 [54].

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Phloroglucinol derivative petiolin C (162), obtained from H. pseudopetiolatum, showed inhibitory activity against Trichophyton mentagrophytes (MIC value 33.3 mg ml 1) [55]. Petiolin J (161) exhibited antimicrobial activities against M. luteus (MIC 8 mg ml 1), Cryptococcus neoformans (16 mg ml 1), and T. mentagrophytes (16 mg ml 1) [56]. The new prenylated acylphloroglucinol, yojironin E (166), isolated from the aerial parts of H. pseudopetiolatum, exhibited antimicrobial activities against Aspergillus niger (IC50 16 mg ml 1), Candida albicans (IC50 4 mg ml 1), C. neoformans (IC50 4 mg ml 1), and T. mentagrophytes (IC50 4 mg ml 1) [58]. A new meroterpenoid, yojironin A (358), displayed antimicrobial activities against A. niger (IC50 8 mg ml 1), C. albicans (IC50 2 mg ml 1), C. neoformans (IC50 4 mg ml 1), T. mentagrophytes (IC50 2 mg ml 1), S. aureus (MIC 8 mg ml 1), and B. subtilis (MIC 4 mg ml 1) [57]. 3.4. Antioxidant Activity. Two new, hyperjovinols A and B (147 and 150, resp.), and three known phloroglucinol derivatives, 148, 149, and 151, isolated from H. jovis, were evaluated for their antioxidant activities in vitro by using the 2,2-diphenyl-1picrylhydrazyl (DPPH) assay and in cell cultures using the dichloro-dihydrofluorescein diacetate (DCFH-DA) assay. All six compounds demonstrated significant antioxidant activities, while the activities of 147 and 136 were comparable to those of the known antioxidant Trolox (H2O-soluble form of vitamin E). Moreover, 147 also was able to prevent the exogenous stimulation of reactive oxygen species (ROS) production by H2O2 [53]. Two new compounds, 2-[(1S,4S)-2,2-dimethyl-4-(prop-1-en-2-yl)cyclopentyl]-1,3,5trihydroxy-9H-xanthen-9-one (272) and 4-benzoyl-2,6-dihydroxyphenyl b-d-glucopyranoside (324), and the known compounds 5-O-demethylpaxanthonin (271) and 3geranyl-1-(3-methylbutanoyl)phloroglucinol (146), isolated from the leaves of H. styphelioides, were evaluated for their antioxidative properties in Trolox-equivalent antioxidant activities (TEAC) and chemiluminescence (CL) assays. The results showed that xanthones 272 and 269 exhibited free-radical-scavenging activities at potency levels comparable to those of the reference antioxidant compounds quercetin (331) and rutin (333), while 324 and 146 showed more moderate activities [52]. Two new benzophenones, cariphenones A and B (325 and 326, resp.), and a phloroglucinol derivative, uliginosin B (127), obtained from H. carinatum, were evaluated for their total antioxidant capacities through a total radical-trapping parameter assay. Only cariphenone A (325) showed moderate antioxidant activity, exhibiting inhibition of chemiluminescence similar to that of quercetin (331) at the same concentration (3.2 mm) [82]. The inhibitory activities of five benzophenone derivatives, 2-(3,5-dihydroxybenzoyl)-3,5-dihydroxyphenyl b-d-xylopyranoside (309), 2-(3,5-dihydroxybenzoyl)-3-hydroxy-5-methoxyphenyl b-d-xylopyranoside (310), 2-(3,5-dihydroxybenzoyl)-3,5-dihydroxyphenyl 4-O-acetyl-b-d-xylopyranoside (311), 2-(3,5-dihydroxybenzoyl)-3,5dihydroxyphenyl 3-O-acetyl-a-l-arabinopyranoside (312), and garcimangosone D (313), and four known flavonoids, quercetin (331), quercitrin (334), isoquercetin (335), and 3,8’’-biapigenin (348), isolated from the AcOEt extract of H. thasium towards the production of ROS by human polymorphoneutrophils (PMNs), were monitored by lucigenin- and luminal-based chemiluminescence assays. The assay results revealed that benzophenones 309 and 311 are extracellular inhibitors of ROS


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production, while flavonoids 331, 333, and 348 can modulate intracellular ROS production [77]. 4. Conclusions. – In this review, comprising 96 references, we compiled 371 secondary metabolites reported from Hypericum species, as well as their biological activities. The compounds isolated from the genus Hypericum are mainly phloroglucinols, xanthones, and flavonoids. For instance, acylphloroglucinol hyperforin (13) is not only the major lipophilic chemical constituent of the medicinal plant H. perforatum in the therapy of depression, but also is an effective antibiotic. This compound has been shown to fight antibiotic-resistant forms of Staphylococcus, as well as other resistant strains of bacteria. From our review, it can be concluded that phytochemical investigations mainly focused on the species H. perforatum, H. chinense, H. sampsonii, H. papuanum, H. beanii, H. drummondii, and H. japonicum. With regard to the 450 species of this genus, there are still many species that have received little or no attention. Meanwhile, Hypericum is still a challenging genus. The structural features, and the diverse biological and pharmacological properties of the constituents are particularly attractive for drug discovery. Therefore, further studies are necessary to illustrate the chemodiversity and biological significance of these compounds and to extend the use of Hypericum species. The authors are grateful to the Scientific Research Fund of Xinxiang Medical University for providing financial support and fellowships.

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