1. Introduction
Naturally occurring benzophenones are considered compounds derived from diphenylmethanone (
Figure 1), in which one or several protons are replaced by hydroxyl, alkyl, alkyloxy groups, or halogen atoms. So far, unsubstituted benzophenone has been found in nature only in
Iris adriatica [1] and
Hemidesmus indicus [2].
Figure 1. The structure of unsubstituted benzophenone.
Despite the large number of isolated compounds over the past 50 years, the few published reviews focused almost entirely on prenylated benzophenones
[3][4][5]. Singh and Bharate reviewed naturally occurring benzophenones with a phloroglucinol ring up to December 2005
[6]. Up to now, a systematic review of the existing naturally occurring simple oxygenated benzophenones and their glycosides has not been performed. This research compiles references from 1850 to 2023 using databases like Chemical Abstracts, Scopus, Google Scholar, PubMed, and ResearchGate. The main goal of this research is to summarize the available information on structural diversity of simple oxygenated benzophenones. A consensus classification of this group of compounds is also lacking. If the biogenesis of xanthones is considered, it can be seen that ring A and the attached CO group are produced by the shikimate pathway, while ring B is formed in the acetate–malonate pathway
[7], yielding an oxygenated benzophenone intermediate, which subsequently undergoes molecular dehydration to give xanthone. Furthermore, it has been reported that the transformation can be accomplished from a benzophenone glycoside by elimination of the glycosidic moiety and subsequent dehydration
[8]. Therefore, simple oxygenated benzophenones and their glycosides are precursors in the biogenesis of xanthones. Thus, the classification for the biosynthetically related xanthones provided by Mandal et al.
[9] is used in this research. Special attention is given to benzophenone C- and O-glycosides. The second goal of this research is to summarize the published information on the distribution of simple oxygenated benzophenones and their glycosides. Some synthetic hydroxy and methoxy benzophenones are heavily used in sunscreens and in personal care cosmetic products and both associated with allergy and photoallergy
[10].
2. Monooxygenated Benzophenones
Only two naturally occurring benzophenones (
Figure 2), which have a hydroxyl or methoxy group in
para position to carbonyl function, were reported in the literature.
p-Hydroxybenzophenone
1 was isolated from 1,2-dichloroethylene extract of
Talauma mexicana (DC.) G.Don leaves
[11] and
p-methoxybenzophenone
2 was found as a component of the essential oil of
Costus speciosus (J.Koenig) Sm.
[12].
Figure 2. The structures of monooxygenated benzophenones.
3. Dioxygenated Bezophenones
The literature survey showed three compounds,
3–
5 (
Figure 3), isolated from the endophytic moss
Polytrichastrum formosum (Hedw.) G.L. Smith
[13], while
6 was found in
Pogonatum inflexum (Lindb.) Sande Lac.
[14]. The nitrogen-containing derivatives of 2,4-dihydrobenzophenone
7 and
8 were isolated from the ethanol extract of the moss
Polytrichum commune Hedw.
[15]. Compounds
9–
11 were found in
Polytrichastrum formosum [13][16] and compound
12 was detected in
Pogonatum inflexum [14]. All of these compounds possess 2,4-dioxygenation pattern only in one of the phenyl rings. O-glycosidic forms of the deoxygenated benzophenones have not been discovered so far, but there was a report of a C-glycoside, namely hyperinone
13, isolated from
Hypericum styphelioides A.Rich.
[17].
Figure 3. The structures of dioxygenated benzophenones.
4. Trioxygenated Bezophenones
The first reports of isolated trioxygenated simple benzophenones date from nearly a century and a half ago, when Jobst and Hesse began to study the composition of Coto and Paracoto barks. Although the origin of the two barks remains still unknown, it can be safely assumed that they belong to the Lauraceae family
[18]. The first isolated compound was cotoin
14 (
Figure 4), which was obtained from a diethyl ether extract of Coto bark
[19][20]. Hydrocotoine
15 and methylhydrocotoine
16 were subsequently isolated from an alcoholic extract of Paracoto bark
[20]. More than a decade later, thanks to the outstanding work of Ciamiciani and Silber, the structures of these compounds were finally established
[21][22][23][24]. 2,4,6-Trihydroxybenzophenone
17 and 2,4-dihydroxy-6-methoxybenzophenone
18 were found to be major components in the methanol extract of leaves and stems of
Helichrysum triplinerve DC.
[25].
Figure 4. The structures of hydroxy, methoxy, and alkyloxy derivatives of trioxygenated benzophenones.
Most of the simply oxygenated naturally occurring benzophenones with 2,4,6-oxygenation patterns were alkyloxy derivatives. Sixteen compounds from this group have been reported to date, fourteen of which have been found in species of the genus
Hypericum. The first alkyloxy benzophenone
19 was discovered in 1978 by Bohlmann and Suwita in the root of
Leontonyx squarrosus DC and aerial parts of
L. spathulatus Less.
[26]. Eleven years later, four more compounds,
20–
23, belonging to this group were isolated from
Helichrysum asperum (Thunb.) Hilliard and B.L.Burtt
[27]. Phytochemical studies of the aerial parts of
Hypericum sampsonii Hance led to the isolation of seven new compounds,
24,
25 [28]; sampbenzophenones D-G (
26–
29)
[29]; and
33 [30]. The compounds hyperinokone
30, elegaphenone
31, and hyperinagasone
32 were isolated from
H. nokoense Ohwi
[31],
H. elegans Steph. ex Willd.
[32] and
H. nagasawae Hayata
[33], respectively. In 1968, the isolation of a trioxygenated benzophenone cearoin
34 from extracts of
Dalbergia cearensis Ducke and
D. miscolobium Benth. was reported
[34]. It was the first natural benzophenone with 2,4,5-trioxygenation pattern. In addition, two compounds with the same oxygenation pattern,
35 and
36, were isolated from
D. odorifera T. C. Chen
[35] and
Securidaca longipedunculata Fresen
[36], respectively. Two benzophenones,
37 and
38, possessing 2,3,4-trioxygenation patterns were isolated from
S. inappendiculata Hassk
[37]. In addition, compound
39 with the same oxygenation was isolated from the dichloromethane extract of
S. diversifolia (L.) Blake
[38]. The only two trioxygenated benzophenones with oxygenation on both rings were
40 and
41 isolated from
Tolpis webbii Sch. Bip.
[39] and
Securidaca longepedunculata Fresen.
[36], respectively.
Fourteen glycosides of trioxygenated benzophenones (
Figure 5) mostly sharing a common 2,4,6-trioxygenation pattern have been reported to date. The first tryoxygenated C-glycoside malaferin A
42 was isolated from an ethanolic extract of twigs and leaves of
Malania oleifera Chun and S.K.Lee
[40], while a di-C-glycoside arrilanin G
43 was obtained from an ethanolic extract of the stem bark of
Polygala rillate Buch.-Ham. ex D.Don
[41]. 2,4,6-Trihydroxybenzophenone
17 was the most common aglycon of the O-glycosides of the of trioxygenated benzophenones. Garcimangosone D
44 was its first O-glycoside isolated from the ethanol extract of
Garcinia mangostana L. fruits
[42]. Furthermore, four 6-O-biosides of
17 including tricornoside A
46 (from
Polygala tricornis Gagnep.)
[43], pyrafortunoside B
47, and C
48 (from
Pyracantha fortuneana (Maxim.) H. Li)
[44] as well as piperwallioside A
49 (from
Piper wallichii (Miq.) Hand.-Mazz.)
[45] were isolated from the respective species. Two 4-O-glycosides of
17 (
50 and
51) were isolated from the ethanol extract of the
Psidium guajava L. leaves
[46][47]. The phytochemical investigations of
Polygala tenuifolia Willd. led to the isolation of three O-glycosides of 2,4-dihydroxy-6-methoxybenzophenone
18, namely tenuiside B
52 and C
45 [48] as well as the O-bioside tenuiphenone A
53 [49]. In addition, a O-bioside
54 of 4-hydroxy-2,6-dimethoxybenzophenone was found in
P. sibirica var. megalopha Franch.
[50]. An O-glycoside pruniflonone B
55 having an unusual aglycone (3,4,5-trihydroxybenzophenone) was isolated from the methanol extract of
Cratoxylum formosum (Jack) Dyer roots
[51].
Figure 5. The structures of C- and O-glycosides of trioxygenated benzophenones.
5. Tetraoxygenated Bezophenones
This group includes eighteen hydroxy and methoxy tetraoxygenated benzophenones (
Figure 6). Only three compounds (
56–
58) have substituents on ring A but not in B and share a common 2,3,4,5-tetraoxygenation pattern. Compounds
56 and
57 were isolated from the wood of
Machaerium scleroxylon Tul.
[52][53], while
58 was found in the roots of
Securidaca longipedunculata [54]. Four compounds (
59–
62) share a common phloroglucinol oxygenation pattern in ring A and a monooxygenation in ring B. The first occurrence in nature of compounds
59–
62 was reported for
Morus alba L.
[55],
Aniba duckei Kosterm.
[56],
Gentiana lutea L.
[57], and for
Allanblackia floribunda Oliv.
[58], respectively. Compounds
63–
65 possess a rare 2,4,5-trioxynation pattern of ring A and structurally differ by the position of the hydroxyl group in ring B. The former two compounds,
64 and
65, were isolated from the heartwood of
Dalbergia melanoxylon Guill. and Perr.
[59][60] while the latter
66 was found in
D. cochinchinensis Pierre
[61]. Compounds
66–
69 shared a common pyrogallol-like ring A and monooxygenated ring B. These compounds were reported as the first to occur in biogenetically different plant species:
66 in
Securidaca diversifolia [38];
67 in
Anemarrhena asphodeloides Bunge
[62];
68 in
Oroxylum indicum (L.) (L.) Benth. ex Kurz
[63]; and
69 in
Garcinia mangostana [64]. Compounds
70–
73 possess di-oxygenation on both rings and were found in
Garcinia cantleyana Whit. var.
cantleyana [65],
Hypericum lanceolatum Lam.
[66],
Garcinia eugenifolia Wall. ex T. Anderson
[67], and
Syzygium polyanthum (Wight) Walp.
[68], respectively.
Figure 6. The structures of hydroxy and methoxy tetraoxygenated benzophenones.
To date, 24 C-glycosides of tetraoxygenated benzophenones (
Figure 7) have been isolated from the plant sources. The aglycone of most of these compounds is iriflophenone
59. The first occurrence of iriflofenone-3-C-β-D-glucoside
74 was reported for the leaf extracts of the ferns
Hypodematium fauriei (Kodama) Tagawa and
H. crenatum (Forssk.) Kuhn
[69]. Two phytochemical studies on mango tree bark and leaves led to the isolation of the galloyl esters
75–
77 [70][71] and one p-hydroxybenzoyl ester
78 [71] of
74. Further galloyl and p-hydroxybenzoyl esters
79–
84, as well as an ester of 3,4-dihydroxy-5-methoxybenzoic acid
85, were isolated from the ethanol extract of the leaves of
Mangifera indica [72][73]. A mixed C,O-diglycoside
86 was isolated from water extract of aerial parts of
Cyclopia genistoides (L.) R.Br.
[74]. A di-C-glycoside
87 of iriflophenone
59 was isolated from the leaves extract of
Aquilaria sinensis (Lour.) Spreng.
[75]. Five C-glycosides
88–
92 of 2,4′,6-trihydoxy-4-methoxybenzophenone
60 were found in leaves of
Mangifera indica [72][73]. The only C-galactosyl benzophenone
93 known up to now was isolated from the leaves of the mango tree
[76]. The only C-glycoside of 2,6,3′-trihydroxy-4-methoxybenzophenone rhodanthenone C
94 was isolated from a methanolic extract of the aerial parts of
Gentiana rhodantha Franch. ex Hemsl.
[77]. The di-C-glucosides
95 and
96 were isolated from
Polygala tenuifolia [49] and
P. glomerata Lour. (
P. chinensis L.)
[78], respectively. Di-C glucoside pseuduvarioside
97 was isolated from the leaves extract of
Pseuduvaria fragrans Y.C.F.Su, Chaowasku and R.M.K.Saunders
[79].
Figure 7. The structures of C-glycosides of tetraoxygenated benzophenones.
Some C-glycosyl tetraoxygenated benzophenones (
Figure 8) form rare spirocyclic systems. The first compound from this group was aquilarinoside A
98, which was isolated from hydroethanolic extract of
Aquilaria sinensis leaves
[80]. Compound
99, similar to
98 but with β-configuration of fructofuranose, was isolated from hydroethanolic extract of mango tree leaves
[76]. In addition,
100 and
101 were found in leaf extract from the later plant
[81][82]. Compounds
102 and
103 were isolated from the later plant source differed from
99 and
101, respectively, by the cyclization type of fructose unit
[76].
Figure 8. The structures of spirocyclic C-glycosides of tetraoxygenated benzophenones.
More than twenty O-glycosides of tetraoxygenated benzophenones (
Figure 9) have been isolated, so far. Most of these compounds (
104–
121) share iriflophenone
59 as their aglycone. The first O-glycoside of iriflophenone
104 was isolated from
Coleogyne ramosissima Torr.
[83]. Three acylated derivatives,
105–
107, of
104 were found in the leaves of
Planchonella obovata (R.Br.) Pierre
[84]. Iriflophenone-2-O-α-L-rhamnoside
108 and its acylated derivatives
109–
112 were reported for
Aquilaria sinensis leaves and flower buds
[75][85][86]. The methyl ester
113 of the later compound was isolated from the pericarps of
A. yunnanensis S. C. Huang
[87]. The presence of five biosides
114–
118 of iriflophenone
59 in
A. sinensis was established
[85][88]. In addition, a 2-O-β-D-xylopyranoside
119 and a 2-O-α-L-arabinopyranoside
120 of
59 were reported for
A. sinensis [86] and
Mangifera indica [76], respectively. The only glycoside
121 with sugar connected to position 4 of iriflophenone was found in
Davallia solida (G.Forst.) Sw. rhizomes
[89]. Three compounds,
122–
124, possess 2,4′,6-trihydroxy-4-methoxybenzophenone
60 as aglycone. The former compound
122 was isolated from the aerial parts of
Gnidia involucrata Steud. ex A.Rich.
[90]. The latter two compounds
123 and
124 were reported for nut shell of
Phaleria macrocarpa (Scheff.) Boerl. fruits
[91] and for roots of
Vangueria agrestis (Schweinf. ex Hiern) Lantz
[92], respectively. Mahkoside A
125 was isolated from the ethanolic extract of
Phlaleria macrocarpa pits
[93]. The tetraoxygenated benzophenone
61 was an aglycone of three glycosides,
126–
128, that were isolated from
Gentiana rhodantha Franch. ex Hemsl.
[77],
G. verna L. subsp.
pontica (Soltok.) Hayek
[94] and
Garcinia mangostana fruit pericarp
[95], respectively. The tetraoxygenated benzophenone O-glycosides
129–
132 that possess unique aglycones were found in
Gentiana verna subsp.
pontica [94],
Tripterospermum japonicum (Siebold and Zucc.) Maxim.
[96],
Cratoxylum formosum [97], and
Anemarrhena asphodeloides [98], respectively.
Figure 9. The structures of O-glycosides of tetraoxygenated benzophenones.
6. Pentaoxygenated Benzophenones
More than 20 non-glycosylated (aglycones) naturally occurring pentaoxygenated benzophenones (
Figure 10) representing seven oxygenation patterns have been reported, so far. Maclurin
133 was the firstly found pentaoxygenated benzophenone possessing 2,3′,4,4′,6-pentaoxygenation pattern. It was isolated in 1850 by Wagner from
Maclura tinctoria (L.) Steud.
[99][100] but its structure was finally established in 1895 by Ciamician and Silber
[101]. Methoxy derivatives
134–
138 of maclurin were found in
Garcinia subelliptica Merr.
[102],
G. multiflora Champ. ex Benth.
[103],
G. mangostana [104],
G. livingstonei T.Anderson
[105], and
G. mangostana [106], respectively. Compounds
139 and
140 were the only methylenedioxy-benzophenones with 2,3′,4,4′,6-pentaoxygenation pattern originally isolated from
Aniba pseudocoto bark
[20][22]. Compounds
141 and
142 were found in
Garcinia subelliptica [107] and
G. smeathmannii (Planch. and Triana) Oliv.
[108], respectively, and shared a common 2,2′,3′,4,6-pentaoxygenation pattern. Compounds
143–
148, possessing a common 2,3′,4,5′,6-pentaoxygenation pattern, were originally isolated from
G. pedunculata Roxb. ex Buch.-Ham.
[109],
G. mangostana [106],
G. hombroniana Pierre
[110],
G. speciosa Wall.
[111],
Hypericum annulatum Moris
[8], and
H. sampsonii [112], respectively. The rare compounds
149 and
150 share common ring A and differ in ring B; both were isolated from
Dalbergia melanoxylon [59][113]. Compounds
151–
153 possess a common 3,3′,4,5,5′-pentaoxygenation pattern. The former
151 and
152 were isolated from the twigs of
Garcinia cantleyana var.
cantleyana [65] while the later
153 was found in the pericarp of mangosteen (
G. mangostana)
[114]. The sole compound
154 with 2,3,3′,4,4′-pentaoxygenation pattern was isolated from the
Securidaca diversifolia roots
[38].
Figure 10. The structures of hydroxy and methoxy pentaoxygenated benzophenones.
More than fifteen C-glycosylated derivatives of the pentaoxygenated benzophenones (
Figure 11) have been found in plants, so far. Most of these compounds possess a 2,3′,4,4′,6-pentaoxygenation pattern. The first report for naturally occurring C-glycosylated pentaoxygenated benzophenones dated from 1984 when Tanaka and coworkers isolated maclurin-3-C-β-D-glucoside
155 along with its galloyl and p-hydroxybenzoyl esters
156–
159 from the
Mangifera indica leaves
[70]. Further galloyl esters
160 and
161 [71] as well as methoxy derivatives
162 [81] and
163 [72] of
155 were found in the same plant source. Additional methoxy derivatives
164–
166 of
155 were isolated from the aerial parts of
Polygala telephioides Willd.
[115][116]. The only di-C-glycoside
167 and C,O-glycoside
168 of pentaoxygenated benzophenones were isolated from an ethanolic extract of
P. glomerata [78]. Compound
169 is the only benzophenone C-glycoside with 2,3′,4′5′,6-pentaoxygenation pattern that was isolated from the aerial parts of
Hypericum humifusum L. ssp.
austral Rouy et Foue
[117]. C-glycosyl benzophenones
170 and
171 share common ring A with 2,3,5,6-oxygenation patters and differ in the hydroxyl place in ring B. The former was isolated from
Gnidia involucrata [90] while the later was found in
Polygala telephioides [115].
Figure 11. The structures of C-glycosides of pentaoxygenated benzophenones.
Over 30 O-glycosides of pentaoxygenated benzophenones (
Figure 12) have been reported to occur in plant species, so far. Contrary to C-glycosides, only six O-glycosides with 2,3′,4,4′,6-pentaoxygenation patterns
172–
177 have been encountered. Maclurin-6-O-β-D-glucopyranoside
172 was simultaneously isolated from
Gentiana verna subsp.
pontica [94] and from
G. rhodantha [77]. Compounds
173,
174, and
177 were isolated from
Dobinea delavayi (Baill.) Baill. roots
[118][119], while
175 and
176 were found in aerial parts of
Polygala tenuifolia [48] and
Garcinia livingstonei [105], respectively. The vast majority of O-glycosides (
178–
205) possess aglycones with 2,3′,4,5′,6-pentaoxygenation pattern and glycosylation at position 6(2), 4 or 3′(5′). The arabinofuranosides
178 and
179 were isolated from the aerial parts of
Hypericum annulatum [120], while
180–
183 were found in
H. thasium Griseb.
[121][122]. The 6(2)-O-rhamosides
187 and
188 were isolated from
H. elegans [123] and
H. pseudopetiolatum Keller, respectively. In addition, compounds
189–
191 were also found in later species
[124]. Further acylated rhamosides
192 and
193 of
143 were isolated from the aerial parts of
H. seniawinii Maxim.
[125]. The 6(2)-O-rhamnosides
194–
196 of
145 were found in aerial parts of
H. wightianum Wall. ex Wight et Arn.
[126]. Only three O-xylopyranosides
197–
199 of penataoxygenated benzophenones were originally isolated from
H. thasium [121], while only two O-arabinopyranosides
200 and
201 were found in
H. humifusum [117]. Compounds
202 and
203 isolated from the later plant
[117] possess glycosylation at position 4, while
204 and
205 were found in
H. sampsonii [112] and
H. ellipticum Hook.
[127], respectively, the sugar was attached at position 5′(3′) position. The compounds
206 and
207 share rare 2,2′,4,5′,6-pentaoxygenation patterns that were isolated from
H. annulatum [8] and
Garcinia mangostana [128], respectively.
Figure 12. The structures of O-glycosides of pentaoxygenated benzophenones.
7. Hexaxygenated Benzophenones
Hexaxygenated benzophenones were rarely found in nature. To date, only three compounds,
208–
210 (
Figure 13), have been isolated from
Garcinia mangostana [128][129].
Figure 13. The structures of hexaoxygenated benzophenones.
8. Uncategorized and Miscellaneous Benzophenones
In addition to the compounds shown so far, there are data on benzophenone derivatives (
Figure 14) in which one or several protons are replaced by a methyl, alcohol, carboxyl, or acyl group, and dimeric compounds with xanthone have also been found. Some glycosides of this class benzophenones have been detected, as well. The first records of this type of benzophenone appeared in 1963 when 6-hydroxy-2,4-dimethoxy-3-methylbenzophenone
211 and its isomer 2-hydroxy-4,6-dimethoxy-3-methylbenzophenone
212 were isolated from the essential oil of
Leptospermum luehmannii F.M.Bailey
[130]. Eighteen years later, bis(2-hydroxy-4,6-dimethoxy-3-methylphenyl)methanone
213 was found in a benzene extract of the wood of
Qualea lubouriauana [131].
Figure 14. The structures of uncategorized and miscellaneous benzophenones.
For the first time, beishouwubenzophenone
214 was isolated from root tubers of
Cynanchum auriculatum Royle ex Wight
[132]. Morintrifolin A
215 and B
216 were obtained from hydromethanolic extract of
Morinda citrifolia L. roots
[133]. Compound
217 was found in an extract of the
Anemarrhena asphodeloides roots
[134]. The adducts of 3,3′,4,4′-trihydroxybenzophenone, and 2-hydroxypropionic acid
218–
221 were isolated from
Ranunculus ssp. The former three compounds were found in
R. ternatus DC.
[135][136], while the later was obtained from
R. muricatus Moench
[137]. The benzophenones
222–
228 have been isolated from fungi mostly belonging to
Ascomycota group. Nidulalin B
222 was found in a dichloromethane extract of
Emericella nidulans var. lata (Thom and Raper) Subram.
[138], while cytosporaphenone A
223 was obtained from an ethyl acetate extract of
Cytospora rhizophorae Kohlm. and E. Kohlm.
[139]. Wentiphenone A
224 was discovered in the ethyl acetate extract of
Aspergillus wentii Wehmer
[140], while
225 was isolated from the fermentation broth of
A. fumigatus Fresen. SWZ01
[141]. A halogenated benzophenone
226 was discovered in an extract of
A. flavipes PJ03-11
[142], while
227 and
228 were found in
A. terreus Thom
[143] and
A. wentii [144], respectively. Garcihombrianone
229, which was found in the roots of
Garcinia hombroniana Pierre
[145], can be viewed as two benzophenone molecules sharing a common benzene nucleus. Three benzophenone-xanthone dimers
230–
232 were isolated from roots of
G. dulcis (Roxb.) Kurz
[146]. Benzophenone O-glucosides
233 and
234 were found in
Mitracarpus villosus (Sw.) DC.
[147] and
Dobinea delavayi [119]. Seven benzophenone O-glucosides
235–
241, some of which were galloyl esters, were isolated from the leaves or fruits of
Psidium guajava [47][148][149][150], while
242 was found in
P. littorale Raddi
[151]. Compounds
243 and
244 were isolated from
Cassia senna var.
angustifolia L.
[152], while
245 and
246 were found in
C. abbreviata Oliv.
[153]. The only C-glycoside
247 of this class of miscellaneous benzophenones was isolated from
Aquilaria sinensis [154]. Two N-containing benzophenones
248 and
249 were found in the moss
Pogonatum spinulosum Mitt.
[155], while
250 was detected in
Anemarrhena asphodeloides [62].