Glochidion Species: A Review on Phytochemistry and Pharmacology

Abstract

Objectives

The genus Glochidion (the family Phyllanthaceae) is used for various medicinal purposes, such as dysentery, diarrhea, cough, and skin protection. A review of phytochemical and pharmacological aspects for this remains unavailable. The current study tends to sum up a detailed list of phytochemicals, and their role in biological examinations.

Methods

References in English were obtained by an extensive search across various electronic data sources, encompassing Web of Science, PubMed, Google Scholar, and Science Direct. The “Sci-Finder” was also utilized to find references and revise chemical structures. Referenced documents have been gathered from the 1960s to date. It also noted that Glochidion, phytochemistry, and pharmacology are likely the keywords to seek for references.

Results

Over 240 naturally occurring phytochemicals were isolated and identified from various Glochidion tissues, including terpenoids, sterols, saponins, lignans, flavonoids, mono-phenols, megastigmanes, butenolides, glycosides, alkaloids, cyanogens, tocopherols, fatty acids, and others. Three naturally occurring triterpenoids glochidonol, glochidiol, and glochidone are the likely characteristic metabolites, being isolated frequently. Glochidion crude extracts and their isolated compounds have been demonstrated as potential agents in various pharmacological targets, such as cytotoxicity, antioxidant, antiinflammation, and neuron and liver protection.

Conclusion

Several isolates acted as promising agents in pharmacological assays. The anticancer mechanisms of various triterpenoids and saponins, especially new and potential compounds, are expected. Pharmacological advancements to enhance the efficacies of Glochidion constituents, such as synergistic combinations and nano-drug formulations, are encouraged.

Introduction

The genus Glochidion contains flowering plants that belong to the family Phyllanthaceae, which was referred to as Cheese trees or Buttonwood in Australia, and Leafflower trees in various scientific documents. About 300 species were recorded, which were widely distributed in the Pacific area, and tropical Asia. ¹ Traditionally, Glochidion plants have been used for both food and local medicinal purposes, in which they were appropriate for the treatments of various ailments, eg, eczema, rheumatoid, arthritis, influenza, dysentery, impaludism, dyspepsia, cold, and fever.^1–3 The Nicobarese people attested to the therapeutic qualities of G. calocarpum, stating that the best treatments for amoebiasis-related, abdominal illnesses are its barks and seeds. ⁴ G. multiloculare fruits were used to cure dysentery, diarrhea, and cough. ⁵ In Thailand, the shoots and young leaves of G. hypoleucum were consumed raw or cooked. ⁶

Accumulative evidence indicated that species of the genus Glochidion were renowned for the presence of diverse phytochemical classes, consisting of the main compounds type terpenoids, sterols, saponins, lignans, flavonoids, mono-phenols, and others.^1,7–15 Aliphatic compounds, monoterpenoids, sesquiterpenoids, and their derivatives appeared as the principal compounds in Glochidion essential oils.^16,17 Crude extracts and natural compounds of Glochidion species have also received much attention in pharmacological studies.^12–17 Triterpenoids and saponins from some Vietnamese Glochidion plants with significant cytotoxic results established the potential for anticancer drugs.^11–15 The alcoholic extract of G. thomsonii barks showed in vivo anti-inflammatory activity against carrageenan-mediated paw edema and xylene-mediated ear edema in mice. ¹⁸ Both the aqueous extracts of G. zylanicum roots and G. velutinum leaves play a great role in in vivo antidiabetic activity since they reduce blood glucose levels in mice.^19,20

To date, there is no in-depth review document on the phytochemical and pharmacological investigations regarding Glochidion species. Hence, the ultimate aim of this communication is to highlight the previous results in several aspects, such as natural occurrence, chemical classification, chromatographic isolation, and structural features, especially in terms of pharmacological experimental applications. It is expected that the research will provide a useful scientific foundation for future studies.

Methodology

An extensive survey of the keywords “Glochidion’’, “Euphorbiaceae”, “phytochemistry”, and “pharmacology” was conducted in scientific databases, including Pubmed, Scopus, Reaxys, and Google Scholar. The search terms “Bentham Science”, “Science Direct”, and “Springer”, etc were used for data collection. The “Sci-Finder” was also utilized to find references and revise chemical structures. In total, 96 publications were included from the 1960s to March 2024. From these references, 44 publications were used for phytochemistry, and 47 studies for pharmacological activities. Articles focused on morphology were excluded.

Phytochemistry

This is the first time that phytochemical studies of Glochidion have been reviewed. A detailed list of Glochidion phytochemicals has been alphabetically ordered in Table 1 and Figures 1–6, including terpenoids 1-61, sterols 62-68, saponins 69-99, lignans 100-140, flavonoids 141-160, mono-phenols 161-183, megastigmanes 184-199, butenolides 200-211, glycosides 212-222, alkaloids 223-227, cyanogens 228-232, tocopherols 233-234, fatty acids 235-236, and others 237-239, as well as compounds isolated from endophytic fungus-associated with Glochidion species 240-242. Herein, the compilation is mostly based on the results of chromatographic columns to completely isolate these compounds as the purified agents, together with the confirmation of their structures by spectroscopic explanations and literature comparisons. In addition, it should be noted that the parts of G. assamicum, G. coccineum, G. daltonii, G. dasyphyllum, G. eriocarpum, G. glomerulatum, G. heyneanum, G. hirsutum, G. hohenackeri, G. hongkongense, G. hypoleucum, G. macrophyllum, G. moonii, G. multiloculare, G. obliquum, G. obovatum, G. philippicum, G. puberum, G. rubrum, G. sphaerogynum, G. sumatranum, G. velutinum, G. venulatum, G. wilsonii, G. wrightii, and G. zeylanicum are the main source for phytochemical investigations (Table 1).

Table 1.

Chemical Constituents from the Genus Glochidion.

No	Compounds	Parts of use	References
Terpenoids
Sesquiterpenoids
1	Glochinoccin A	G. coccineum rhizomes	8
2	Glochinoccin B	G. coccineum rhizomes, and G. wilsonii roots	1,8
3	Glochinoccin C	G. coccineum rhizomes	8
4	Glochinoccin D	G. coccineum rhizomes, G. puberum aerial parts, and G. wilsonii roots	1,8,21
5	Glochicoccinoside A	G. hirsutum aerial parts, and G. wilsonii roots	1,7
6	Glochicoccinoside B	G. hirsutum aerial parts, and G. wilsonii roots	1,7
7	Glochiwilsonoside A	G. wilsonii roots	1
8	Glochiwilsonoside B	G. wilsonii roots	1
9	Glochiwilsonoside C	G. wilsonii roots	1
10	Phyllaemblic acid	G. coccineum rhizomes, G. puberum aerial parts, and G. wilsonii roots	1,8,21
11	Phyllaemblic acid methyl ester	G. coccineum rhizomes, and G. wilsonii roots	1,8
Diterpenoid
12	5-Methyl-5-(4,8,12-trimethyltridecyl)-dihydro-furan-2-one	G. wrightii stems and leaves	10
Triterpenoids
13	β-Amyrin	G. heyneanum aerial parts	30
14	Arjunolic acid	G. assamicum aerial parts	37
15	Betulin	G. puberum stems and twigs, and G. wrightii stems and leaves	10,38
16	21β-(Benzoyloxy)olean-12-ene-3β,16β,23,28-tetraol	G. assamicum leaves and twigs	9
17	21β-(Benzoyloxy)olean-12-ene-3β,16β,28-triol	G. assamicum leaves and twigs	9
18	21β-[(E)-Cinnamoyloxy]olean-12-ene-3β,16β,23,28-tetraol	G. assamicum leaves and twigs	9
19	21β-[(Z)-Cinnamoyloxy]olean-12-ene-3β,16β,23,28-tetraol	G. assamicum leaves and twigs	9
20	3β-O-trans-Coumaroylbetulin	G. puberum stems and twigs	38
21	3β-O-trans-Coumaroylbetulinic acid	G. puberum stems and twigs	38
22	Epimachaerinic acid	G. heyneanum aerial parts	30
23	5α,6α-Epoxy D:C-friedoolean-8-en-3β-ol	G. obliquum leaves	14
24	Euphorginol	G. obliquum leaves	35
25	Friedelin (Friedelan-3-one)	G. macrophyllum stems and leaves, G. obliquum leaves, G. puberum leaves and stems, and G. wrightii stems and leaves	11,23–25,28
26	Friedelan-3β-ol	G. macrophyllum stems and leaves, G. puberum leaves and stems, and G. wrightii stems and leaves	10,23–25,28
27	3β-O-trans-Feruloylbetulin	G. puberum stems and twigs	38
28	3β-O-trans-Feruloylbetulinic acid	G. puberum stems and twigs	38
29	(20S)-3α-Hydrolupan-29-oic acid	G. puberum stems and twigs	38
30	3β-Hydroxyglutin-5-ene (Glutinol)	G. obliquum leaves, and G. wrightii stems and leaves	10,11
31	Glochidol	G. eriocarpum stems	27
32	Glochidonol	G. daltonii roots and stems, G. eriocarpum aerial parts, roots and stems, G. heyneanum aerial parts, G. hongkongense stems, G. macrophyllum stems, G. moonii barks, G. multiloculare aerial parts, G. obliquum leaves, G. puberum stems and twigs, G. sphaerogynum roots and stems, G. venulatum leaves, G. wrightii stems and leaves, and G. zeylanicum stem barks	10,11,23–27,29–32,34,36,38,39
33	Glochidiol	G. assamicum aerial parts, G. daltonii roots and stems, G. dasyphyllum stems, G. eriocarpum aerial parts, roots and stems, G. heyneanum aerial parts, G. hohenackeri barks, G. hongkongense stems, G. macrophyllum stems, G. moonii barks, G. multiloculare aerial parts, G. puberum stems and twigs, G. sphaerogynum roots and stems, G. wrightii stems and leaves, and G. zeylanicum stem barks	22–25,27–32,34,36–39
34	Glochidone	G. assamicum aerial parts, G. daltonii roots and stems, G. dasyphyllum stems, G. eriocarpum aerial parts, roots and stems, G. heyneanum aerial parts, G. hohenackeri barks, G. hongkongense stems, G. macrophyllum stems, G. multiloculare aerial parts, G. obliquum leaves, G. puberum stems and twigs, G. wrightii stems and leaves, and G. zeylanicum stem barks	10,11,22–24,27,30–33,36–39
35	Glochidpurnoid A	G. puberum stems and twigs	38
36	Glochidpurnoid B	G. puberum stems and twigs	38
37	Glochieriol	G. eriocarpum aerial parts	34
38	Lupenone	G. dasyphyllum stems, G. eriocarpum roots and stems, G. hongkongense stems, and G. wrightii stems	23,24,27,32
39	Lupeol	G. eriocarpum aerial parts and stems, G. hongkongense stems, G. multiloculare aerial parts, G. obliquum leaves, G. puberum leaves, stems and twigs, and G. wrightii stems and leaves	10,11,23,24,27,28,34,36,38
40	Lup-20(29)-ene-1,3-dione	G. puberum leaves	28
41	Lup-20(29)-ene-1β-ol-3α-yl acetate	G. puberum stems	28
42	Lup-20(29)-ene-3α-ol-1β-yl acetate	G. puberum stems	28
43	Lup-20(29)-ene-1β,3β-diol	G. eriocarpum aerial parts, roots and stems, G. heyneanum aerial parts, G. macrophyllum stems, G. wrightii stems and leaves, and G. zeylanicum stem barks	10,24,27,30–33
44	Lup-20(29)-ene-3β,16β-diol	G. wrightii stems and leaves	10
45	Lup-20(29)-ene-3α,23-diol	G. daltonii roots and stems, G. macrophyllum stems, G. moonii barks, G. sphaerogynum roots and stems, and G. puberum stems and twigs	25,29,32,38,39
46	Lup-20(29)-ene-3β,23-diol	G. eriocarpum aerial parts	33
47	Lup-20(30)-ene-3β,29-diol	G. puberum stems and twigs	38
48	3α,20-Lupandiol	G. puberum stems and twigs	38
49	3-epi-Lupeol	G. daltonii roots and stems, G. eriocarpum aerial parts, roots and stems, G. hohenackeri barks, G. hongkongense stems, and G. puberum stems and twigs	22,24,32,34,38,39
50	29-nor-Lup-1-ene-3,20-dione	G. puberum stems and twigs	38
51	Maslinic acid	G. wrightii stems and leaves	10
52	Morolic acid acetate	G. puberum stems and twigs	38
53	Obibanmol I	G. puberum stems and twigs	38
54	Oleanolic acid	G. wrightii stems and leaves	10
55	Rotundic acid	G. obliquum leaves	35
56	Simiarenol	G. wrightii stems and leaves	10
57	3,4-Secofriedelan-3-oic acid	G. wrightii stems and leaves	10
58	Taraxerol	G. obliquum leaves	35
59	3β-Tetradecanoyloxy-1β-hydroxylup-20(29)-ene	G. wrightii stems and leaves	10
60	2,3,24-Trihydroxyurs-12-en-28-oic acid	G. obliquum leaves	35
61	Ursolic acid	G. wrightii stems and leaves	10
Sterols
62	Chlorogenin	G. assamicum aerial parts	37
63	β-Sitosterol	G. dasyphyllum stems and leaves, G. eriocarpum stems, G. hongkongense stems and leaves, G. macrophyllum stems and leaves, G. moonii barks, G. obliquum leaves, G. puberum aerial parts, leaves and stems, G. venulatum leaves, and G. wrightii stems and leaves	10,23–29,35,40
64	Sistosterol-5-en-3β-hydroxy-7-one	G. wrightii stems and leaves	10
65	Sistosterol-5-en-3β,7α-diol	G. wrightii stems and leaves	10
66	Sistosterol-5-en-3β,7β-diol	G. wrightii stems and leaves	10
67	Stigmasterol	G. dasyphyllum stems, G. heyneanum aerial parts, G. macrophyllum stems and leaves, and G. multiloculare aerial parts	24,25,30,36
68	Stigmast-6β-hydroxyl-4-en-3-one	G. wrightii stems and leaves	10
Saponins
69	Assamicoside A	G. assamicum aerial parts	37
70	Daucosterol	G. heyneanum aerial parts, G. multiloculare aerial parts, G. obliquum leaves, G. puberum aerial parts, and G. wrightii stems and leaves	10,30,35,36,40
71	Glochidioside	G. coccineum rhizomes, and G. heyneanum aerial parts	21,41
72	Glochidioside N	G. heyneanum aerial parts	30
73	Glochidioside Q	G. heyneanum aerial parts	30
74	Glochierioside A	G. eriocarpum aerial parts	33
75	Glochierioside B	G. eriocarpum aerial parts	33
76	Glochierioside C	G. eriocarpum aerial parts	34
77	Glochierioside D	G. eriocarpum aerial parts	34
78	Glochierioside E	G. eriocarpum aerial parts	34
79	Glomeruloside A	G. glomerulatum leaves	11
80	Glomeruloside B	G. glomerulatum leaves	11
81	Glomeruloside C	G. glomerulatum leaves	11
82	Glomeruloside D	G. glomerulatum leaves	11
83	Glomeruloside E	G. glomerulatum leaves	11
84	Glomeruloside F	G. glomerulatum leaves	11
85	Glomeruloside G	G. glomerulatum leaves	11
86	Glomeruloside H	G. glomerulatum leaves	11
87	Glomeruloside I	G. glomerulatum leaves	13
88	Glomeruloside II	G. glomerulatum leaves	13
89	Hirsutoside A	G. hirsutum leaves	42
90	Hirsutoside B	G. hirsutum leaves	42
91	Hirsutoside C	G. hirsutum leaves	42
92	Hirsutoside D	G. hirsutum leaves	42
93	Hirsutoside E	G. hirsutum leaves	42
94	Puberoside A	G. puberum aerial parts	43
95	Puberoside B	G. puberum aerial parts	43
96	Puberoside C	G. puberum aerial parts	44
97	Puberoside D	G. puberum aerial parts	44
98	Puberoside E	G. puberum aerial parts	44
99	Pedunculoside	G. obliquum leaves	35
Lignans
Aryltetralins
100	(+)-Isolariciresinol	G. wilsonii roots	1
101	(+)-Isolariciresinol 2a-O-β-D-glucopyranoside ((+)-Isolariciresinol 9-O-β-D-glucopyranoside)	G. rubrum leaves, G. wilsonii roots, and G. zeylanicum leaves	1,45,46
102	(–)-Isolariciresinol 2a-O-β-D-glucopyranoside	G. rubrum leaves	46
103	(+)-Isolariciresinol 3a-O-β-D-glucopyranoside	G. rubrum leaves, and G. zeylanicum leaves	45,46
104	(+)-Isolariciresinol 9-O-β-D-xylopyranoside	G. wilsonii roots	1
105	(+)-Isolariciresinol 9'-O-β-D-xylopyranoside	G. wilsonii roots	1
106	(–)-Secoisol ariciresinol	G. wilsonii roots	1
Furan
107	(+)-Laricerisnol	G. wilsonii roots, and G. wrightii stems and leaves	1,10
Furofurans
108	Balanophonin B	G. wilsonii roots	1
109	Clemaphenol A	G. wilsonii roots	1
110	4,4'-Dimethoxy-3'-hydroxy-7,9':7′,9-diepoxylignan-3-O-β-D-glucopyranoside	G. coccineum rhizomes	47
111	(+)-Mediresinol	G. assamicum aerial parts, and G. wilsonii roots	1,37
112	(+)-Pinoresinol	G. obliquum leaves, G. wrightii stems and leaves, and G. wilsonii roots	1,10,15
113	(+)-Syringaresinol	G. obliquum leaves, G. puberum aerial parts, G. wilsonii roots, and G. wrightii stems and leaves	1,10,15,40
114	Yangambin	G. wilsonii roots	1
Phenylpropanoids
115	Dihydroconiferyl alcohol	G. wilsonii roots	1
116	(E)-4-Hydroxycinnamyl alcohol-4-O-β-D-glucopyranoside	G. wilsonii roots	1
117	Evofolin B	G. wilsonii roots	1
118	rel-(1R,2S)-1,2-bis (4-Hydroxy-3-methoxy-phenyl)-1,3-propanediol	G. wilsonii roots	1
119	Leptolepisol C	G. wilsonii roots	1
120	Leptolepisol D	G. wilsonii roots	1
121	Syringin	G. eriocarpum whole plant, and G. obliquum leaves	35,48
122	(7R,8S)-4,7,9,9'-Tetrahydroxy-3,3'-dimethoxy-8-O-4'- neolignan 7-O-β-D-glucopyranoside	G. rubrum leaves	46
123	(7R,8R)-4,7,9,9'-Tetrahydroxy-3,3'-dimethoxy-8-O-4'- neolignan 7-O-β-D-glucopyranoside	G. rubrum leaves	46
Benzofurans
124	9'-Dehydro-valadion F	G. wilsonii roots	1
125	Dehydrodiconiferyl alcohol	G. wilsonii roots	1
126	Dihydrodehydrodiconiferyl alcohol	G. wilsonii roots	1
127	Dihydrodehydrodiconiferyl alcohol 9'-O-sulfate	G. zeylanicum leaves	45
128	7R,8S-Dihydrodehydrodiconiferyl alcohol 4-O-β-D-glucopyranoside	G. eriocarpum whole plant, and G. zeylanicum leaves	45,48
129	7S,8R-Dihydrodehydrodiconiferyl alcohol 4-O-β-D-glucopyranoside	G. eriocarpum whole plant, and G. zeylanicum leaves	45,48
130	Dihydrodehydrodiconiferyl alcohol 9-O-β-D-glucopyranoside	G. zeylanicum leaves	45
131	9,9'-Dihydroxy-3,4-methylenedioxy-3'-methoxy [7-O-4’,8-5’] neolignan	G. wilsonii roots	1
132	Glochidioboside (Dihydrodehydrodiconiferyl alcohol 9'-O-β-D-glucopyranoside)	G. obliquum leaves, and G. zeylanicum leaves	45,49
133	Glochiwilsonise A	G. wilsonii roots	1
134	Glochiwilsonise B	G. wilsonii roots	1
135	Glochiwilsonise C	G. wilsonii roots	1
136	Glochiwilsonise D	G. wilsonii roots	1
137	Glochiwilsonise E	G. wilsonii roots	1
138	4-O-Methylcedrusin	G. wilsonii roots	1
139	Phyllnirurin	G. wilsonii roots	1
Lignanoid
140	Glochinin A	G. puberum aerial parts	21
Flavonoids
Flavones
141	6''-O-Acetylorientin	G. obliquum leaves	15
142	Globlin A	G. obliquum leaves	35
143	Isoorientin	G. hypoleucum leaves, and G. zeylanicum leaves	6,50
144	Isovitexin	G. hirsutum stems	7
145	Isovitexin 7-O-xyloside	G. hirsutum stems	7
146	Orientin	G. hypoleucum leaves	6
147	Vitexin	G. hypoleucum leaves, G. obliquum leaves, G. puberum aerial parts, and G. zeylanicum leaves	6,15,35,40,50
Flavans
148	(+)-Epigallocatechin 3-O-gallate	G. acuminatum leaves	51
149	Glochiflavanoside A	G. zeylanicum leaves	50
150	Glochiflavanoside B	G. zeylanicum leaves	50
151	Glochiflavanoside C	G. zeylanicum leaves	50
152	Glochiflavanoside D	G. zeylanicum leaves	50
153	Glochiin C1	G. rubrum leaves	52
Flavanones
154	(2R,3R)-Dihydromyricetin-4'-O-(3''-O-methyl)-gallate	G. sumatranum leaves and twigs	53
155	(2R,3R)-Dihydromyricetin-3'-O-(3''-O-methyl)-gallate	G. sumatranum leaves and twigs	53
156	(2R,3R)-Dihydromyricetin-4'-O-gallate	G. sumatranum leaves and twigs	53
157	(2R,3R)-Dihydromyricetin-3'-O-gallate	G. sumatranum leaves and twigs	53
158	(2R,3R)-Dihydromyricetin	G. sumatranum leaves and twigs	53
159	Naringenin	G. wrightii stems and leaves	10
Chalcone
160	Phloretin 4'-O-β-D-glucopyranoside	G. acuminatum leaves	51
Mono-phenols
161	Bergenin	G. eriocarpum whole plant, G. hirsutum stems, G. obliquum leaves, G. obovatum leaves, G. rubrum leaves, and G. wilsonii roots	1,7,35,46,48,49
162	Decoumaroylibotanolide	G. hirsutum stems	7
163	4-O-Ethylgallic acid	G. assamicum aerial parts, G. hirsutum stems, and G. puberum aerial parts	7,37,40
164	1,2-Dimethoxyphenyl-4-O-β-D-glucoside	G. eriocarpum whole plant	48
165	3,4-Dimethoxyphenyl-β-D-glucoside	G. assamicum aerial parts	37
166	Gallic acid	G. hypoleucum leaves, and G. puberum aerial parts	6,40
167	1-β-D-Glucopyranosyloxy-3-methoxy-5-hydroxybenzene	G. eriocarpum whole plant	48
168	Glochidacuminoside A	G. acuminatum leaves, and G. wilsonii roots	1,54
169	Glochiin M1	G. rubrum leaves	52
170	Glochiin M2	G. rubrum leaves	52
171	Glochiwilsophenoside	G. wilsonii roots	1
172	2-β- D-Glucopyranosyloxy-4-methoxy-6-hydroxy-isovalero-phenone	G. eriocarpum whole plant	48
173	Glucosyringic acid	G. wilsonii roots	1
174	p-Hydroxybenzaldehyde	G. wilsonii roots	1
175	Koaburaside	G. eriocarpum whole plant	48
176	Koaburaside monomethyl ether	G. eriocarpum whole plant	48
177	Methyl gallate	G. hypoleucum leaves, and G. superbum leaves	6,55
178	Methyl 2-(2-hydroxyphenyl) acetate β-D-glucopyranoside	G. acuminatum leaves	51
179	3-O-Methylgallic acid	G. hirsutum stems	7
180	Syringaldehyde	G. wilsonii roots	1
181	Tachioside 2'-O-4''-O-methylgallate	G. rubrum leaves	46
182	24,6-Trimethoxyphenol-1-O-β-D-glucoside	G. assamicum aerial parts, and G. wilsonii roots	1,37
183	Vanillic acid-4- O-β-D-glucopyranoside	G. wilsonii roots	1
Megastigmanes
184	Blumenol C glucoside	G. eriocarpum whole plant, G. obliquum leaves, and G. zeylanicum leaves	48,49,56
185	Cannabiside D	G. eriocarpum whole plant	48
186	Corchoionoside C	G. assamicum aerial parts, and G. rubrum leaves	37,46
187	Dendranthemoside B	G. obliquum leaves	49
188	6β,9β:9,13-Diepoxymegastig-4-en-3β-ol	G. obliquum leaves	14
189	Glochidionionoside A	G. eriocarpum whole plant, G. rubrum leaves, and G. zeylanicum leaves	46,48,56
190	Glochidionionoside B	G. rubrum leaves, and G. zeylanicum leaves	46,56
191	Glochidionionoside C	G. eriocarpum whole plant, G. rubrum leaves, and G. zeylanicum leaves	46,48,56
192	Glcochidionionoside D	G. zeylanicum leaves	56
193	Glochidionionoside E	G. eriocarpum whole plant, and G. zeylanicum leaves	48,56
194	(Z)-4-[3'-(β-D-Glucopyranosyloxy)butylidene]-35,5-trimethyl-2-cyclohexen-l-one	G. eriocarpum whole plant	48
195	Icariside B1	G. obliquum leaves	49
196	(6R,9S)-3-oxo-α-Ionol β-D-glucopyranoside	G. eriocarpum whole plant	48
197	(3S,5R,6R,7E,9S)-Megastigman-7-ene-3,5,6,9-tetrol 3-O-β-D-glucopyranoside	G. zeylanicum leaves	57
198	(3S,5R,6R,7E,9S)-Megastigman-7-ene-3,5,6,9-tetrol 9-O-β-D-glucopyranoside	G. zeylanicum leaves	57
199	(6S,9S)-Roseoside	G. eriocarpum whole plant	48
Butenolides
200	(+)-Aquilegiolide	G. acuminatum leaves	51
201	Isoglochidiolide	G. acuminatum leaves	54
202	Glochidiolide	G. acuminatum leaves, and G. wilsonii roots	1,54,58
203	Glochidionolactone A	G. zeylanicum leaves	59
204	Glochidionolactone B	G. zeylanicum leaves	59
205	Glochidionolactone C	G. zeylanicum leaves	59
206	Glochidionolactone D	G. zeylanicum leaves	59
207	Glochidionolactone E	G. zeylanicum leaves	59
208	Glochidionolactone F	G. zeylanicum leaves	59
209	(–)-Loliolide	G. acuminatum leaves	51
210	(+)-Menisdaurilide	G. acuminatum leaves	51
211	Phyllanthurinolactone	G. zeylanicum leaves	59
Glycosides
212	Icariside D1	G. rubrum leaves	46
213	Icariside F2	G. assamicum aerial parts, and G. rubrum leaves	37,46
214	β-D-Galactopyranosyl-(3→3)-O-β-D-galactopyranose	G. puberum aerial parts	40
215	n-Butyl-α-D-fructofuranoside	G. hirsutum stems	7
216	n-Butyl-β-D-fructofuranoside	G. hirsutum stems	7
217	E-2-Hexenyl-D-glucopyranoside	G. puberum aerial parts	40
218	Glochidacuminoside B	G. acuminatum leaves	54
219	Glochidacuminoside C	G. acuminatum leaves	54
220	Z-3-Hexenyl-D-glucopyranoside	G. acuminatum leaves, and G. puberum aerial parts	40,54
221	D-Mannitol	G. heyneanum aerial parts	30
222	myo-Inositol	G. obliquum leaves	35
Alkaloids
223	Acumiaminoside	G. acuminatum leaves	54
224	Glochidine	G. philippicum leaves	60
225	Glochidicine	G. philippicum leaves	60
226	Nα-(4-Oxodecanoyl)-histamine	G. philippicum leaves	60
227	Nα-cinnamoylhistamine	G. philippicum leaves	60
Cyanogens
228	2-(2,4-Dihydroxyphenyl) acetonitrile 2-O-β-D-glucopyranoside 6'-O-p-hydroxybenzoate	G. acuminatum leaves	51
229	2-(2,4-Dihydroxyphenyl) acetonitrile 2-O-β-D-glucopyranoside 6'-O-(S)-2-(4-hydrocyclohex-1-en-1-yl)acetate	G. acuminatum leaves	51
230	2-(2,4-Dihydroxyphenyl) acetonitrile 2-O-β-D-glucopyranoside 6'-O-gallate	G. acuminatum leaves	51
231	2-(2,4-Dihydroxyphenyl) acetonitrile 2-O-β-D-glucopyranoside 3’,6'-O-digallate	G. acuminatum leaves	51
232	Glochidacuminoside D	G. acuminatum leaves	54
Tocopherols
233	α-Tocospiro A	G. wrightii stems and leaves	10
234	β-Tocospiro B	G. wrightii stems and leaves	10
Fatty acids
235	(9E,11E)-13-oxo-9, 11-Octadecadienoic acid	G. wilsonii roots	1
236	Rabdosia acid A	G. wilsonii roots	1
Others
237	(S)-Methyl 2-[4-sulfooxycyclohex-1-en-1-yl] acetate	G. acuminatum leaves	51
238	p-Pentadecayl ethyl cinnamate	G. velutinum leaves	61
239	Resveratrol-12-C-β-glucopyranoside	G. wilsonii roots	1
Compounds isolated from endophytic fungus-associated with Glochidion species
240	Eupenoxide	Eupenicillium sp.-parasited G. ferdinandi	62
241	Phomoxin B	Eupenicillium sp.-parasited G. ferdinandi	62
242	Phomoxin C	Eupenicillium sp.-parasited G. ferdinandi	62

Terpenoids, Sterols, and Saponins

Terpenoids derived from Glochidion plants can be divided into sesquiterpenoids 1-11,^1,7,8,21 diterpenoid 12, ¹⁰ and triterpenoids 13-61^{9–11,14,22–39} (Table 1 and Figure 1). The most striking feature is that norbisabolane is the principal skeleton of Glochidion sesquiterpenoids 1-11. ¹ Xiao et al ⁸ successfully separated four new derivatives glochinoccins A-D (1-4), and two known analogs phyllaemblic acid (10) and phyllaemblic acid methyl ester (11) from the 90% ethanol extract of G. coccineum rhizomes. Two new bisabolane-type sesquiterpenoids glochicoccinosides A-B (5-6) were first isolated from G. hirsutum aerial parts, and then found in G. wilsonii roots.^1,7 Three new sesquiterpenoids glochiwilsonosides A-C (7-9) were among the secondary metabolites present in the polar extract of G. wilsonii roots. ¹ To date, 5-methyl-5-(4,8,12-trimethyltridecyl)-dihydro-furan-2-one (12), a secondary metabolite of G. wrightii stems and leaves, is a unique diterpenoid detected in the genus Glochidion. ¹⁰

Figure 1.

Terpenoids and sterols from Glochidion.

As shown in Table 1, triterpenoids can be seen as the main chemical class of Glochidion. G. assamicum, G. daltonii, G. dasyphyllum, G. eriocarpum, G. heyneanum, G. hohenackeri, G. hongkongense, G. macrophyllum, G. moonii, G. multiloculare, G. obliquum, G. puberum, G. sphaerogynum, G. venulatum, G. wrightii, and G. zeylanicum were the main plants contained triterpenoids. It is also possible to conclude that glochidonol (32), glochidiol (33), glochidone (34), lupeol (39), lup-20(29)-ene-1β,3β-diol (43), lup-20(29)-ene-3α,23-diol (45), and 3-epi-lupeol (49) were the major components (Table 1). As an example, compound 31 was detectable in G. daltonii roots and stems, G. eriocarpum aerial parts, roots and stems, G. heyneanum aerial parts, G. hongkongense stems, G. macrophyllum stems, G. moonii barks, G. multiloculare aerial parts, G. obliquum leaves, G. puberum stems and twigs, G. sphaerogynum roots and stems, G. venulatum leaves, G. wrightii stems and leaves, and G. zeylanicum stem barks.^{10,11,23–32,34,36,38,39} Of note, triterpenoid compounds 16-19, 31-37, 40-43, 45, and 59 were new in the literature.

G. heyneanum aerial parts have been documented to contain two known compounds β-amyrin (13) and epimachaerinic acid (22), whereas arjunolic acid (14) represented G. assamicum aerial parts.^30,37 Phytochemical research of the 95% ethanol extract of G. assamicum leaves and twigs can lead to the purification of four new triterpenoids 21β-(benzoyloxy)olean-12-ene-3β,16β,23,28-tetraol (16), 21β-(benzoyloxy)olean-12-ene-3β,16β,28-triol (17), 21β-[(E)-cinnamoyloxy]olean-12-ene-3β,16β,23,28-tetraol (18), and 21β-[(Z)-cinnamoyloxy]olean-12-ene-3β,16β,23,28-tetraol (19). ⁹ A report in 2023 indicated that the 95% ethanol extract of G. puberum stems and twigs encompassed two new metabolites glochidpurnoids A-B (35-36), and the known ones betulin (15), 3β-O-trans-coumaroylbetulin (20), 3β-O-trans-coumaroylbetulinic acid (21), 3β-O-trans-feruloylbetulin (27), 3β-O-trans-feruloylbetulinic acid (28), (20S)-3α-hydrolupan-29-oic acid (29), glochidonol (32), glochidiol (33), glochidone (34), lupeol (39), lup-20(29)-ene-3α,23-diol (45), lup-20(30)-ene-3β,29-diol (47), 3α,20-lupandiol (48), 3-epi-lupeol (49), morolic acid acetate (52), and obibanmol I (53). ³⁸

Besides the known triterpenoids, two new analogs 5α,6α-epoxy D:C-friedoolean-8-en-3β-ol (23) and glochieriol (37) have been observed in Vietnamese G. obliquum leaves and G. eriocarpum aerial parts, respectively.^14,34 In the meantime, glochidol (31) was also a new triterpenoid found in Chinese G. eriocarpum stems. ²⁷ New triterpenoid lup-20(29)-ene-1,3-dione (40) originated from G. puberum leaves, while its stems consisted two new ones lup-20(29)-ene-1β-ol-3α-yl acetate (41), and lup-20(29)-ene-3α-ol-1β-yl acetate (43). ²⁸ Two new triterpenoids lup-20(29)-ene-1β,3β-diol (43) and lup-20(29)-ene-3α,23-diol (45) were first isolated from G. macrophyllum stems.^24,25 They were then found to be available in the genus Glochidion (Table 1). Among various triterpenoids in the 95% ethanol extract of G. wrightii stems and leaves, 3β-tetradecanoyloxy-1β-hydroxylup-20(29)-ene (59) was elucidated as a new triterpenoid. ¹⁰

The known compounds 62-68 belong to the group of sterols (Table 1 and Figure 1).^{10,23–29,35,40} β-Sitosterol (63) was isolated frequently, which it was detected in G. dasyphyllum stems and leaves, G. eriocarpum stems, G. hongkongense stems and leaves, G. macrophyllum stems and leaves, G. moonii barks, G. obliquum leaves, G. puberum aerial parts, leaves and stems, G. venulatum leaves, and G. wrightii stems and leaves.^{10,23–29,35,40} Similarly, stigmasterol (67) was also a characteristic sterol present in this genus, and it can be found in G. dasyphyllum stems, G. heyneanum aerial parts, G. macrophyllum stems and leaves, and G. multiloculare aerial parts.^24,25,30,36 G. assamicum aerial parts was reported to contain chlorogenin (62), while the 95% methanol extract of G. wrightii stems and leaves was associated with the appearance of sistosterol-5-en-3β-hydroxy-7-one (64), sistosterol-5-en-3β,7α-diol (65), sitosterol-5-en-3β,7β-diol (66), and stigmast-6β-hydroxyl-4-en-3-one (68).^10,37

In general, Glochidion saponins 69-99 have been structurally formulated by a combination of aglycone oleanane and glycone at carbon C-3 (Table 1 and Figure 2).^{10,12,13,30,33–37,40–44,47} Glucopyranose and arabinopyranose are the main units in glycone parts. Remarkably, all the isolated saponins were new in the literature except for daucosterol (70) and pedunculoside (99). A new triterpene saponin 69, namely assamicoside A, was isolated from the 95% ethanol extract of G. assamicum aerial parts. ³⁷ Various species were found to contain compound 70, eg, G. heyneanum aerial parts, G. multiloculare aerial parts, G. obliquum leaves, G. puberum aerial parts, and G. wrightii stems and leaves.^{10,30,35,36,40} Glochidioside (71), and glochidiosides N and Q (72-73) were other triterpene saponins isolated from the acolholic extract of G. heyneanum aerial parts.^30,41 Five new saponins glochieriosides A-E (74-78) were among phytochemicals present in Vietnamese G. eriocarpum aerial parts.^33,34 In the same manner, serial new saponins glomerulosides A-H (79-86) and glomerulosides I-II (87-88) have been purified from Vietnamese G. glomerulatum leaf extract.^12,13 The last serial new saponins hirsutosides A-E (89-93) and puberosides A-E (94-98) presented in the alcoholic extracts of G. hirsutum leaves and G. puberum aerial parts, respectively.^42–44

Figure 2.

Saponins from Glochidion.

Lignans, Flavonoids, and Mono-Phenols

About forty lignans have been isolated and structurally identified, and they can be categorized as aryltetralins 100-106,^1,45,46 furan 107,^1,10 furofurans 108-114,^{1,10,15,37,40,47} phenylpropanoids 115-123,^1,35,46,48 benzofurans 124-139,^1,45,48,49 and lignanoid 140 ²¹ (Table 1 and Figure 3).

Figure 3.

Lignans from Glochidion.

Taking aryltetralins type lignan 100-106 into consideration, almost all of them were derivatives of isolariciresinol. The water-soluble extract of G. wilsonii roots was composed of four known metabolites (+)-isolariciresinol (100), (+)-isolariciresinol 3a-O-β-D-glucopyranoside (104), (+)-isolariciresinol 9'-O-β-D-xylopyranoside (105), and (–)-secoisol ariciresinol (106). ¹ (+)-Isolariciresinol 2a-O-β-D-glucopyranoside (101) was a new aryltetralin found in G. zeylanicum leaves, but its isomer 102 was first isolated from G. rubrum leaves.^45,46 So far compounds 101-103 were proved to be presented in the leaves of G. rubrum leaves. ⁴⁶ (+)-Laricerisnol (107) is a unique furan-type ligan found in both G. wilsonii roots, and G. wrightii stems and leaves.^1,10

A total of seven furofuran-type lignans 108-114 were summarized, in which (+)-pinoresinol (112) and (+)-syringaresinol (113) were isolated frequently. For instance, compound 113 was recorded in G. obliquum leaves, G. puberum aerial parts, G. wilsonii roots, and G. wrightii stems and leaves.^1,10,15,40 In the meantime, balanophonin B (108), clemaphenol A (109), 4,4'-dimethoxy-3'-hydroxy-7,9':7′,9-diepoxylignan-3-O-β-D-glucopyranoside (110), and yangambin (114) were isolated from the genus Glochidion for the first time.^1,47

A report published by Gao and partners indicated that G. wilsonii plant is thought to be a reservoir of lignans. Its roots contained six phenylpropanoids type lignan dihydroconiferyl alcohol (115), (E)-4-hydroxycinnamyl alcohol-4-O-β-D-glucopyranoside (116), evofolin B (117), rel-(1R,2S)-1,2-bis(4-hydroxy-3-methoxy-phenyl)-1,3-propanediol (118), and leptolepisols C-D (119-120). ¹ Another well-known phenylpropanoid, namely syringin (121), was found in both G. eriocarpum whole plant and G. obliquum leaves.^35,48 It is marked that (7R,8S)-4,7,9,9'-tetrahydroxy-3,3'-dimethoxy-8-O-4'-neolignan 7-O-β-D-glucopyranoside (122) and (7R,8R)-4,7,9,9'-tetrahydroxy-3,3'-dimethoxy-8-O-4'-neolignan 7-O-β-D-glucopyranoside (123) were two new phenylpropanoids appeared in the leaves of G. rubrum. ⁴⁶

Benzofurans type lignan were also characteristics of G. wilsonii, in which alcoholic extract of its roots consisted of five new derivatives glochiwilsonises A-E (133-137), together with six known ones 9'-dehydro-valadion F (124), dehydrodiconiferyl alcohol (125), dihydrodehydrodiconiferyl alcohol (126), 9,9'-dihydroxy-3,4-methylenedioxy-3'-methoxy [7-O-4’,8-5’] neolignan (131), 4-O-methylcedrusin (138), and phyllnirurin (139). ¹ The remaining benzofurans, including two new metabolites dihydrodehydrodiconiferyl alcohol 9'-O-sulfate (127) and glochidioboside (132), and three known analogs 7R,8S-dihydrodehydrodiconiferyl alcohol 4-O-β-D-glucopyranoside (128), 7S,8R-dihydrodehydrodiconiferyl alcohol 4-O-β-D-glucopyranoside (129), and dihydrodehydrodiconiferyl alcohol 9-O-β-D-glucopyranoside (130), which were found in G. eriocarpum whole plant and/or G. zeylanicum leaves^45,48 (Table 1). In the last case, novel and unique lignanoid glochinin A (140) was extracted from the 75% ethanol extract of G. puberum aerial parts. ²¹

As shown in Table 1 and Figure 4, Glochidion flavonoids were found to contain the subclasses of flavones 141-147,^{6,15,35,40,50} flavans 148-153,^50–52 flavanones 154-159,^10,53 and chalcone 160. ⁵¹ Together with 8-C-glucosylated flavone 6''-O-acetylorientin (141), G. obliquum leaves was reported to contain new 6-O-glycosylated flavone globlin A (142).^15,35 In the search for cytotoxic agents from natural plants, three well-known flavones isoorientin (143), orientin (145), and vitexin (146) were isolated from the methanol extract of G. hypoleucum leaves. ⁶ Compound 146 was further detected in G. obliquum leaves, G. puberum aerial parts, and G. zeylanicum leaves.^15,35,40,50 By silica gel and Sephadex-LH20 chromatographic separation, two other known flavones isovitexin (144) and its 7-O-xyloside (145) were purified from the ethanol extract of G. hirsutum stems. ⁷

Figure 4.

Flavonoids and mono-phenols from Glochidion.

Among the isolated flavans 148-153, compounds 149-153 were new secondary metabolites with the same absolute configuration at carbons C-2 and C-3. Glochiflavanosides A-D (149-152) were fractionated from the methanol extract of G. zeylanicum leaves, whereas the bulk metabolite glochiin C₁ (153) originated from the aqueous acetone homogenate of G. rubrum leaves.^50,52 Besides the known flavanone (2R,3R)-dihydromyricetin (158), four new analogs (2R,3R)-dihydromyricetin-4'-O-(3''-O-methyl)-gallate (154), (2R,3R)-dihydromyricetin-3'-O-(3''-O-methyl)-gallate (155), (2R,3R)-dihydromyricetin-4'-O-gallate (156), and (2R,3R)-dihydromyricetin-3'-O-gallate (157) had been observed in G. sumatranum leaves and twigs. ⁵³ The last flavanone narigenin (159) arose from G. wrightii stems and leaves. ¹⁰ Chalcone 160, namely phloretin 4'-O-β-D-glucopyranoside, was among the isolates present in G. acuminatum leaves. ⁵¹

Mono-phenols are widely found in higher plants, as well as they appear in the form of mono-phenol or their precursors. Mono-phenols exhibited a great number of pharmacological activities such as antioxidant, antimicrobial, antiviral, and antiinflammatory activities.^63–65 It turns out that the genus Glochidion is also rich in this type with more than twenty compounds 161-183 being isolated (Table 1 and Figure 4).^{1,6,7,35,37,40,46,48,49,51,52,54,55} G. eriocarpum whole plant, G. hirsutum stems, G. obliquum leaves, G. obovatum leaves, G. rubrum leaves, and G. wilsonii roots were recorded to encompass bergenin (161).^{1,7,35,46,48,49} In addition, 4-O-ethylgallic acid (163), gallic acid (166), glochidacuminoside A (168), methyl gallate (177), and 24,6-trimethoxyphenol-1-O-β-D-glucoside (182) were found in two or three species, whereas the remaining mono-phenols were isolated from the genus Glochidion for the first time (Table 1). Significantly, several compounds were identified to be new derivatives. Glochidacuminoside A (168), which was a new mono-phenol isolated from G. acuminatum leaves, existed as a salt of several metal ions. ⁵⁰ Methyl 2-(2-hydroxyphenyl) acetate β-D-glucopyranoside (175) was another new mono-phenol found in G. acuminatum leaves. ⁵¹ The leaf extract of G. rubrum was associated with the presence of three new phytochemicals glochiins M₁ and M2 (169-170) and tachioside 2'-O-4''-O-methylgallate (181).^46,52 Two last new mono-phenolic compounds glochiwilsophenoside (171) and 2-β-D-glucopyranosyloxy-4-methoxy-6-hydroxy-isovalero-phenone (172) were fractionated from the methanol extract of G. wilsonii roots and G. eriocarpum whole plant, respectively.^1,48

Megastigmanes, Butenolides, and Glycosides

Phytochemical studies of Glochidion species further reported the presence of megastigmanes 184-199 (Figure 5).^{14,37,46,48,49,56,57} To date, this chemical class can be found in G. assamicum, G. obliquum, G. rubrum, and G. zeylanicum, especially G. eriocarpum (Table 1). Besides the known compounds, G. obliquum leaves collected from Vietnam, have been reported to compose of an unusual novel megastigmane 6β,9β:9,13-diepoxymegastig-4-en-3β-ol (187). ¹⁴ Based on chemical and spectroscopic methods, glochidionionosides A-D (189-192), (3S,5R,6R,7E,9S)-megastigman-7-ene-3,5,6,9-tetrol 3-O-β-D-glucopyranoside (197), and (3S,5R,6R,7E,9S)-megastigman-7-ene-3,5,6,9-tetrol 9-O-β-D-glucopyranoside (198) were confirmed to be six new megastigmane glycosides, and they were derived from Japanese G. zeylanicum leaves.^56,57

Figure 5.

Megastigmanes, butenolides, and glycosides from Glochidion.

It matches well with previous evidence since butenolides were also characteristic compounds of Euphorbiaceae plants. Regarding the genus Glochidion, more than ten isolates 200-211 have been summarized (Table 1 and Figure 5).^{1,51,54,58,59} In addition to the known metabolites (+)-aquilegiolide (200) and (–)-loliolide (209), and (+)-menisdaurilide (210), two new butenolides isoglochidiolide (201) and glochidiolide (202) were separated from Japanese Glochidion species, G. acuminatum leaves.^49,51,54 Six new glycosylated isolates glochidionolactones A-F (203-208) and the known analog phyllanthurinolactone (211) were also purified from the methanol extract of another Japanese Glochidion species, G. zeylanicum leaves. ⁵⁹

Glochidion glycosides 212-222 appeared in free forms or in combination with aliphatic aglycones (Table 1 and Figure 5).^{7,30,35,37,40,46,54} Glycoside derivatives can be found in aerial parts of several Glochidion plants, such as G. assamicum, G. heyneanum, G. hirsutum, G. puberum, G. obliquum, and G. rubrum (Table 1). Among these glycosides, the isolated compounds 218-219 were identified to be two new compounds, which were trivially named glochidacuminosides B-C, and were extracted from the 95% aqueous fraction of G. acuminatum leaves. ⁵⁴

Alkaloids, Cyanogens, Tocopherols, Fatty Acids, and Others

Alkaloids are the next phytochemical class found in the genus Glochidion (Table 1 and Figure 6). Acuminaminoside (223) represented an alkaloidal glycoside containing an unusual dimeric phenylethane backbone, which was isolated from the methanol extract of G. acuminatum leaves for the first time. ⁵⁴ Three new histamine alkaloids glochidine (224), glochidicine (225), and Nα-(4-oxodecanoyl)-histamine (226), along with a known analog N^α-cinnamoylhistamine (227) were detected in a New Guinea Glochidion plant, G. philippicum leaves. ⁶⁰

Figure 6.

Alkaloids, cyanogens, tocopherols, fatty acids, and others from Glochidion.

Natural compounds bearing the CN functional group were also present in Glochidion plants (Table 1 and Figure 6). Significantly, all the isolated cyanogen glycosides, consisting of 2-(2,4-dihydroxyphenyl) acetonitrile 2-O-β-D-glucopyranoside 6'-O-p-hydroxybenzoate (228), 2-(2,4-dihydroxyphenyl) acetonitrile 2-O-β-D-glucopyranoside 6'-O-(S)-2-(4-hydrocyclohex-1-en-1-yl)acetate (229), 2-(2,4-dihydroxyphenyl) acetonitrile 2-O-β-D-glucopyranoside 6'-O-gallate (230), 2-(2,4-dihydroxyphenyl) acetonitrile 2-O-β-D-glucopyranoside 3’,6'-O-digallate (231), and glochidacuminoside D (232) were new in literature, and were only found in G. acuminatum leaves.

The chromatographic procedure of the alcoholic extract of G. wrightii stems and leaves resulted in the isolation of two known tocopherols α-tocospiro A (233) and β-tocospiro B (234), whereas two known fatty acids (9E,11E)-13-oxo-9,11-octadecadienoic acid (235) and rabdosia acid A (236) were derived from G. wilsonii roots (Table 1 and Figure 6).^1,10

Phytochemical studies aided by the NMR spectral data also revealed the presence of three other phytochemicals (S)-methyl 2-[4-sulfooxycyclohex-1-en-1-yl] acetate (237), p-pentadecayl ethyl cinnamate (238), and resveratrol-12-C-β-glucopyranoside (239) in G. acuminatum leaves, G. velutinum leaves, and G. wilsonii roots, respectively.^1,51,61 Among them, compounds 237-238 were new in nature. Chromatographic column procedure to the methanol extract of the endophytic fungus Eupenicillium sp. parasited-G. ferdinandi can lead to the separation of two new polyketides phomoxins B-C (241-242), and a known analog eupenoxide (240). ⁶²

the GC/LC-MS, and Other Phytochemical Analyses

Plants in the genus Glochidion are also the main object of essential oil studies. Following the GC-MS analysis, linalool (59.76%) and (E)-2-hexen-1-ol (7.76%) can be seen as the main agents of G. sphaerogynum male flowers. ¹⁷ (E)-2-Nonenal (36.6%) and (E)-2-nonen-1-ol (14.14%) accounted for 36.6 and 14.14% of G. hirsutum male flowers, respectively. ¹⁷ G. zeylanicum male flowers were dominated by (E)-2-nonenal (23.5%) and (E)-2-nonen-1-ol (11.17%), whereas (E)-β-ocinene (42.6%) was predominant in G. eriocarpum female flowers. ¹⁷ In another study, (E)-β-ocinene reached up to 25.66 and 94.34% in the flowers of G. rubrum and G. acuminatum, respectively. ¹⁶ (E)-Linalool oxide (furanoid) fluctuated from 45.88 to 73.19% in the flowers of G. lanceolatum, G. obovatum, and G. rubrum. ¹⁶ The GC-MS analysis identified the main compounds of G. sphaerogynum bark methanol extract as aliphatic compounds, whereas the atomic absorption spectrometry (ASS) analysis affirmed the concentration of metals Na and Ca at 8–10 ppm. ⁶⁶ The phytochemical profile of G. velutinum leaf extracts using LC-MS/MS-based molecular networking was associated with the presence of mono-phenols and flavonoids. ⁶⁷ For instance, its n-butanol fraction contained quinic acid, trehalose, isovitexin, hyperoside, and luteolin 4'-O-glucoside. ⁶⁷

Total phenolic content (TPC) and total flavonoid content (TFC) in the methanol extract of G. ellipticum leaves were found to be 252.67 mg gallic acid equivalent (GAE)/100 g dried weight (DW) and 179.58 mg catechin equivalent (CE)/100 DW, and were better than those in the chloroform extract (136.34 mg GAE/100 g DW and 78.79 mg CE/100 g DW) and petroleum extract (25.86 mg GAE/100 g DW and 14.71 mg CE/100 g DW). ⁶⁸ The TPC and TFC values of G. hirsutum leaf ethanol extract were 11.57 mg GAE/g DW and 3.02 mg CE/g DW, respectively, whereas those of G. sphaerogynum leaf ethanol extract were 4.83 mg GAE/g DW and 1.93 mg CE/g DW. ⁶⁹ In another report, the TPC and TFC values of G. zeylanicum leaf methanol extract were 320.14 mg GAE/g DW, and 52.54 mg quercetin equivalent (QE)/g DW, respectively. ⁷⁰ Cyanidin and anthocyanidin amounts in G. perakense young leaves were about 13.29 mg/100 g fresh weight (FW), whereas their TPC value was about 4762.76 mg GAE/100 g FW. ⁷¹ G. perakense young leaves were also rich in β-carotene, lutein, and vitamins C and E. ⁷¹

Pharmacological Activities

Cytotoxicity

New sesquiterpenoid glochiwilsonoside A (7) inhibited the proliferation of A-549 cancer cells with the IC₅₀ value of 34.5 µM. ¹ Two triterpenoids lup-20(29)-ene-1β,3β-diol (43), and lup-20(29)-ene-3β,23-diol (46), especially two new saponins glochieriosides A-B (74-75) exhibited cytotoxicity against four cancer cell lines HL-60, HT-29, MCF-7, and SK-OV-3 with the IC₅₀ values of 5.5-67.0 µM, but triterpenoid glochidone (34) failed to do so (IC₅₀> 100 µM, inactive). ³³ The difference in results between two saponins may be due to a great role of the glycone part at carbinol carbon C-3.

Triterpenoids 32-33, and 45 had strong inhibitory effects against three cancer cell lines MCF-7, NCI-H460, and SF-268 (GI₅₀≤ 20 µM), triterpenoid 49 was less active (GI₅₀> 50 µM). ³² Triterpenoid 43 only moderately affected MCF-7 with the GI₅₀ value of 79.2 µM, while compound 43, once again, was found to be inactive. ³² The functional groups at carbon C-3 were responsible for the differential results of compounds 32-33 and 43, while the difference among 32-33 and 45 was deduced from the functional groups at carbons C-3 and C-24. ³² As we know, the capability to suppress Epstein-Barr virus early antigen (EBV-EA) activation by tumor promoters correlated with their capability to inhibit tumor enhancement. Triterpenoids 32-34, and 43 exhibited significant inhibitory effects on EBV-EA activation induced by 12-O-tetradecanoylphorbol 13-acetate (TPA), which were better than the standard curcumin (IC₅₀ 343 mol ratio/32 pmol TPA). ³¹

A publication in 2023 revealed that new triterpenoid 36, and its known analogs 15, 21, 32-33, and 52 showed the IC₅₀ values of 0.80–2.99 µM lower than that of the standard 5-fluorouracil (IC₅₀ 3.79 µM). ³⁸ In addition, anticancer mechanism of compound 36 is due to its endoplasmic reticulum stress-mediated apoptosis and enhancement of the sensitivity of HCT-16 cells to 5-fluorouracil. ³⁸ Among tested compounds, only triterpenoid rotundic acid (55) was cytotoxic against three cancer cell lines Daoy, HepG2, MCF-7, and HeLa with the ED₅₀ values of 24.67–29.43 µM, when mitomycin was used as a positive control (IC₅₀ 0.21–0.30 µM. ³⁵

Glochidion saponins are the next chemical class used for cytotoxic examinations. Triterpene saponins 74-77 having a benzoyl group at carbon C-22 generated the IC₅₀ values of less than 6.33 µM in cytotoxic assay against HL-60 and HCT-116 cancer cells, which were better than analog 78 without a benzoyl group at carbon C-22 (IC₅₀ 29.62-34.00 µM), and the standard mitoxantrone (IC₅₀ 7.23-8.40 µM). ⁷² Further evidence revealed that the potential saponins 74-77 induced apoptosis in HCT-116 cells by phosphorylation of ERK and p38. ⁷²

Serial new triterpene saponins glomerulosides A-H (79-86) exerted the IC₅₀ values of 8.2–94.9 µM against four cancer cell lines A-549, HT-29, OVCAR, and MCF-7. ¹² Among these, compound 80 without the functional groups at carbons C-16 and C-22 remarkably controlled the growth of A-549 and HT-29 cancer cells with the IC₅₀ values of 9.7 and 7.5 µM. ¹² In contrast to compounds 84-86, compounds 81 and 83 having a benzoyloxy group at carbon C-22 exhibited strong activity against A-549, HT-29, and OVCAR cancer cells with the IC₅₀ values of 5.9-9.8 µM. ¹²

In another report, four new triterpenoid saponins hirsutosides A-B and D-E (89-90 and 92-93) possessed the IC₅₀ values of 3.4–10.2 µM against four cancer cell lines HepG-2, A-549, MCF-7, and SW-626, whereas those of hirsutoside C (91) were 47.0–54.4 µM. ⁴² Considering structure activity relationship among metabolites 89–91, compound 90 with an additional sugar unit at Glc C(3'‘) showed stronger cytotoxicity, but with the introduction of the AcO group to Glc C(6'‘) of compound 91, activity will be decreased.

Both the methanol extract of G. velutinum leaves and its n-hexane, chloroform, ethyl acetate, n-butanol, and aqueous fractions were reported to show cytotoxicity towards two cancer cell lines MCF-7 and PC-3 (Table 2). ⁶⁷ At the same dose of 20 mg/kg, i.p., the methanol extract and its petroleum ether, carbon tetrachloride, and chloroform fractions of G. multiloculare stem barks increased the survival time of mice bearing EAC (Ehrlich's ascites carcinoma) from 21 to 27 days, compared to the control group (20 days). ⁷³ The effect was also associated with a restoration of heamoglobin, a remarkable decrease in red blood cells, and an increase in white blood cells. ⁷³

Table 2.

Pharmacological Activities of Constituents from Glochidion species.

Compounds	Models	Effect	References
Cytotoxicity
7	In vitro	IC50 = 34.5 µM/A-549	1
15	In vitro	IC50 = 1.89 µM/HCT-116	38
21	In vitro	IC50 = 1.16 µM/HCT-116	38
32	In vitro	IC50 = 2.4 µM/HCT-116 GI50 = 9.0 µM/MCF-7 GI50 = 4.9 µM/NCI-H460 GI50 = 9.8 µM/SF-268	32,38
32	In vitro	IC50 = 325 mol ratio/32 pmol TPA/EBV-EA induced by TPA	31
33	In vitro	IC50 = 2.91 µM/HCT-116 GI50 = 6.6 µM/MCF-7 GI50 = 7.5 µM/NCI-H460 GI50 = 9.7 µM/SF-268	32,38
33	In vitro	IC50 = 290 mol ratio/32 pmol TPA/EBV-EA induced by TPA	31
34	In vitro	IC50 = 341 mol ratio/32 pmol TPA/EBV-EA induced by TPA	31
36	In vitro	IC50 = 0.80 µM/HCT-116	38
43	In vitro	IC50 = 43.3 µM/HL-60 IC50 = 67.0 µM/HT-29 IC50 = 66.1 and 72.9 µM/MCF-7 IC50 = 48.0 µM/SK-OV-3	32,33
43	In vitro	IC50 = 300 mol ratio/32 pmol TPA/EBV-EA induced by TPA	31
45	In vitro	GI50 = 12.7 µM/MCF-7 GI50 = 17.9 µM/NCI-H460 and SF-268	32
46	In vitro	IC50 = 13.7 µM/HL-60 IC50 = 71.7 µM/HT-29 IC50 = 46.1 µM/MCF-7	33
49	In vitro	GI50 = 75.6 µM/MCF-7 GI50 = 86.1 µM/NCI-H460 GI50 = 80.9 µM/SF-268	32
52	In vitro	IC50 = 2.99 µM/HCT-116	38
55	In vitro	ED50 = 24.67 µM/Daoy ED50 = 29.22 µM/HepG2 ED50 = 29.43 µM/MCF-7	35
74	In vitro	IC50 = 1.16 µM/HCT-116 IC50 = 5.5 µM/HL-60 IC50 = 6.8 µM/HT-29 IC50 = 29.1 µM/MCF-7 IC50 = 22.7 µM/SK-OV-3	33,72
75	In vitro	IC50 = 0.41 µM/HCT-116 IC50 = 6.6 µM/HL-60 IC50 = 18.6 µM/HT-29 IC50 = 36.1 µM/MCF-7 IC50 = 16.0 µM/SK-OV-3	33,72
76	In vitro	IC50 = 5.07 µM/HL-60 IC50 = 0.94 µM/HCT-116	72
77	In vitro	IC50 = 6.33 µM/HL-60 IC50 = 0.73 µM/HCT-116	72
78	In vitro	IC50 = 29.62 µM/HL-60 IC50 = 34.00 µM/HCT-116	72
79	In vitro	IC50 = 41.0 µM/A-549 IC50 = 7.3 µM/HT-29 IC50 = 6.6 µM/OVCAR IC50 = 58.4 µM/MCF-7	12
80	In vitro	IC50 = 9.7 µM/A-549 IC50 = 7.5 µM/HT-29 IC50 = 41.5 µM/OVCAR IC50 = 60.7 µM/MCF-7	12
81	In vitro	IC50 = 7.9 µM/A-549 IC50 = 5.9 µM/HT-29 IC50 = 9.8 µM/OVCAR IC50 = 42.8 µM/MCF-7	12
82	In vitro	IC50 = 58.2 µM/A-549 IC50 = 49.3 µM/HT-29 IC50 = 59.4 µM/OVCAR IC50 = 69.3 µM/MCF-7	12
83	In vitro	IC50 = 8.2 µM/A-549 IC50 = 5.9 µM/HT-29 IC50 = 8.6 µM/OVCAR IC50 = 63.5 µM/MCF-7	12
84	In vitro	IC50 = 94.9 µM/A-549 IC50 = 45.0 µM/HT-29 IC50 = 34.1 µM/OVCAR IC50 = 86.3 µM/MCF-7	12
85	In vitro	IC50 = 58.1 µM/A-549 IC50 = 49.1 µM/HT-29 IC50 = 45.8 µM/OVCAR IC50 = 67.5 µM/MCF-7	12
86	In vitro	IC50 = 51.7 µM/A-549 IC50 = 58.7 µM/HT-29 IC50 = 27.7 µM/OVCAR IC50 = 77.2 µM/MCF-7	12
89	In vitro	IC50 = 8.2 µM/HepG-2 IC50 = 9.3 µM/A-549 IC50 = 9.2 µM/MCF-7 IC50 = 8.5 µM/SW-26	42
90	In vitro	IC50 = 3.4 µM/HepG-2 IC50 = 4.4 µM/A-549 IC50 = 4.7 µM/MCF-7 IC50 = 6.6 µM/SW-26	42
91	In vitro	IC50 = 47.0 µM/HepG-2 IC50 = 49.3 µM/A-549 IC50 = 51.9 µM/MCF-7 IC50 = 54.4 µM/SW-26	42
92	In vitro	IC50 = 7.6 µM/HepG-2 IC50 = 8.0 µM/A-549 IC50 = 8.8 µM/MCF-7 IC50 = 9.1 µM/SW-26	42
93	In vitro	IC50 = 9.9 µM/HepG-2 IC50 = 8.6 µM/A-549 IC50 = 10.2 µM/MCF-7 IC50 = 10.1 µM/SW-26	42
The methanol extract of G. velutinum leaves	In vitro	IC50 = 431.78 µg/mL/MCF-7 IC50 = 89.02 µg/mL/PC-3	67
The n-hexane fraction of G. velutinum leaves	In vitro	IC50 = 523.63 µg/mL/MCF-7 IC50 = 325.87 µg/mL/PC-3	67
The chloroform fraction of G. velutinum leaves	In vitro	IC50 = 222.27 µg/mL/MCF-7 IC50 = 27.63 µg/mL/PC-3	67
The ethyl acetate fraction of G. velutinum leaves	In vitro	IC50 = 226.35 µg/mL/MCF-7 IC50 = 196.83 µg/mL/PC-3	67
The n-butanol fraction of G. velutinum leaves	In vitro	IC50 = 123.36 µg/mL/PC-3	67
The aqueous fraction of G. velutinum leaves	In vitro	IC50 = 522.41 µg/mL/MCF-7 IC50 = 36.95 µg/mL/PC-3	67
The methanol extract of G. multiloculare stem barks (20 mg/kg, i.p.)	In vivo	24 Days of survival/mice bearing EAC	73
The petroleum ether fraction of G. multiloculare stem barks (20 mg/kg, i.p.)	In vivo	26 Days of survival/mice bearing EAC	73
The carbontetrachloride fraction of G. multiloculare stem barks (20 mg/kg, i.p.)	In vivo	21 Days of survival/mice bearing EAC	73
The chloroform fraction of G. multiloculare stem barks (20 mg/kg, i.p.)	In vivo	27 Days of survival/mice bearing EAC	73
Antioxidative activity
143	In vitro	IC50 = 11.1 µg/mL/DPPH radicals	6
146	In vitro	IC50 = 13.0 µg/mL/DPPH radicals	6
166	In vitro	IC50 = 2.5 µg/mL/DPPH radicals	6
177	In vitro	IC50 = 4.2 µg/mL/DPPH radicals	6
238	In vitro	IC50 = 302.5 µg/mL/DPPH radicals	61
The methanol extract of G. sphaerogynum barks	In vitro	IC50 = 37.4479 µg/mL/DPPH radicals	66
The methanol extract of G. hypoleucum leaves	In vitro	IC50 = 40 µg/mL/DPPH radicals	6
The 95% ethanol extracts of G. hirsutum leaves	In vitro	181.74 µg AAE/g DW/DPPH radicals	69
The 95% ethanol extracts of G. sphaerogynum leaves	In vitro	42.19 µg AAE/g DW/DPPH radicals	69
The methanol extract of G. zeylanicum leaves	In vitro	IC50 = 6.56 µg/mL/DPPH radicals	70
The methanol extract of G. zeylanicum leaves	In vitro	IC50 = 3.76 µg/mL/ABTS radicals	70
The 80% ethanol extract of G. wallichianum leaves	In vitro	2.3 mmole TE/g DW/DPPH radicals 1.9 mmole TE/g DW/ABTS radicals 1.1 mmole TE/g DW/FRAP	74
The methanol extract of G. multiloculare barks	In vitro	IC50 = 16.46 µg/mL/DPPH radicals	75
Antimicrobial activity
31	In vitro	MIC = 128 µM/B. subtilis and MRSA	76
31 + tetracycline	In vitro	FICI = 0.5156 and time-kill of 4.0 h/B. subtilis FICI = 0.5313 and time-kill of 6.0 h/MRSA	76
32	In vitro	MIC = 64 µM/P. aeruginosa	39
33	In vitro	MIC = 64 µM/P. aeruginosa and E. coli	39
34	In vitro	MIC = 2048 µM/P. aeruginosa	39
45	In vitro	MIC = 512 µM/P. aeruginosa and E. coli	39
49	In vitro	MIC = 2048 µM/E. coli MIC = 1024 µM/P. aeruginosa	39
154	In vitro	71% Inhibition/P. aeruginosa at 175 µM 49% Inhibition/S. aureus at 175 µM	53
156	In vitro	56% Inhibition/P. aeruginosa at 17.5 µM 70% Inhibition/S. aureus at 70 µM	53
158	In vitro	52% Inhibition/P. aeruginosa at 175 µM	53
177	In vitro	MIC = 50 µg/mL and MBC = 100 µg/mL/MRSA	55
238	In vitro	IZ = 12 mm/B. cereus IZ = 9 mm/S. aureus IZ = 10 mm/E. faecalis and P. vulgaris IZ = 8 mm/E.coli EPEC, E. coli ATCC, and K. oxytoca IZ = 7 mm/K. michiganensis IZ = 5 mm/E.coli ETEC IZ = 11 mm/S. typhi	61
The petroleum ether extract of G. multiloculare barks	In vitro	IZ = 10 mm/V. parahemolyticus, C. albicans, A. niger, and S. cerevaceae IZ = 9 mm/B. cerus, B. megaterium, B. subtilis, S. lutea, Sh. boydii, and V. mimicus IZ = 8 mm/E. coli, P. aeruginosa, S. typhi, and Sh. dysenteriae	77
The chloroform extract of G. multiloculare barks	In vitro	IZ = 12 mm/B. subtilis IZ = 11 mm/E. coli IZ = 10 mm/B. cerus, B. megaterium, S. lutea, P. aeruginosa, S. typhi, Sh. dysenteriae, Sh. boydii, V. parahemolyticus, and S. cerevaceae IZ = 9 mm/V. mimicus, C. albicans, and A. niger	77
The carbon tetrachloride extract of G. multiloculare barks	In vitro	IZ = 7 mm/Sh. boydii, and V. mimicus IZ = 8 mm/B. cerus, B. megaterium, S. lutea, P. aeruginosa, S. typhi, Sh. dysenteriae, C. albicans, and V. parahemolyticus IZ = 9 mm/E. coli, S. cerevaceae, and A. niger	77
G. candolleanum leaf-silver nanoparticles	In vitro	IZ = 12.2 mm/S. enterica IZ = 11.8 mm/P. aeruginosa	78
The ethanol extract of G. puberum roots	In vitro	MIC = 100 µg/mL/B. subtitis MIC = 200 µg/mL/P. aeruginosa	79
Antiinflammatory activity
7	In vitro	IC50 = 16 µM/NO	1
24	In vitro	IC50 = 60.5 µM/NOS	35
55	In vitro	IC50 = 39.5 µM/NOS IC50 = 80.9 µM/NOX	35
58	In vitro	IC50 = 60.6 µM/NOS IC50 = 52.2 µM/NOX	35
99	In vitro	IC50 = 78.7 µM/NOS	35
121	In vitro	IC50 = 78.9 µM/NOS	35
142	In vitro	IC50 = 80.1 µM/NOS	35
147	In vitro	IC50 = 65.7 µM/NOS	35
161	In vitro	IC50 = 98.4 µM/NOS	35
The ethanol extract of G. thomsonii barks (250 and 500 mg/kg, p.o.)	In vivo	To inhibit carrageenan mediated paw edema and xylene mediated ear edema in mice	18
The n-hexane, dichloromethane, and n-butnanol extracts of G. ellipticum leaves (200 mg/kg, p.o.)	In vivo	To ameliorate DSS-stimulated colitis in mice via the NF-κB signaling inhibition	80
The methanol extract and its petroleum ether, carbon tetrachloride, and chloroform fractions of G. multiloculare stem bark (100 mg/kg, i.p.)	In vivo	To inhibit carrageenan induced paw edema in mice	73
Antidiabetic activity
The 95% ethanol extract of G. hirsutum leaves	In vitro	IC50 = 1.01 mg/mL/α-amylase IC50 = 0.59 mg/mL/α-glucosidase	69
The 95% ethanol extract of G. sphaerogynum leaves	In vitro	IC50 = 2.21 mg/mL/α-amylase IC50 = 2.84 mg/mL/α-glucosidase	69
The ethanol extract of G. arborescens leaves and C. ramiflora leaves	In vitro	IC50 = 374.47 ppm/α-glucosidase enzyme	81
The ethanol extract of G. velutinum leaves (200 and 400 mg/kg, p.o.)	In vivo	To inhibit streptozotocin-nicotinamide stimulated type 2 diabetic mice	82
The aqueous extract of G. zylanicum roots (200 and 400 mg/kg, p.o.)	In vivo	To reduce blood glucose levels in mice	19
The aqueous extract of G. velutinum leaves (400 mg/kg, p.o.)	In vivo	To reduce blood glucose levels in mice	20
Antiurolithiatic activity
The methanol extract of G. velutinium leaves (500 mg/kg, p.o.)	In vivo	To suppress the CAOX crystal formation in calculogenic mice	83
Antidiarrheal activity
The ethanol extract of G. thomsonii barks (500 mg/kg, p.o.)	In vivo	To inhibit castor oil induced diarrhea in mice by 54.47%, and reduce the intestinal fluid accumulation by 51.6%	84
Analgesic activity
The methanol extract of G. multiloculare stem barks (20 mg/kg, i.p.)	In vivo	70% Inhibition/acetic acid induced writhing in mice	73
The petroleum ether fraction of G. multiloculare stem barks (20 mg/kg, i.p.)	In vivo	66.36% Inhibition/acetic acid induced writhing in mice	73
The carbontetrachloride fraction of G. multiloculare stem barks (20 mg/kg, i.p.)	In vivo	83.25% Inhibition/acetic acid induced writhing in mice	73
The chloroform fraction of G. multiloculare stem barks (20 mg/kg, i.p.)	In vivo	84.09% Inhibition/acetic acid induced writhing in mice	73
The ethanol extract of G. thomsonii barks (250 and 500 mg/kg, p.o.)	In vivo	To suppress formalin mediated paw licking and acetic acid mediated writhing in mice	18
Sedative activity
The methanol extract of G. multiloculare leaves (200 mg/kg, p.o.)	In vivo	To decrease the locomotor activity of mice in hole cross, opening field, and prolonging the sleeping time	5
Neuroprotective activity
The ethanol extract of G. zeylanicum leaves (10 µg/mL)	In vitro	To protect against glutamate/H2O2-induced toxicity in HT-22 and Neuro-2a neuronal cells	85
The ethanol extract of G. zeylanicum leaves (5 µg/mL)	In vitro	To protect against Aβ-induced toxicity in C. elegans and enhance neuritogenesis in neuro-2a cells	85
The aqueous extract of G. littorale leaves at the concentration of 100–200 µg/mL	In vitro	To protect against MMP+ induced toxcity in C. elegans by DAF-16 transcription activation	86
Liver protective activity
The ethanol extract of G. wallichianum leaves (300 and 600 mg/kg, p.o.)	In vivo	To suppress ethanol induced liver damage in mice via antioxdative activity	87
Skin protective activity
The methanol extract G. zeylanicum leaves	In vitro	IC50 = 47.94 µg/mL/elastase IC50 = 76.00 µg/mL/tyrosine	70
Anti 5α-reductase acitivity
The 50% ethanol extract of G. eriocarpum roots (200 µg/mL)	In vitro	25.5% Inhibition/5α-reductase enzyme	88
Hemolysis
The ethanol leaf extract of G. zeylanicum (75 µg/mL)	In vitro	60.52% Inhibition/red blood cell destruction	89
Mosquito larvicidal activity
The ethyl acetate extract of G. laneolarium leaves	In vitro	-80% Morality rate, LC50 = 55.73 ppm and LC90 = 127 ppm/Cx. vishnui third larvae for 24 h -85.33% Morality rate, LC50 = 52.10 ppm and LC90 = 89.24 ppm/Cx. vishnui third larvae for 48 h -100% Morality rate, LC50 = 48.68 ppm and LC90 = 74.64 ppm/Cx. vishnui third larvae for 24h	90
Toxicology
The methanol extract of G. multiloculare leaves	In vitro	LC50 = 37.19 µg/mL/A. salina	5
The n-hexane extract of G. velutinum leaves	In vitro	LC50 = 598.54 µg/mL/A. salina	91
The ethyl acetate extract of G. velutinum leaves	In vitro	LC50 = 651.92 µg/mL/A. salina	91
The methanol extract of G. velutinum leaves	In vitro	LC50 = 428.47 µg/mL/A. salina	91
The petroleum ether extract of G. multiloculare barks	In vitro	LC50 = 3.11 µg/mL/A. salina	77
The carbon tetrachloride extract of G. multiloculare barks	In vitro	LC50 = 4.96 µg/mL/A. salina	77
The chloroform extract of G. multiloculare barks	In vitro	LC50 = 7.56 µg/mL/A. salina	77
The methanol extract of G. multiloculare barks	In vitro	LC50 = 9.23 µg/mL/A. salina	77
The aqueous extract of G. multiloculare barks	In vitro	LC50 = 16.32 µg/mL/A. salina	77

Antioxidative Activity

It was noted that flavones 143 and 146 and mono-phenols 166 and 177 may become potential agents for antioxidative drug development since they are comparable to the positive control ascorbic acid (IC₅₀ 12.5 µg/mL) to scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals. ⁶ In another report, new cinnamate derivative 238 exhibited antioxidative activity to capture DPPH radicals with the IC₅₀ value of 302.5 µg/mL. ⁶¹

The methanol extract of G. sphaerogynum barks scavenged DPPH radicals with the IC₅₀ value of 37.4479 µg/mL, in comparison with that of the methanol extract of G. hypoleucum leaves (IC₅₀ 40 µg/mL.^6,66 The DPPH radical quenching activity of the 95% ethanol extracts of G. hirsutum leaves and G. sphaerogynum leaves corresponds to 181.74 and 42.19 µg AAE (ascorbic acid equivalent)/g DW. ⁶⁹ G. zeylanicum leaf methanol extract strongly quenched DPPH and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radicals with the IC₅₀ values of 6.56 and 3.76 µg/mL, respectively. ⁷⁰ The 80% ethanol extract of G. wallichianum leaves caused antioxidative activity against DPPH, and ABTS radicals and ferric reducing antioxidant power (FRAP) activity with 2.3, 1.9, and 1.1 mmole trolox equivalent (TE)/g DW, respectively. ⁷⁴ In addition, this extract at the concentration of 0.01% could significantly maintain oxidative stability and physicochemical quality of the cooked sausage model system, which were comparable to or better than those of the standard butylated hydroxyl toluene (BHT). ⁷⁴ The methanol extract of G. multiloculare barks containing about 100 mg GAE/mg DW caused the IC₅₀ value of 16.46 µg/mL, which was stronger than the positive control BHT (IC₅₀ 20.45 µg/mL) against DPPH radicals. ⁷⁵

Antimicrobial Activity

Glochidol (31) has shown antimicrobial activity against the bacteria Bacillus subtilis and MRSA (methicillin-resistant Staphylococcus aureus) with the same minimum inhibitory concentration (MIC) value of 128 µM. ⁷⁶ The synergistic effect in combination of triterpenoid 31 and the standard tetracycline against Escherichia coli and Pseudomonas aerugiosa was accompanied by the corresponding fractional inhibitory concentration index (FICI) values of 0.5156 and 0.5313, and a decrease in time-kill of 4.0 and 6.0 h, respectively. ⁷⁶ Mono-phenol methyl gallate (177) exerted the MIC of 50 µg/mL and MBC of 100 µg/mL against MRSA. ⁵⁵

Glochidiol (32) was comparable with the standard tetracycline in antibacterial assay against bacterium P. aeruginosa with the same MIC value of 64 µM. ³⁹ Meanwhile, the MIC values of 512–2048 µM were assignable to other tested triterpenoids 33-34, 45 and 49. ³⁹ Additionally, triterpenoid 45 also significantly inhibited the growth of bacterium E. coli with the MIC value of 512 µM. ³⁹

New flavanones 154, 156, and known analog 158 possessed inhibitory percentages of 71, 56, and 52% to P. aeruginosa, respectively. ⁵³ Compounds 154 and 156 were also found to suppress S. aureus up to 49% and 70%, respectively. The difference among these flavanones can be explained by the functional groups at carbons C-3’ and C-4’.

Natural metabolite 238 was also responsible for antimicrobial activity against a panel of bacterial strains B. cereus, S. aureus, Enterococcus faecalis, E. coli EPEC, E. coli ETEC, E. coli ATCC, Klebsiella oxytoca, K. michiganensis, Salmonella typhi, and Proteus vulgaris with the inhibition zone (IZ) values of 5–12 mm. ⁶¹

In general, the use of halogenated solvents should be appropriate since the chloform extract of G. multiloculare barks with the IZ values of 9–12 mm was better than other typical extracts in antimicrobial experiments against B. cerus, B. megaterium, B. subtilis, Sarcina lutea, E. coli, P. aeruginosa, S. typhi, Shigella dysenteriae, Sh. boydii, Vibrio mimicus, V. parahemolyticus, Candida albicans, Aspergillus niger, and Sacharomyces cerevaceae. ⁷⁷

The silver nanoparticles synthesized from G. candolleanum leaves inhibited the growth of bacteria Salmonella enterica and P. aeruginosa with the IZ values of 12.2 and 11.8 mm, respectively. ⁷⁸ The ethanol extract of G. puberum roots monitored the proliferation of B. subtitis and P. aeruginosa with the corresponding MIC values of 100 and 200 µg/mL, but was inactive to bacteria E. coli and S. aureus (MIC > 200 µg/mL). ⁷⁹

Antiinflammatory Activity

Sesquiterpenoid 7 displayed an antiinflammatory effect in lipopolysaccharide (LPS)-stimulated nitric oxide (NO) production with the IC₅₀ value of 16.0 µM. ¹ As shown in Table 2, the isolated compounds 24, 55, 58, 99, 121, 142, 147, and 161 from Vietnamese G. obliquum leaves exhibited anti-inflammatory effects in LPS-stimulated inducible nitric oxide (iNOS) dependent NO production in microglial cells with the IC₅₀ values of 39.5–98.4 µM. ³⁵ However, only triterpenoids 55 and 58 inhibited NOX (NADPH oxidase)-dependent reactive oxygen species (ROS) production in microglial cells. ³⁵

The ethanol extract of G. thomsonii barks (250 and 500 mg/kg, p.o.) was able to protect against inflammation in two models of carrageenan-mediated paw edema and xylene-mediated ear edema in mice. ¹⁸ Besides anticancer activity, at the same dose of 100 mg/kg, i.p., the methanol extract and its petroleum ether, carbon tetrachloride, and chloroform fractions of G. multiloculare stem barks also exhibited antiinflammatory effect in carrageenan-induced paw edema in mice. ⁷³

An inflammatory bowel disease called ulcerative colitis makes your digestive system inflamed and produces ulcers, or sores.^92,93 The rectum and the innermost lining of your large intestine, commonly referred to as the colon, are affected by ulcerative colitis. For the majority of persons, symptoms typically appear gradually as opposed to abruptly. It turns out that the treatment of G. ellipticum leaf extracts (n-hexane, dichloromethane, and n-butanol), at the same dose of 200 mg/kg, p.o., could ameliorate DSS (dextran sulfate sodium)-stimulated colitis in mice via the nuclear factor-kappa B (NF-κB) signaling inhibition. ⁸⁰ The expressions included reductions in NO, ROS, pro-inflammatory cytokines, iNOS, and cyclooxygenase-2 (COX-2). ⁸⁰

Antidiabetic Activity

The 95% ethanol extract of G. hirsutum leaves suppressed α-amylase and α-glucosidase enzymes with the IC₅₀ values of 0.59–1.01 mg/mL, as compared with those of the 95% ethanol extract of G. sphaerogynum leaves (IC₅₀ 2.21-2.84 mg/mL). ⁶⁹

The ethanol extract from a combination of G. arborescens leaves and Cynometra ramiflora leaves showed in vitro α-glucosidase inhibition with an IC₅₀ value of 374.47 ppm, when acarbose was used as a positive control (IC₅₀ 14.17 ppm). ⁸¹ The oral administration of G. velutinum leaf ethanol extract at the two doses of 200 and 400 mg/kg inhibited streptozotocin-nicotinamide stimulated type 2 diabetic mice by reducing glucose levels, and altering lipid, glutamic-oxaloacetic transaminase, and alanine aminotransferase levels. ⁸² At the same two doses, the aqueous extract of G. zylanicum roots possessed hypoglycemic activity by lowering blood glucose levels in mice, which was comparable to that of the standard glibenclamide at 10 mg/kg. ¹⁹ In the same manner, the aqueous extract of G. velutinum leaves significantly reduced blood glucose levels at the dose of 400 mg/kg, p.o. for 15-day treatment. ²⁰

Antiurolithiatic, and Antidiarrheal Activities

The methanol extract of G. velutinium leaves (500 mg/kg, p.o.) established antiurolithiatic action via suppression of the CAOX crystal formation in calculogenic mice. ⁸³ The obtained results involved decreases in the levels of calcium, phosphorus, and oxalate in both the urine and kidney, and the levels of BUN, creatinine, and uric acid in the serum, especially a reduction of stone-forming constituents in the kidney. ⁸³

The ethanol extract of G. thomsonii barks at two doses of 250 and 500 mg/kg, p.o., has a marked antidiarrheal effect again the episode number of defecation and diarrheal feces. ⁸⁴ This extract at a higher dose protected against castor oil-induced diarrhea in mice by up to 54.47%, as well as reduced intestinal fluid accumulation by 51.6%. ⁸⁴

Analgesic, and Sedative Activities

From Table 2, at the same dose of 100 mg/kg, i.p., the methanol extract and its petroleum ether, carbon tetrachloride, and chloroform fractions of G. multiloculare stem barks demonstrated inhibitions to acetic acid induced writhing in mice from 66.36 to 84.09%, when diclofenac-Na was used as a positive control (86.36% inhibition). ⁷³

Besides antiinflammatory effect, at the same doses of 250 and 500 mg/kg, the ethanol extract of G. thomsonii barks suppressed formalin-mediated paw licking and acetic acid-mediated writhing in mice, and two phases of formalin-induced paw-licking models of pain. ¹⁸ Sedative activity of the methanol extract of G. multiloculare leaves (200 mg/kg, p.o.) was accompanied by decreasing the locomotor activity of mice in hole cross, opening field, and prolonging the sleeping time. ⁵

Neuroprotective Activity

The ethanol extract of G. zeylanicum leaves may be a viable therapy option for oxidative stress-induced Alzheimer's and other neurodegenerative diseases due to its intriguing neuritogenesis and neuroprotective properties. Herein, it protected against glutamate/H₂O₂-induced toxicity in HT-22 and neuro-2a neuronal cells by suppressing the intracellular ROS generation and enhancing the expression of endogenous antioxidative enzymes SODs, GPx, and GSTs at the concentration of 10 µg/mL. ⁸⁵ This extract also triggered SIRT1/Nrf2 protein expression and mRNA transcription of antioxidative genes NQO1, GCLM, and EAAT3. In addition, at the concentration of 5 µg/mL, it showed protective activity against Aβ (amyloid-β)-induced toxicity in Caenorhabditis elegans and enhanced neuritogenesis in neuro-2a cells. ⁸⁵

The neuroprotective effect of G. zelanicum leaf extract was explained by extending lifespan and oxidative stress suppression in C. elegans via DAF-16/FoxO and SKN-1/Nrf-2 signaling pathways.^2,3 The aqueous extract of G. littorale leaves at the concentration of 100–200 µg/mL ameliorated H₂O₂ induced oxidative stress by ROS accumulation, and 1-methyl-4-phenylpyridinium ion (MMP⁺) induced neurodegeneration in C. elegans by DAF-16 transcription activation. ⁸⁶

Liver, and Skin Protective Activities

Chronic ethanol consumption can lead to a drastic growth of liver ailments. ⁸⁷ It was noted that the ethanol extract of G. wallichianum leaves at two doses of 300 and 600 mg/kg, p.o., suppressed ethanol-stimulated liver damage in mice for 28 days via antioxidative activity. ⁸⁷ Herein, the mechanism of action involved decreases in alanine aminotransferase (ALT), hepatic malondialdehyde (MDA) levels, an increase in catalase (CAT) activity, and an improvement in histopathological alterations. ⁸⁷ In a clinical setting, the dogs treated with G. ferdinandi roots for 30 days revealed a health status with serum biochemical and coagulation profile within reference intervals. ⁹⁴

The methanol extract of G. zeylanicum leaves possessed the IC₅₀ values of 47.94 and 76.00 µg/mL in elastase and tyrosine inhibitory assays, respectively. ⁷⁰ Microemulsions containing G. wallichianum extract and surfactants (labrasol/HCO-40 (1:1) with transcutol (1:1, 2:1, 3:1), and tween 80/span 80 (3:2) with transcutol or propylene glycol/ethanol (1:1)) have potential for transdermal and topical skin delivery of gallic acid. ⁹⁵

Other Activities

As we know, the 5α-reductase suppressor plays a great role in the management of male pattern hair loss. It turns out that the 50% ethanol extract of G. eriocarpum roots at 200 µg/mL inhibited 25.5% growth of the 5α-reductase enzyme. ⁸⁸ The ethanol leaf extract of G. zeylanicum at the concentration of 75 µg/mL induced 60.52% inhibition of red blood cell destruction, as compared with that of the standard diclofenac (75.78%). ⁸⁹ At a concentration of 50 ppm, the ethyl acetate extract of G. laneolarium leaves showed mosquito larvicidal activity against Culex vishnui third larval instars with mortality rates of 80, 85.33, and 100% for 24, 48, and 72 h treatments, respectively. ⁹⁰

Toxicology

The methanol extract of G. multiloculare leaves and the standard vincristine sulfate showed the corresponding LC₅₀ values of 37.19 and 10.50 µg/mL in a brine shrimp lethal assay against Artemia salina. ⁵ In the same model, the n-hexane, ethyl acetate, and methanol extracts of G. velutinum leaves exerted the LC₅₀ values of 598.54, 651.92, and 428.47 µg/mL, respectively. ⁹¹ The extracts of G. multiloculare barks induced resistance to A. salina with the LC₅₀ values of 3.11–16.32 µg/mL. ⁷⁷

Conclusions and Perspectives

The current study first reviews full information about the phytochemistry and pharmacology aspects of Glochidion species. About 25 species have been the main objects of phytochemical research. Through chromatographic separation and NMR elucidation, more than 240 sary metabolites have been isolated and identified. They included terpenoids, sterols, saponins, lignans, flavonoids, mono-phenols, megastigmanes, butenolides, glycosides, alkaloids, cyanogens, tocopherols, fatty acids, and others. Three triterpenoids glochidonol, glochidiol, and glochidone can be seen as characteristic compounds present in this genus since they were found in frequency. The GC-MS studies reported the presence of aliphatic and terpenic compounds in Glochidion essential oils, whereas total phenolic and flavonoid contents were found to be different in each Glochidion species. Plants from this genus were documented to exhibit a wide range of in vitro pharmacological values, consisting of cytotoxic, antioxidative, antimicrobial, antiinflammatory, antidiabetic, antiurolithiatic, antidiarrheal, analgesic, and sedative activities, as well as living organ protection.

Although there have been plenty of phytochemical investigations, the isolated compounds were present in trace amounts. It is necessary to propose an advanced method to obtain huge amounts. Most pharmacological results were obtained at in vivo levels, and biomedical examinations of various compounds, especially in terms of new compounds are still unknown. Besides this, pharmacokinetics, clinical applications, nano-encapsulations, and synergistic combinations are expected.