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Abstract

Paramignya trimera (P. trimera (Oliv.) Guillaum), a Vietnamese plant has showed potential anticancer activities. Extracts from the plant's roots, stems, and leaves have shown cytotoxicity against a variety of cancer cell lines. The mechanisms behind these anticancer actions include triggering apoptosis, blocking cell invasion, and targeting particular signaling pathways. This review has collected data from available literature on P. trimera's anticancer properties and compiled a database of its isolated compounds. Results indicate that P. trimera extracts and specific compounds, such as coumarins and acridones, possess anticancer potential. Particularly, acridones exhibited comparable or superior cytotoxicity against HepG2 and MCF-7 cells (IC₅₀ values 0.43-1.19 μM and 0.22-0.40 μM, respectively) compared to doxorubicin (IC₅₀ values 0.28 μM and 1.31 μM). Coumarins like 8-geranylumbelliferone and ostruthin target IKKβ, while paratrimerin W shows cytotoxicity against various cancers. Paratrimerin I exhibit cytotoxicity due to the N-methyl, C-4 methoxy, and C-5 hydroxy groups in the acridone skeleton. However, further research is needed to elucidate the precise mechanisms of action and to evaluate the safety and efficacy of P. trimera-derived compounds in clinical settings. The identification of 146 compounds in P. trimera provides a valuable resource for future drug discovery efforts.

Keywords

cancer phytochemicals

Introduction

Cancer remains a major global health challenge. In 2022, 9.7 million people succumbed to this illness, while an additional 20 million were diagnosed with cancer.¹ Plant-derived phytochemicals offer a rich source of inspiration for innovative drug discovery, particularly in the field of cancer prevention and treatment.^2,3 Phytochemicals and their therapeutic potential have engaged much attention in line with new, notable findings regarding the pathogenesis, characteristics, and possible treatments of cancers.^4–7 Coumarins, a class of benzopyrone compounds found in various plants, have shown significant antitumor activity. Due to their diverse mechanisms of action and minimal side effects, coumarin-class phytochemicals hold considerable potential as therapeutic agents for gynecological cancers.⁸ The structural diversity of coumarins, coupled with the variety of possible substitutions, provides flexibility in their mechanisms of action, contributing to their anticancer effects.^9–12 Coumarins can also help reduce the side effects of radiotherapy.¹³ Consequently, coumarin-containing plants are of significant interest in the discovery of new anticancer compounds.

Paramignya trimera (Oliv.) Guillaum (also called Xao tam phan in Vietnamese) is a plant endemic to Vietnam and belongs to the Rutaceae family. Xao tam phan is used in Vietnamese folk medicine for liver problems including cancer-related symptoms. The presence of diverse coumarins, alkaloids, flavonoids, and saponins in this plant makes P. trimera a valuable and promising medicinal herb.¹⁴ This herb has attracted great interest and has been widely studied for its anti-cancer properties.^15,16 Vietnam's National Institute of Medicinal Materials has pioneered research on the chemical composition of P. trimera from Hon Heo, Khanh Hoa, and its cytotoxic effects on five cancer cell lines: HepG2, HTC116, MDA-MB-231, OVCAR-8, and Hela.¹⁷

P. trimera's role and promise in cancer therapy have been proven in various in vitro studies. Researchers have found that P. trimera root extract can effectively inhibit the invasion as well as induce apoptosis of MCF-7 human breast cancer cells in 3D conditions.¹⁸ In another study, its peel essential oil displayed a potent cytotoxic effect on HepG2 liver cancer and A549 lung cancer cells.¹⁹ Powdered P. trimera leaf extract has also exhibited great anti-proliferative capacity on different cancer cell lines, including pancreas, colon, ovarian, skin, and prostate.¹⁸ Due to its many chemical constituents, there may be multiple molecular mechanisms behind the anticancer capability of P. trimera. For instance, it is revealed that 8-geranylumbelliferone isolated from P. trimera triggers programmed cell death by targeting TNRF1 ligation, leading to the inhibition of IKKα/β phosphorylation and the enhancement of the cytotoxic effect of RIPK1 on cells.²⁰ On the other hand, β-caryophyllene oxide, which can be found in P. trimera essential oil, has been shown to suppress growth and induce apoptosis by targeting STAT3 signaling pathway, inhibiting NF-κB activation, altering MAPK activation, and PI3 K/AKT/mTOR/S6K1 pathways.^21–23

In Vietnamese folk medicine, the root of P. trimera is the part used. However, the stem is also used as a substitute. Evaluation of the active components of the parts may be useful for the use of this medicinal plant. In addition, while some compounds have been identified, a more comprehensive chemical profile of P. trimera, is needed to discover new bioactive compounds. The aim of this study is to review the anti-cancer properties of P. trimera and to build a data set of its isolated compounds, serving as a reference for subsequent screening studies.

Materials and Methods

Search Strategy

We conducted a search on PubMed and Google Scholar with the keyword “Paramignya trimera” on January 7, 2024. We selected original studies reporting experimental anti-tumor activity of extracts or substances isolated from P. trimera. There were no limitations on the study design. Articles that are not original researches were excluded.

Analysis of Literature

The data on the anti-tumor effects of extracts or substances isolated from P. trimera was extracted and double-checked carefully, including names of compound, extraction solvents, extraction parts, cell lines, and results. Data not related to anti-tumor activity would not be extracted.

Collection of Phytochemical Data of P. trimera

Articles from PubMed and Google Scholar reporting phytochemical compounds isolated from P. trimera were also selected to create the compound database. The structures of these compounds were searched by name (if reported) or redrawn on PubChem (https://pubchem.ncbi.nlm.nih.gov/#draw = true) to collect their Simplified Molecular Input Line Entry System (SMILES). Those with identical SMILES are considered duplicates and merged under one ID. The majority of molecule editors support the import of SMILES strings, enabling the reconstruction of molecular diagrams or models. Therefore, we present a database of compound names and SMILES for the convenience of subsequent computer-aided drug design.

Results

Search Results

With the keyword “Paramignya trimera” we have found 18 results from PubMed and 530 results from Google Scholar. After removing duplicates by EndNote X9, there were 532 results. Among them, 34 papers were chosen for full-text screening, and finally, 12 papers were included to extract the desired data ( Figure 1 ).

Figure 1.

The PRISMA diagram of selected articles. *PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Anticancer Properties of Paramignya trimera

Anticancer properties of P. trimera are presented in Table 1 , which were retrieved from 12 in vitro and no in vivo studies. The solvents used for extraction are methanol,^1,24–26 ethanol,¹⁶ distilled water,²⁷ chloroform,²⁸and ethyl acetate.²⁹ The compounds and extracts are from the stem,¹⁶ peel essential oil,¹⁹ root,^1,25,26,28 and leaf³⁰ of P. trimera. The cancer cell lines used to test the plant materials consist of HepG2,^19,24,28 MCF-7,^25,28,30,31 BxPC3, CFPACA1,²⁶ AGS,²⁷ VNBRCA1,¹ Hep3B,²⁹ Huh7, HT1080,¹⁶ HT29,^16,25 MiaPaCa2, A2780, H460, A431, Du145, BE2-C, MCF-10A, U87, SJ-G2, SMA,²⁵ and A549.¹⁹ There are no tests for significance employed to analyze the data. 6 studies do not use any error estimates,^24,26–30 while the others utilize either standard deviation^{1,16,19,25,31} or standard error (n = 3).²⁰ 11 compounds isolated from various parts of P. trimera have been tested for their antitumor capabilities, and only 7 have shown cytotoxicity towards cancer cell lines.

Table 1.

The in vitro Inhibitory/Cytotoxic Activities Against Cancer Cell Lines of P. trimera Extracts and Compounds.

Author (Year)	Name of the compound	Result(Mean ± SD/SE)	Conclusion
Nguyen et al, (2020)²⁴	P. trimera methanol extract	IC₅₀= 582.533 ± 16.521 µg/ml (HepG2 cells) IC₅₀= 268.976 ± 19.325 µg/ml (ADSCs/normal cell control) SEI = 2.175 ± 0.12 %apoptosis = 32.39 ± 2.28 (apoptotic in HepG2 cells, 500 µg/ml) %apoptosis = 14.63 ± 1.59 (necrotic cells, 500 µg/ml)	P. trimera methanol extract could inhibit HepG2 cells proliferation by inducing apoptosis and has less side effect on normal cells compared to doxorubicin.
Nguyen et al, (2020)²⁴	Doxorubicin (positive control)	IC₅₀= 55.13 ± 2.028 ng/ml (HepG2 cells) IC₅₀= 5.96 ± 0.56 ng/ml (ADSCs/normal cell control) SEI = 8.71 ± 0.36
Nguyen-Thi et al, (2020)³¹	P. trimera methanol root extract	IC₅₀= 168.9 ± 11.65 μg/ml (3D model) IC₅₀= 260.8 ± 16.54 μg/ml (2D model) Completely inhibit the invasion ability of MCF-7 spheroids at 250 μg/ml %apoptosis = 98.41 ± 0.87 (250 μg/ml)	P. trimera extract could inhibit MCF-7 cell proliferation by constraining the invasion of MCF-7 spheroids and inducing cell apoptosis.
	Doxorubicin (positive control)	IC₅₀= 58.56 ± 15.82 μM (3D model) IC₅₀= 1.31 ± 0.69 μM (2D model) Completely inhibit the invasion ability of MCF-7 spheroids at 2 μg/ml %apoptosis = 78.90 ± 1.91 (2 μg/ml)
	Tirapazamin (positive control)	IC₅₀= 45.75 ± 24.87 μM (3D model) IC₅₀= 136.6 ± 19.78 μM (2D model) Completely inhibit the invasion ability of MCF-7 spheroids at 60 μg/ml %apoptosis = 97.01 ± 1.04 (60 μg/ml)
Nguyen and Scarlett (2019)²⁶	P. trimera root extract	IC₅₀= 32.12 μg/mL (BxPC3 cells) IC₅₀= 36.65 μg/mL (CFPAC1 cells)	P. trimera root extract is a lead source for the potential development of novel anti-pancreatic cancer drugs and/or functional foods.
Hao et al, (2023)²⁷	P. trimera extract	IC₅₀= 50 μg/mL mL (AGS cells)	P. trimera extract and AgNPs with P. trimera extract could inhibit AGS cell line by breaking or changing the cell's shape.
Hao et al, (2023)²⁷	Silver nanoparticles (AgNPs) prepared from Paramignya trimera extract	IC₅₀= 30 μg/mL (AGS cells)
Nguyen et al, (2019)¹	P. trimera methanol root extract	IC₅₀= 106 ± 10 μg/mL (VNBRCA1 cells, 72 h) SI = 2.92	P. trimera methanolic extract selectively killed VNBRCA1 cell lines.
Nguyen et al, (2019)¹	Doxorubicin (positive control)	IC₅₀= 0.63 ± 0.12 μg/mL (VNBRCA1 cells, 48 h) SI = 0.21
Nguyen et al, (2021)²⁸	paratrimerin I	IC₅₀= 0.43 μM (HepG2 cells) IC₅₀= 0.26 μM (MCF-7 cells)	All studied acridones were both cytotoxic against HepG2 and MCF-7 but the cytotoxicity against HepG2 cells was weaker than that against MCF-7 cells.
	citrusinine-I	IC₅₀= 0.54 μM (HepG2 cells) IC₅₀= 0.22 μM (MCF-7 cells)
	oriciacridone E	IC₅₀= 1.19 (HepG2 cells) IC₅₀= 0.40 μM (MCF-7 cells)
	5-hydroxynoracronycin	IC₅₀> 10 μM (HepG2 cells) IC₅₀= 3.92 μM (MCF-7 cells)
	Doxorubicin (positive control)	IC₅₀= 0.28 (HepG2 cells) IC₅₀= 1.31 μM (MCF-7 cells)
Dang et al, (2024)²⁹	Paratrimerin Z	did not show cytotoxicity at 100 μM (Hep3B cells)	Paratrimerin Z isolated from the root of P. trimeria showed no cytotoxicity to the human cancer cell line.
Quan et al, (2021)¹⁶	Paratrimerin W	IC₅₀= 14.9 μM (Huh7 cells) IC₅₀= 18.4 μM (HT1080 cells) IC₅₀= 22.5 μM (HT29 cells)	Paratrimerin W showed moderate cytotoxicity against Huh7 hepatocellular carcinoma, HT1080 fibrosarcoma, and HT29 Ras/Raf mutant colorectal cancer cells.
Tran et al, (2023)³⁰	25-O-methyl-1,2-dihydroprotoxylocarpin D	did not show cytotoxicity at 100 μM (MCF-7 cells)	None of the three compounds exhibited cytotoxicity when tested at a concentration of 100 μM using MCF-7 cells
	7α,24,25-trihydroxy-3-oxoapotirucalla-14-en-21,23-olide
	(20S,21R,23R)-21,23-epoxy-7α,24,25-trihydroxy-21- O-methyl-3-oxoapotirucalla-14-ene
Nguyen et al, (2017)²⁵	P. trimera root extract	GI₅₀= 23 ± 2.7 μg/mL (MiaPaCa2 cells) GI₅₀= 30 ± 1.6 μg/mL (HT29 cells) GI₅₀= 15 ± 2.5 μg/mL (A2780 cells) GI₅₀= 30 ± 2.1 μg/mL (H460 cells) GI₅₀= 29 ± 4.3 μg/mL (A431 cells) GI₅₀= 23 ± 2.5 μg/mL (Du145 cells) GI₅₀= 32 ± 2.6 μg/mL (BE2-C cells) GI₅₀= 23 ± 2.3 μg/mL (MCF-7 cells) GI₅₀= 32 ± 0.9 μg/mL (MCF-10A cells) GI₅₀= 32 ± 0.7 μg/mL (U87 cells) GI₅₀= 24 ± 3.8 μg/mL (SJ-G2 cells) GI₅₀= 23 ± 2.3 μg/mL (SMA cells)	PTR extract greatly influenced cell viability of MiaPaCa2, A2780, SMA, SJ-G2.
Nguyen Thi et al, (2022)¹⁹	P. trimera peel essential oil	IC₅₀= 21 µg/mL (HepG2 cells) IC₅₀= 73.65 µg/mL (A549 cells)	P. trimeria peel essential oil showed greater cytotoxicity to the HepG2 cell line than the A549 cell line.
Nguyen Thi et al, (2022)¹⁹	Camptothecin (positive control)	IC₅₀= 0.4 µg/mL (HepG2 cells) IC₅₀= 0.2 µg/mL (A549 cells)
Piao et al, (2021)²⁰	ostruthin	Inhibit TNF-induced IKK phosphorylation	8-GU facilitates RIPK1 activation by inhibiting IKKβ, which might provide new anticancer strategies focused on controlling the cytotoxic ability of RIPK1 to trigger dual modes of programmed cell death.
Piao et al, (2021)²⁰	8-geranylumbelliferone	Inhibit TNF-induced IKK phosphorylation

*IC_50: Half maximal inhibitory concentration, ADSCs: Adipose-derived stem cells, SEI: Side effect index, HepG2: HepG2 hepatocellular carcinoma cells, MCF-7: MCF-7 breast cancer cells, BxPC3: BxPC3 pancreatic cancer cells, CFPAC1: CFPAC1 pancreatic cancer cells, AGS: AGS gastric cancer cells, VNBRCA1: VNBRCA1 Vietnamese breast cancer stem cells, SI: Selectivity index, Hep3B: Hep3B human cancer cells, Huh7: Huh7 hepatocellular carcinoma cells, HT1080: HT1080 fibrosarcoma cells, HT29: HT29 colorectal cancer cells, GI₅₀: Half maximal growth inhibitory concentration, MiaPaCa2: MiaPaCa-2 pancreatic cancer cells, A2780: A2780 ovarian cancer cells, H460: H460 lung cancer cells, A431: A431 skin cancer cells, Du145: Du145 prostate cancer cells, BE2-C: BE2-C neuroblastoma cells, MCF-10A: MCF-10A normal breast cells, U87: glioblastoma cells, SJ-G2: glioblastoma cells, SMA: glioblastoma cells, A549: A549 lung cancer cells, TNF: Tumor necrosis factor, IKK: Inhibitor of nuclear factor kappa-B kinase, RIPK1: Receptor-interacting serine/threonine-protein kinase 1, IKKβ: Inhibitor of nuclear factor kappa-B kinase subunit beta

The extract of P. trimera exhibited cytotoxic activity against various cancer cell lines in in vitro assays. Nguyen and Scarlett (2019) investigated the cytotoxic effects of extracts and fractions from the roots of P. trimera on pancreatic cancer cell lines.²⁶ The extract inhibits BxPc3 cells with an IC₅₀ value of 32.12 μg/mL and CFPAC1 cells with an IC₅₀ value of 36.65 μg/mL.²⁶ Earlier, Nguyen, et al (2017) explored the ability of P. trimera root extract to inhibit various cancer cell lines. It has the most significant effect on A2780 cells, with GI₅₀ at 15 ± 2.5 μg/mL. This extract has substantial toxicity on MiaPaCa2, Du145, MCF-7, and SMA cells, with GI₅₀ of approximately 23 μg/mL. Other cell lines, such as HT29, H460, and A431, have GI₅₀ between 23 and 32 μg/mL.²⁵ For liver cancer, Nguyen et al (2020) showed that the P. trimera methanol extract can inhibit HepG2 but with lower efficacy (IC50: 582.533 µg/ml) than doxorubicin – the positive control (IC₅₀: 55.13 ± 2.028 ng/ml).²⁴ However, P. trimera extract has less side effect on normal cells than doxorubicin, their side effect index (SEI) values around 2.175 ± 0.12 and 8.71 ± 0.36, respectively.²⁴ P. trimera extract is also proven to induce apoptosis in almost 50% of HepG2 cells at the concentration of 500 µg/ml.²⁴ Nguyen et al (2019) examined the ability of the methanolic extract from P. trimera root to induce apoptosis in breast cancer stem cells in vitro.¹ The results indicate that the methanol extract inhibits VNBRCA1 cells within 72 h, with an IC₅₀ value of approximately 106 ± 10 μg/mL. In comparison, doxorubicin, the positive control, shows lower efficacy with an IC₅₀ value of around 0.63 ± 0.12 μg/mL after 48 h. However, the methanol extract from P. trimera exhibits greater selectivity for cancer cells than doxorubicin, with selectivity index (SI) values of 2.92 and 0.21, respectively.

The cytotoxic effectiveness of P. trimera methanol root extract against MCF-7 cells was reported by Nguyen-Thi et al (2020).³¹ In 3D and 2D models, the extract exhibited strong anti-proliferation activity with the IC₅₀ values of 168.9 ± 11.65 µg/ml and 260.8 ± 16.54 µg/ml, respectively. At the concentration of 250 µg/ml, P. trimera methanol root extract completely inhibited the invasion of MCF-7 spheroids and induced programmed cell death in 98.41 ± 0.87% of MCF-7 cells. In comparison with the positive controls (doxorubicin and tirapazamin), it is either similar in effectiveness (60 μM tirapazamin - 97.01 ± 1.04%) or significantly better (2 μg/ml doxorubicin - 78.90 ± 1.91%).

Hao et al (2023) explored a quick, efficient, and environmentally friendly approach for producing silver nanoparticles (AgNPs) using the solution plasma method with P. trimera extracts.²⁷ The P. trimera extract and AgNPs made with it could inhibit the AGS cell line by changing or damaging the cell shape. The results revealed that the P. trimera extract inhibits AGS cells with an IC₅₀ value of 50 μg/mL. In contrast, AgNPs produced from P. trimera extract inhibit AGS cells more effectively, with the IC₅₀ value of 30 μg/mL.

While the root remains the most researched part of P. trimera, its peel oil has also been proven to have many exciting bioactivities, including the cytotoxicity against HepG2 and A549 cells. While P. trimera peel oil can inhibit the growth of HepG2 cells at the IC₅₀ value of 21 μg/mL, A549 cells seem less sensitive to the oil since the IC₅₀ value is at 73.65 μg/mL. Compared to that, camptothecin, the positive control, displayed remarkable cytotoxicity to A549 cells with IC₅₀ of 0.2 μg/mL and HepG2 with IC₅₀ of 0.4 μg/mL.¹⁹

The cytotoxic activity of different acridones obtained from the fractions of P. trimera root was examined by Nguyen et al (2021) and it was proven that all studied acridones ( Figure 2 ) can inhibit both MCF-7 and HepG2 cells.²⁸ However, those compounds showed weaker cytotoxic effect on the latter compared to the former. Paratrimerin I and citrusinine-I showed notable cytotoxicity against both cell lines, with the IC₅₀ value varied from 0.22 to 0.54 μM. Oriciacridone E effectively inhibited the growth of MCF-7 and HepG2 cell lines with IC₅₀ values of 0.40 and 1.19 μM, respectively. Meanwhile, 5-hydroxynoracronycin showed a modest effect on both MCF-7 and HepG2 cell lines with IC₅₀ values of 3.92 and 18.83 μM, respectively. Compared to the positive control (doxorubicin), those compounds are more effective in inhibiting HepG2 cells (IC₅₀ doxorubicin - 0.28 μM). Nevertheless, with MCF-7 cells, doxorubicin is more effective (IC₅₀ doxorubicin - 1.31 μM), with the exception of 5-hydroxynoracronycin.²⁸

Figure 2.

Coumarins and acridones from P. trimera have inhibitory activity against human cancer cell lines.

Concerning P. trimera as a newly emerging medical resource for liver cancer, the cytotoxicity of some of the new dimeric coumarins obtained from P. trimera stem extract was evaluated against a wide range of human cancer cell lines. Paratrimerin W ( Figure 2 ) showed moderate cytotoxicity against Huh7 hepatocellular carcinoma, HT1080 fibrosarcoma, and HT29 Ras/Raf mutant colorectal cancer cells with IC₅₀ values of 14.9, 18.4, and 22.5 μM, respectively.¹⁶

Piao et al (2021) provided a new anticancer strategy by discovering ostruthin and 8-geranylumbelliferone ( Figure 2 ) isolated from P. trimera.²⁰ It was shown that both 8-GU and ostruthin drastically inhibited TNF-induced IKK phosphorylation. Based on the result, they proposed that 8-GU facilitated RIPK1 activation by inhibiting IKKβ, which might provide new anticancer strategies focused on controlling cytotoxic ability of RIPK1 to trigger dual modes of programmed cell death ( Figure 3 ).²⁰

Figure 3.

Anticancer mechanism, structure-activity relationship and effect on multiple cell lines of phytochemicals in P. trimera.

On the other hand, paratrimerin Z isolated from an EtOAc-soluble fraction of P. trimera roots was explored to have no cytotoxic effect on Hep3B human liver cancer cell line.²⁹ 25-O-methyl-1,2-dihydroprotoxylocarpine D, (20S,21R,23R)-21,23-epoxy-7α,24,25-trihydroxy-21-O-methyl-3-oxoapotirucalla-14-ene, and 7α,24,25-trihydroxy-3-oxoapotirucalla-14-en-21,23-olide, isolated from P. trimera leaves, showed no cytotoxicity against MCF-7 cells at a concentration of 100 μM.³⁰

Phytochemicals from Paramignya trimera

After extracting data from 16 articles and removing duplicates, we have aggregated 146 compounds. Their names and SMILES notations are presented in Table 2 , while their 2D structures are presented in Supplemental material.

Table 2.

Details of Compounds Isolated from P. trimera.

Author (Year)	Plant organs	ID	Name of Compound	SMILES
An et al, (2021)³²	root	P001	ostruthin	CC(=CCCC(=CCC1 = C(C = C2C(=C1)C = CC(=O)O2)O)C)C
Nguyen et al, (2015)³³	root	P002	gallic acid	C1 = C(C = C(C(=C1O)O)O)C(=O)O
		P003	chlorogenic acid	C1C(C(C(CC1(C(=O)O)O)OC(=O)C = CC2 = CC(=C(C = C2)O)O)O)O
		P004	caffeic acid	C1 = CC(=C(C = C1C = CC(=O)O)O)O
		P005	(-)-epicatechin	C1[C@H]([C@H](OC2 = CC(=CC(=C21)O)O)C3 = CC(=C(C = C3)O)O)O
		P006	syringic acid	COC1 = CC(=CC(=C1O)OC)C(=O)O
		P007	p-coumaric acid	C1 = CC(=CC = C1C = CC(=O)O)O
		P008	rutin	CC1C(C(C(C(O1)OCC2C(C(C(C(O2)OC3 = C(OC4 = CC(=CC(=C4C3 = O)O)O)C5 = CC(=C(C = C5)O)O)O)O)O)O)O)O
		P009	myricetin	C1 = C(C = C(C(=C1O)O)O)C2 = C(C(=O)C3 = C(C = C(C = C3O2)O)O)O
		P010	quercetin	C1 = CC(=C(C = C1C2 = C(C(=O)C3 = C(C = C(C = C3O2)O)O)O)O)O
		P011	(+)-catechin	C1C(C1[C@@H]([C@H](OC2 = CC(=CC(=C21)O)O)C3 = CC(=C(C = C3)O)O)OC(OC2 = CC(=CC(=C21)O)O)C3 = CC(=C(C = C3)O)O)O
		P012	kaempferol	C1 = CC(=CC = C1C2 = C(C(=O)C3 = C(C = C(C = C3O2)O)O)O)O
Cuong et al, (2015)¹⁴	root and stem	P013	paratrimerin A	O = C1C = CC2 = C(O1)C = C(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)C(/C = C/[C@]4(C)[C@H](C5 = CC(C = CC6 = O)=C(O6)C = C5O[C@@H]7O[C@H](CO)[C@@H](O)[C@H](O)[C@H]7O)C = C(C)CC4)=C2
		P014	paratrimerin B	O = C1C = CC2 = C(O1)C = C(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)C(/C = C/[C@]4(C)[C@H](C5 = CC(C = CC6 = O)=C(O6)C = C5O[C@@H]7O[C@H](CO[C@@H]8OC[C@@](CO)(O)[C@H]8O)[C@@H](O)[C@H](O)[C@H]7O)C = C(C)CC4)=C2
		P015	6-(6-hydroxy-3,7-dimethylocta- 2,7-dienyl)-7-hydroxycoumarin	O = C1OC2 = C(C = C(CC = C(C)CCC(O)C(C)=C)C(O)=C2)C = C1
		P001	ostruthin	CC(=CCCC(=CCC1 = C(C = C2C(=C1)C = CC(=O)O2)O)C)C
		P016	ninhvanin	O = C1C = CC2 = CC(CC = C(C)CC/C = C(C)\C)=C(O)C(OC)=C2O1
Dang et al, (2017)¹⁵	root	P017	paratrimerin C	O = C1C2 = C(C(O)=CC = C2)N(C)C3 = C1C(O)=CC4 = C3C = CO4
		P018	paratrimerin D	O = C1C2 = C(C(O)=CC = C2)N(C)C3 = CC(OC(C)(C)[C@@]4([H])CC[C@@](C)(O)C[C@]45[H])=C5C(O)=C13
		P019	paratrimerin E	O = C1C = CC2 = C(O1)C = C(O)C(C/C = C(C)/CCC(O)C(C)(O)C)=C2
		P020	paratrimerin F	O = C1C = CC2 = CC([C@@]([C@]34[H])([H])C(C)(C)[C@@]4([H])CC[C@@]3(C)O5)=C5C = C2O1
		P001	ostruthin	CC(=CCCC(=CCC1 = C(C = C2C(=C1)C = CC(=O)O2)O)C)C
		P022	umbelliferone	C1 = CC(=CC2 = C1C = CC(=O)O2)O
		P016	ninhvanin	O = C1C = CC2 = CC(CC = C(C)CC/C = C(C)\C)=C(O)C(OC)=C2O1
		P021	xanthyletin	CC1(C = CC2 = C(O1)C = C3C(=C2)C = CC(=O)O3)C
		P023	pandanusin A	O = C1C = CC2 = CC3 = C(OC([C@](CC/C = C(C)\C)(O)C)C3)C = C2O1
		P025	citrusinine-I	CN1C2 = C(C = CC = C2O)C(=O)C3 = C1C(=C(C = C3O)OC)OC
		P024	glycocitrine-III	O = C1C2 = C(C(O)=CC = C2)N(C)C3 = CC(O)=C(C/C = C(C)/CC/C = C(C)\C)C(O)=C13
		P026	oriciacridone E	O = C1C2 = C(C(O)=CC = C2)N(C)C3 = C(C/C = C(C)\C)C(O)=CC(O)=C13
		P027	5-hydroxynoracronycin	CC1(C = CC2 = C(O1)C = C(C3 = C2N(C4 = C(C3 = O)C = CC = C4O)C)O)C
		P028	daedalin A	CC1(C = CC2 = C(O1)C = CC(=C2)O)CO
		P029	vanillic acid	COC1 = C(C = CC(=C1)C(=O)O)O
Dang et al, (2022)²⁹	root	P030	paratrimerin Z	O[C@H]1[C@H](O)[C@@H](CO)O[C@@H](OCCC2 = CC = C(OC(C)(C)C = C3)C3 = C2)[C@@H]1O
Huong et al, (2019)³⁴	root and stem	P031	ninhvanin B	O = C1OC2 = C(C = C(CC(O)C(CC/C = C(C)\C)=C)C(O)=C2)C = C1
		P032	paramitrimerol	OC[C@]1(C)C = CC2 = C(O1)C = CC(/C = C/CO)=C2
		P033	parabacunoic acid	C[C@]12[C@@]([C@H]3C(O[C@H]2C4 = COC = C4)=O)(O3)[C@]5(C)[C@H](O[C@H]6[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O6)CC7[C@@](C(CC(O)=O)OC7(C)C)(C)C5CC1
		P025	citrusinine-I	CN1C2 = C(C = CC = C2O)C(=O)C3 = C1C(=C(C = C3O)OC)OC
Nguyen et al, (2021)²⁸	root	P034	paratrimerin I	O = C1C2 = C(C(OC)=C(O)C = C2OC)N(C)C3 = C(O)C = CC = C31
		P025	citrusinine-I	CN1C2 = C(C = CC = C2O)C(=O)C3 = C1C(=C(C = C3O)OC)OC
		P026	oriciacridone E	O = C1C2 = C(C(O)=CC = C2)N(C)C3 = C(C/C = C(C)\C)C(O)=CC(O)=C13
		P027	5-hydroxynoracronycin	CC1(C = CC2 = C(O1)C = C(C3 = C2N(C4 = C(C3 = O)C = CC = C4O)C)O)C
Nguyen et al, (2018)³⁵	stem	P035	paratrimerin G	O[C@H]1C(C)(C)OC2 = C(C = C(CCO)C = C2)[C@@H]1O
		P036	paratrimerin H	O = C(O)C1 = CC = C(OCC(O)C(C)(O)C)C = C1
		P037	methyl 4-hydroxybenzoate	COC(=O)C1 = CC = C(C = C1)O
		P038	vanillin	COC1 = C(C = CC(=C1)C = O)O
		P029	vanillic acid	COC1 = C(C = CC(=C1)C(=O)O)O
		P039	methyl protocatechuate	COC(=O)C1 = CC(=C(C = C1)O)O
		P040	methyl vanillate	COC1 = C(C = CC(=C1)C(=O)OC)O
		P006	syringic acid	COC1 = CC(=CC(=C1O)OC)C(=O)O
		P041	methyl syringate	COC1 = CC(=CC(=C1O)OC)C(=O)OC
		P042	methyl trans-p-coumarate	COC(=O)C = CC1 = CC = C(C = C1)O
		P043	methyl trans-ferulate	COC1 = C(C = CC(=C1)C = CC(=O)OC)O
		P044	methyl trans-sinapate	O = C(OC)/C = C\C1 = CC(OC)=C(O)C(OC)=C1
		P001	ostruthin	CC(=CCCC(=CCC1 = C(C = C2C(=C1)C = CC(=O)O2)O)C)C
		P045	demethylsuberosin	CC(=CCC1 = C(C = C2C(=C1)C = CC(=O)O2)O)C
		P046	5-O-methylanisocoumarin B	[H]C1 = C(O[CH]/C = C(C)\C)C = C(OC(C = C2)=O)C2 = C1OC
		P047	psoralene	C1 = CC(=O)OC2 = CC3 = C(C = CO3)C = C21
		P048	(S)-marmesin	CC(C)([C@@H]1CC2 = C(O1)C = C3C(=C2)C = CC(=O)O3)O
		P049	xylobuxin	OC(C(OC)=C1)=CC = C1[C@@H](O2)[C@H](CO)C3 = C2C(OC)=CC(/C = C/C(OC)=O)=C3
		P057	liquiritigenin	C1C(OC2 = C(C1 = O)C = CC(=C2)O)C3 = CC = C(C = C3)O
		P050	pterocarpol	CC12CCC(CC1C(=C)CC(C2)O)C(C)(C)O
		P051	trans-3,4-dihydroxy-3,4-dihydro-anofinic acid	CC1([C@H]([C@@H](C2 = C(O1)C = CC(=C2)C(=O)O)O)O)C
		P052	5-hydroxy-3,7,8,3′,4′-pentamethoxyflavone	O = C1C(OC)=C(C2 = CC = C(OC)C(OC)=C2)OC3 = C1C(O)=CC(OC)=C3OC
		P053	5,7,8,3′,4′-pentamethoxyflavone	COC1 = C(C = C(C = C1)C2 = CC(=O)C3 = C(O2)C(=C(C = C3OC)OC)OC)OC
		P054	5,7,8,4′-tetramethoxyflavone	COC1 = CC = C(C = C1)C2 = CC(=O)C3 = C(O2)C(=C(C = C3OC)OC)OC
		P055	5,6,7,8,3′,4′-hexamethoxyflavone	COC1 = C(C = C(C = C1)C2 = CC(=O)C3 = C(O2)C(=C(C(=C3OC)OC)OC)OC)OC
		P056	5-hydroxy-3,6,7,8,3′,4′-hexamethoxyflavone	COC1 = C(C = C(C = C1)C2 = C(C(=O)C3 = C(C(=C(C(=C3O2)OC)OC)OC)O)OC)OC
Nguyen et al, (2017)³⁶	stem	P058	(E)-2-(prop-1-enyl)-N-methylquinolinium-4-olate	[O-]C1 = C2C = CC = CC2 = [N + ](C)C(/C = C/C)=C1
Nguyen et al, (2017)³⁶	stem	P059	(R)-2-ethylhexyl 2H-12,3-triazole-4-carboxylat	O = C(C1 = NNN = C1)OC[C@H](CC)CCCC
Nguyen Thi et al, (2022)¹⁹	peel (essential oil)	P060	trans-muurola-4(14),5-diene	CC1CCC(C2 = CC(=C)CCC12)C(C)C
		P061	α-humulene	C/C/1 = C\CC(/C = C/C/C(=C/CC1)/C)(C)C
		P062	β-caryophyllene	C/C/1 = C\CCC(=C)[C@H]2CC([C@@H]2CC1)(C)C
		P063	α-pinene	CC1(C)C2CC = C(C)C1C2
		P064	sabinene	CC(C)C12CCC(=C)C1C2
		P065	α-phellandrene	CC1 = CCC(C = C1)C(C)C
		P066	δ-Carene 3	CC1 = CCC2C(C1)C2(C)C
		P067	Sylvestrene	CC1 = CCCC(C1)C(=C)C
		P068	α-Terpinene	CC1 = CC = C(CC1)C(C)C
		P069	Isomenthone	CC1CCC(C(=O)C1)C(C)C
		P070	Pulegone	CC1CCC(=C(C)C)C(=O)C1
		P071	Isospathulenol	CC1 = C2CCC(C2C3C(C3(C)C)CC1)(C)O
		P072	β-Caryophyllene oxide	C[C@@]12CC[C@@H]3[C@H](CC3(C)C)C(=C)CC[C@H]1O2
		P073	Germacrene	CC1 = CCC/C(=C/C[C@@H](CC1)C(=C)C)/C
		P074	δ-Cadinene	CC1 = CC2C(CC1)C(=C)CCC2C(C)C
		P075	Valencene	CC1CCC = C2C1(CC(CC2)C(=C)C)C
		P076	Bicyclogermacrene	C/C/1 = C\CC/C(=C/[C@H]2[C@H](C2(C)C)CC1)/C
		P077	Premnaspirodiene	CC1CCC = C(C12CCC(C2)C(=C)C)C
		P078	cis Muurola-4(15),5-diene	C[C@@H]1CC[C@@H](C2 = CC(=C)CCC12)C(C)C
		P079	γ-Muurolene	CC1 = C[C@@H]2[C@H](CC1)C(=C)CC[C@H]2C(C)C
		P080	α-Copaene	CC1 = CCC2C3C1C2(CCC3C(C)C)C
		P081	α-Cubebene	CC1CCC(C2C13C2C(=CC3)C)C(C)C
		P082	δ-Elemene	CC(=C1CC[C@@]([C@@H](C1)C(=C)C)(C)C = C)C
		P083	Safrole	C = CCC1 = CC2 = C(C = C1)OCO2
Piao et al, (2021)²⁰	stem	P084	8-geranylumbelliferone	CC(=CCCC(=CCC1 = C(C = CC2 = C1OC(=O)C = C2)O)C)C
Piao et al, (2021)²⁰	stem	P001	ostruthin	CC(=CCCC(=CCC1 = C(C = C2C(=C1)C = CC(=O)O2)O)C)C
Quan et al, (2021)¹⁶	stem	P085	paratrimerin J	O = C(O1)C = CC2 = C1C = C(O[C@H]3[C@@H]([C@H]([C@@H]([C@@H](CO)O3)O)O)O)C([C@H]4[C@](/C = C/C5 = C(OC6[C@@H]([C@H]([C@@H]([C@@H](CO)O6)O)O)O)C = C(OC(C = C7)=O)C7 = C5)(C)CCC(C)=C4)=C2
		P086	paratrimerin K	O = C(O1)C = CC2 = C1C = C(OC3[C@@H]([C@H]([C@@H]([C@@H](CO[C@H]4[C@@H]([C@H]([C@@H](CO4)O)O)O)O3)O)O)O)C([C@H]5[C@](/C = C/C6 = C(OC7[C@@H]([C@H]([C@@H]([C@@H](CO)O7)O)O)O)C = C(OC(C = C8)=O)C8 = C6)(C)CCC(C)=C5)=C2
		P087	paratrimerin L	O = C(O1)C = CC2 = C1C = C(OC3[C@@H]([C@H]([C@@H]([C@@H](CO[C@H]4[C@@H]([C@H]([C@@H](CO4)O)O)O)O3)O)O)O)C([C@@H]5[C@@](/C = C/C6 = C(OC7[C@@H]([C@H]([C@@H]([C@@H](CO)O7)O)O)O)C = C(OC(C = C8)=O)C8 = C6)(C)CCC(C)=C5)=C2
		P088	paratrimerin M	C[C@]1(/C = C/C2 = C(O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)C(OC(C = C4)=O)=C4C = C2)CC = C(C)C[C@@H]1C5 = CC(C = CC(O6)=O)=C6C = C5O[C@H]7[C@@H](O)[C@H](O)[C@@H](O)[C@H](CO[C@H]8[C@H](O)[C@@H](O)[C@H](O)CO8)O7
		P089	paratrimerin N	O = C(O1)C = CC2 = C1C = C(O[C@H]3[C@@H]([C@H]([C@@H]([C@@H](CO)O3)O)O)O)C([C@@H]4[C@@](/C = C/C5 = C(OC6[C@@H]([C@H]([C@@H]([C@@H](CO[C@H]7[C@@H]([C@H]([C@@H](CO7)O)O)O)O6)O)O)O)C = C(OC(C = C8)=O)C8 = C5)(C)CCC(C)=C4)=C2
		P090	patratrimerin O	O = C(O1)C = CC2 = C1C = C(O[C@H]3[C@@H]([C@H]([C@@H]([C@@H](CO)O3)O)O)O)C([C@H]4[C@](/C = C/C5 = C(OC6[C@@H]([C@H]([C@@H]([C@@H](CO[C@H]7[C@@H]([C@H]([C@@H](CO7)O)O)O)O6)O)O)O)C = C(OC(C = C8)=O)C8 = C5)(C)CCC(C)=C4)=C2
		P091	paratrimerin P	C[C@]1(/C = C/C2 = C(O[C@H]3[C@@H](O)[C@H](O)[C@@H](O)[C@H](CO[C@H]4[C@H](O)[C@@H](O)[C@H](O)CO4)O3)C(OC(C = C5)=O)=C5C = C2)CC = C(C)C[C@@H]1C6 = CC(C = CC(O7)=O)=C7C = C6O[C@H]8O[C@H](CO)[C@@H](O)[C@H](O)[C@H]8O
		P092	paratrimerin Q	O = C(O1)C = CC2 = C1C = C(OC3[C@@H]([C@H]([C@@H]([C@@H](CO[C@H]4[C@@H]([C@H]([C@@H](CO4)O)O)O)O3)O)O)O)C([C@H]5[C@@](/C = C/C6 = C(OC7[C@@H]([C@H]([C@@H]([C@@H](CO)O7)O)O)O)C = C(OC(C = C8)=O)C8 = C6)(C)CCC(C)=C5)=C2
		P093	paratrimerin R	O = C(O1)C = CC2 = C1C = C(O[C@@H]3[C@@H]([C@H]([C@@H]([C@H](O3)CO[C@H]4[C@@H]([C@@](CO)(CO4)O)O)O)O)O)C([C@H]5[C@](/C = C/C6 = C(O[C@H]7[C@@H]([C@H]([C@@H]([C@@H](CO)O7)O)O)O)C = C(OC(C = C8)=O)C8 = C6)(C)CCC(C)=C5)=C2
		P094	paratrimerin S	O = C(O1)C = CC2 = C1C = C(O[C@H]3[C@@H]([C@H]([C@@H]([C@@H](CO)O3)O)O)O)C([C@@H]4[C@@](/C = C/C5 = C(OC6[C@@H]([C@H]([C@@H]([C@H](O6)CO[C@H]7[C@@H]([C@@](CO)(CO7)O)O)O)O)O)C = C(OC(C = C8)=O)C8 = C5)(C)CCC(C)=C4)=C2
		P095	paratrimerin T	O = C(O1)C = CC2 = C1C = C(O[C@H]3[C@@H]([C@H]([C@@H]([C@@H](CO)O3)O)O)O)C([C@H]4[C@](/C = C/C5 = C(OC6[C@@H]([C@H]([C@@H]([C@H](O6)CO[C@H]7[C@@H]([C@@](CO)(CO7)O)O)O)O)O)C = C(OC(C = C8)=O)C8 = C5)(C)CCC(C)=C4)=C2
		P096	paratrimerin U	O = C(O1)C = CC2 = C1C = C(OC3[C@@H]([C@H]([C@@H]([C@@H](CO[C@H]4[C@@H]([C@H]([C@@H](CO4)O)O)O)O3)O)O)O)C([C@@H]5[C@@](/C = C/C6 = C(OC7[C@@H]([C@H]([C@@H]([C@@H](CO[C@H]8[C@@H]([C@H]([C@@H](CO8)O)O)O)O7)O)O)O)C = C(OC(C = C9)=O)C9 = C6)(C)CCC(C)=C5)=C2
		P097	paratrimerin V	O = C(O1)C = CC2 = C1C = C(OC3[C@@H]([C@H]([C@@H]([C@@H](CO[C@H]4[C@@H]([C@H]([C@@H](CO4)O)O)O)O3)O)O)O)C([C@H]5[C@](/C = C/C6 = C(OC7[C@@H]([C@H]([C@@H]([C@@H](CO[C@H]8[C@@H]([C@H]([C@@H](CO8)O)O)O)O7)O)O)O)C = C(OC(C = C9)=O)C9 = C6)(C)CCC(C)=C5)=C2
		P098	paratrimerin W	C/C(C)=C\COC1 = CC = C2C(OC(C = C2)=O)=C1CC[C@@H](C(O)(C)C)OC(/C = C/C3 = C(C = C(C(C/C = C(CC/C = C(C)\C)\C)=C3)O)O)=O
		P099	paratrimerin X	C/C(C)=C/COC1 = CC = C2C(OC(C = C2)=O)=C1CC[C@H](OC(/C = C/C3 = C(O)C = C(O)C([CH]/C = C(C)\C)=C3)=O)C(C)(O)C
		P100	paratrimerin Y	C/C(C)=C/CC/C(C)=C/CC(C(O)=C1)=CC2 = C1OC(C(C(O3)CC4 = C3C = C(OC(C = C5)=O)C5 = C4)=C2)=O
		P013	paratrimerin A	O = C1C = CC2 = C(O1)C = C(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)C(/C = C/[C@]4(C)[C@H](C5 = CC(C = CC6 = O)=C(O6)C = C5O[C@@H]7O[C@H](CO)[C@@H](O)[C@H](O)[C@H]7O)C = C(C)CC4)=C2
		P014	paratrimerin B	O = C1C = CC2 = C(O1)C = C(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)C(/C = C/[C@]4(C)[C@H](C5 = CC(C = CC6 = O)=C(O6)C = C5O[C@@H]7O[C@H](CO[C@@H]8OC[C@@](CO)(O)[C@H]8O)[C@@H](O)[C@H](O)[C@H]7O)C = C(C)CC4)=C2
Tran et al, (2023)³⁰	leaf	P101	25-O-methyl- 1,2-dihydroprotoxylocarpin D	O = C1CC[C@@]2(C)[C@](C[C@@H](O)[C@]3(C)[C@]2([H])CC[C@]4(C)C3CC[C@@]4([H])[C@]5([H])C[C@@]([C@H](O)C(C)(C)OC)([H])C[C@@H]5OC)([H])C1(C)C
		P102	7α,24,25-trihydroxy-3- oxoapotirucalla-14-en-21,23-olide	CC1(C)C(CC[C@]2(C)[C@@]3([H])CC[C@@]4(C)[C@H]([C@@H](C(O5)=O)CC5C(O)C(C)(O)C)CC = C4[C@@](C)3[C@H](O)CC12)=O
		P103	(20S,21R,23R)-21,23-epoxy- 7α,24,25-trihydroxy-21-O- methyl-3-oxoapotirucalla-14-ene	CC1(C)C(CC[C@]2(C)[C@@]3([H])CC[C@@]4(C)[C@H]([C@@H](CO5C)C[C@@H]5C(O)C(C)(O)C)CC = C4[C@@](C)3[C@H](O)CC12)=O
Trinh et al, (2020)¹⁸	root	P104	paramicoumarin A	C/C(C)=C/CC/C(C)=C/CC1 = C(O)C(O)=C(OC(C = C2)=O)C2 = C1
		P105	paramicoumarin B	O = C(C = C1)OC(C1 = C2)=CC3 = C2C = CC(CC/C = C(C)/C)(C)O3
		P106	paramiacridone	C/C(C)=C/CC/C(C)=C/CC1 = C(O)C = C(O)C2 = C1N(C)C3 = C(O)C = CC = C3C2 = O
		P109	7-hydroxy-8-geranylcoumarin	O = C1OC2 = C(C = CC(O)=C2C/C = C(CC/C = C(C)\C)\C)C = C1
		P107	nodakenetin	CC(C)(C1CC2 = C(O1)C = C3C(=C2)C = CC(=O)O3)O
		P023	pandanusin A	O = C1C = CC2 = CC3 = C(OC([C@](CC/C = C(C)\C)(O)C)C3)C = C2O1
		P020	paratrimerin F	O = C1C = CC2 = CC([C@@]([C@]34[H])([H])C(C)(C)[C@@]4([H])CC[C@@]3(C)O5)=C5C = C2O1
		P029	vanillic acid	COC1 = C(C = CC(=C1)C(=O)O)O
		P004	caffeic acid	C1 = CC(=C(C = C1C = CC(=O)O)O)O
		P108	ferulic acid	COC1 = C(C = CC(=C1)C = CC(=O)O)O
Tuan Anh et al, (2017)³⁷	stem	P110	luvangetin	CC1(C = CC2 = C(O1)C(=C3C(=C2)C = CC(=O)O3)OC)C
		P016	ninhvanin	O = C1C = CC2 = CC(CC = C(C)CC/C = C(C)\C)=C(O)C(OC)=C2O1
		P001	ostruthin	CC(=CCCC(=CCC1 = C(C = C2C(=C1)C = CC(=O)O2)O)C)C
		P111	6-(7-hydroperoxy-3,7- dimethylocta-2,5-dienyl)-7-hydroxycoumarin	O = C1OC2 = C(C = C(CC = C(C)CC = CC(C)(OO)C)C(O)=C2)C = C1
		P084	8-geranyl-7-hydroxycoumarin	CC(=CCCC(=CCC1 = C(C = CC2 = C1OC(=O)C = C2)O)C)C
		P112	6-(6′,7′-dihydroxy-3′,7′- dimethylocta-2′-enyl)-7-hydroxycoumarin	O = C1OC2 = C(C = C(CC = C(C)CCC(O)C(C)(O)C)C(O)=C2)C = C1
		P113	6-(2-hydroxyethyl)-2,2- dimethyl-2H-1-benzopyran	CC1(C = CC2 = C(O1)C = CC(=C2)CCO)C
Tuan et al, (2019)³⁸	leaf (essential oil)	P114	Geijerene	C = C([C@@H]1C = CCC[C@]1(C = C)C)C
		P115	Pregeijerene	CC1 = CCCC(=CC = CCC1)C
		P116	β-Pinene	CC1(C2CCC(=C)C1C2)C
		P082	δ-Elemene	CC(=C1CC[C@@]([C@@H](C1)C(=C)C)(C)C = C)C
		P080	α-Copaene	CC1 = CCC2C3C1C2(CCC3C(C)C)C
		P117	8-epi-Dictamnol	C[C@]1(CCC2C1C = CCCC2 = C)O
		P118	β-Bourbonene	CC(C)[C@@H]1CC[C@@]2([C@H]1[C@@H]3[C@H]2CCC3 = C)C
		P119	β-Cubebene	C[C@@H]1CC[C@H]([C@H]2[C@]13[C@@H]2C(=C)CC3)C(C)C
		P120	β-Elemene	CC(=C)[C@@H]1CC[C@@]([C@@H](C1)C(=C)C)(C)C = C
		P062	β-Caryophyllene	C/C/1 = C\CCC(=C)[C@H]2CC([C@@H]2CC1)(C)C
		P121	Dictamnol	C[C@@]1(CCC2C1C = CCCC2 = C)O
		P082	γ-Elemene	CC(=C1CC[C@@]([C@@H](C1)C(=C)C)(C)C = C)C
		P122	α-trans-Bergamotene	CC1 = CCC2CC1C2(C)CCC = C(C)C
		P061	α-Humulene	C/C/1 = C\CC(/C = C/C/C(=C/CC1)/C)(C)C
		P123	(E)-β-Farnesene	CC(=CCC/C(=C/CCC(=C)C = C)/C)C
		P079	γ-Muurolene	CC1 = C[C@@H]2[C@H](CC1)C(=C)CC[C@H]2C(C)C
		P124	α-Curcumene	CC1 = CC = C(C = C1)C(C)CCC = C(C)C
		P076	Bicyclogermacrene	C/C/1 = C\CC/C(=C/[C@H]2[C@H](C2(C)C)CC1)/C
		P125	β-Bisabolene	CC1 = CC[C@H](CC1)C(=C)CCC = C(C)C
		P126	Sesquicineole	CC(=CCCC1(C2CCC(O1)(CC2)C)C)C
		P074	δ-Cadinene	CC1 = CC2C(CC1)C(=C)CCC2C(C)C
		P134	α-Calacorene	CC1 = CC[C@H](C2 = C1C = CC(=C2)C)C(C)C
		P127	cis-Sesquisabinene hydrate	CC(CCC = C(C)C)C12CCC(C1C2)(C)O
		P135	Germacrene B	CC1 = CCCC(=CCC(=C(C)C)CC1)C
		P136	(E)-Nerolidol	CC(=CCCC(=CCCC(C)(C = C)O)C)C
		P137	Spathulenol	CC1(C2C1C3C(CCC3(C)O)C(=C)CC2)C
		P072	β-Caryophyllene oxide	C[C@@]12CC[C@@H]3[C@H](CC3(C)C)C(=C)CC[C@H]1O2
		P138	Salvial-4(14)-en-1-one	CC(C)C1CCC2(C1CC(=C)CCC2 = O)C
		P139	Rosifoliol	CC1CCCC2(C1 = CC(CC2)C(C)(C)O)C
		P140	Humulene epoxide II	CC1 = CCC(C = CCC2(C(O2)CC1)C)(C)C
		P141	β-Atlantol	C = C(C1CC = C(C)CC1)CC(O)/C = C(C)\C
		P142	10-epi-γ-Eudesmol	CC1 = C2C[C@@H](CC[C@@]2(CCC1)C)C(C)(C)O
		P143	Camphoric acid	CC1(C(CCC1(C)C(=O)O)C(=O)O)C
		P144	allo-Aromadendrene epoxide	CC1CCC2C1C3C(C3(C)C)CCC24CO4
		P145	epi-α-Cadinol	CC1 = C[C@H]2[C@@H](CC[C@]([C@@H]2CC1)(C)O)C(C)C
		P146	Cubenol	CC1CCC(C2C1(CCC(=C2)C)O)C(C)C
		P133	7-epi-α-Eudesmol	CC1 = CCC[C@]2([C@H]1C[C@H](CC2)C(C)(C)O)C
		P132	Khusilol	C = CC1CCC(=C)C2C1C = C(CC2)CO
		P130	epi-α-Bisabolol	CC1 = CC[C@H](CC1)[C@@](C)(CCC = C(C)C)O
		P131	epi-β-Bisabolol	CC1 = CC[C@](CC1)([C@@H](C)CCC = C(C)C)O
		P128	β-Costol	CC12CCCC(=C)C1CC(CC2)C(=C)CO
		P129	α-Bisabolol	CC1 = CC[C@@H](CC1)[C@@](C)(CCC = C(C)C)O

The most found bioactive compounds in P. trimera root are coumarin derivatives (P045-048, P084-100, P110-112) and flavonoids (P052-057). As for its stem, coumarins are also the most common constituents (P001, P019-023, P104, P015, P107, P109), followed by anthranilic acid alkaloids (P017, P018, P024-027, P034, P106). Coumarins remain the major components in root and stem extracts of P. trimera (P013-P016, P031). On the other hand, sesquiterpenoids (P114-146) account for the majority of the compounds isolated from leaf and leaf essential oil. Essential oil from its peel contains mostly sesquiterpenoids (P060-062, P071-082) and monoterpenoids (P063-070).

Discussion

The presented literature collectively underscores the promising anticancer potential of Paramignya trimera. A consistent theme emerging from these studies is the plant's potent cytotoxicity against a diverse spectrum of cancer cell lines, including hepatocellular carcinoma (HepG2),^19,24,28 breast cancer (MCF-7),^25,28,31 pancreatic cancer (BxPc3, CFPAC1),²⁶ and others. The cytotoxic effects of P. trimera are multifaceted. The plant extract and its derived compounds have demonstrated the ability to inhibit cell proliferation, induce apoptosis, and suppress cell invasion. While the exact mechanisms underlying these effects are not fully elucidated, the involvement of multiple cellular pathways is suggested. The induction of apoptosis,^24,31 as observed in several studies, is a crucial mechanism for cancer cell death. Moreover, the ability of the extract to inhibit cell invasion highlights its potential to target cancer metastasis.³¹

A comparative analysis of the cytotoxic potency of P. trimera extracts and compounds with standard chemotherapeutic agents reveals both strengths and limitations. While the plant extracts often exhibit higher IC₅₀ values than doxorubicin, a commonly used anticancer drug, it's essential to consider other factors such as selectivity and side effects. In vitro studies showed that P. trimera extract has more selective toxicity on cancer cells than doxorubicin¹ and has a lower side effect index (SEI) value.²⁴ Although there are 146 compounds isolated from various parts of P. trimera, only 7 were reported to have cytotoxicity in vitro. The isolation and characterization of those specific compounds, such as acridones and coumarins, have revealed compounds with potent anticancer activity.^16,20,28 Some promising coumarins are 8-geranylumbelliferone, ostruthin, and paratrimerin W. The first two are major geranylated 7-hydroxy coumarins with similar molecular mechanism: targeting IKKβ upon TNFR1 ligation.²⁰ Paratrimerin W, on the other hand, displays cytotoxicity towards various lines of cancer (Huh7 hepatocellular carcinoma, HT1080 fibrosarcoma, and HT29 Ras/Raf mutant colorectal cancer) while its exact mechanism remains unknown.¹⁶ All four acridones (paratrimerin I, citrusinine-I, oriciacridone E, and 5-hydroxynoracronycin) show remarkable to moderate effects on MCF-7 and HepG2.²⁸ Their cytotoxicity, according to the results, is due to the N-methyl, C-4 methoxy, and C-5 hydroxy groups in the acridone skeleton. An additional activity comparison between P. trimera and other natural compounds/extracts may be insightful and vital to evaluate its potential as a chemotherapeutic.

Three positive controls employed in the presented studies are doxorubicin, tirapazamin, and camptothecin. Although doxorubicin is deemed as an effective chemotherapeutic drugs with both DNA- and chromatin-damaging activity,³⁹ its toxicity during- and post-treatment has limited its use.⁴⁰ Tirapazamin is a selective hypoxic cytotoxins,⁴¹ and camptothecin is a topoisomerase I inhibitor.⁴² In general, P. trimera extracts and its constituents were no more effective than controls in inhibiting cancer cell growth; their IC₅₀ are approximately 1.5 to 200 times larger than those of the positive controls. An exception is the CHCl₃-soluble extract from the root of P. trimera and doxorubicin on liver and breast cancer.²⁸ Compared to doxorubicin, the acridones isolated from the extract prove to be corresponding in terms of their effect towards HepG2 (0.43-1.19 μM; 0.28 μM) and or even better regarding MCF-7 (0.22-0.40 μM; 1.31 μM).²⁸ Overall, the various kinds of P. trimera extracts and compounds display satisfactory activity against HepG2 and MCF-7, with the exception of three apotirucallane-type protolimonoids found in its leaf.³⁰ Given the encouraging in vitro results, it is crucial and favorable to examine that P. trimera's anticancer capability in actual clinical settings, namely in vivo models. Additionally, combining low doses of P. trimera with positive control (cancer therapeutics) in in vivo experiments should be considered to see if such combination can help overcome drug resistance in cancer treatment.

The exact mechanisms of action of P. trimera and its compounds against cancer remain ambiguous as very few studies have given any satisfactory and thorough explanation for the molecular pathways involved. The phytochemical structures showing cytotoxicity were mainly coumarin and acridone alkaloids. Looking into the mechanisms of such groups can provide some helpful insights into the way these compounds might function. Several coumarin derivatives have known antitumor mechanisms such as irosustat (phase II study) which is a steroid sulfatase inhibitor.⁴³ In addition, some studies show that coumarin inhibit carbonic anhydrase, preventing tumor cell growth by disrupting pH balance.^44,45 They also target the PI3 K/AKT/mTOR pathway,⁴⁶ reducing cell proliferation and inducing autophagy in cancer cells.^47,48 Meanwhile, acridone derivatives have also been reported to interact with various molecular targets in cancer such as topoisomerase II,⁴⁹ telomerase/telomere,⁵⁰ and protein kinase.^51,52 Nonetheless, further investigations into the molecular mechanisms of P. trimea are strongly needed and encouraged to give a more detailed understanding of how the plant and its constituents wield their anticancer effects.

Extracts and compounds isolated from P. trimera have been reported to exert cytotoxicity in a dose-dependent manner. For example, late apoptosis increased by 6.69–49.28% at 60–1000 µg/ml of the P. trimera methanol extract.²⁴ Its methanol root extract appeared to induce apoptosis in a similar manner in the concentration range of 0–125 µg/mL.¹ In addition, dose-response relationships are also expressed through the inhibition of TNF-induced IKK phosphorylation by ostruthin and the cytotoxicity of paratrimerin W on Huh7, HT1080, and HT29 cancer cells.¹⁶ These dose-dependent effects are important to understand the therapeutic potential of P. trimera. Considerations of the bioavailability and metabolic fate of P. trimera compounds in biological systems and their potential toxicity are important to understand their practical applications. Unfortunately, no studies on metabolism and bioavailability have been conducted and very few toxicological assessments have been made, and only the methanol root extract has been investigated to have selective severe toxicity against cancer cell VNBRCA1 but not normal human fibroblast cells.¹

Hedyotis diffusa is one of the most well-known and well-documented anticancer agents.⁵³ Compared to P. trimera, it shares some similarities while also bears certain differences. The two medicinal herbs both have chemical components like quercetin, rutin, kaempferol, caffeic acid, ferulic acid, and gallic acid.⁵³ Iridoids and flavonoids are the primary phytochemical groups contributing to Hedyotis diffusa's antitumor activity, whereas P. trimera's seven anticancer compounds belong to the coumarin and acridone groups. Although they both show significant cytotoxic effects against MCF-7 breast cancer, A549 lung cancer, and HepG2 hepatocellular carcinoma cell lines, H. diffusa's molecular mechanisms by active ingredients are more rigorously investigated than that of P. trimera such as activation of the Ca²⁺/calpain/caspase-4 - mediated apoptosis,⁵⁴ and modulation of IL-6-induced JAK2/STAT3 pathway.⁵⁵ In addition, esculetin a hydroxy coumarin from H. diffusa and many other species,⁵⁶ with a structural framework similar to ostruthin (substituent at C6 is OH instead of geranyl) also showed anticancer activity with multiple mechanisms.⁵³ Therefore, the phytochemical profile of P. trimera is favorable for further studies for the anticancer purposes of this medicinal plant. On the other hand, studies on the structure-activity relationship of coumarins may also be considered.

The broad-spectrum anticancer activity of P. trimera and its constituents warrants further investigation for drug development. Due to its anti-hepatoma and anti-breast cancer properties, P. trimera may be beneficial for patients with liver and breast cancer. To fully realize the therapeutic potential of P. trimera, in vivo studies are essential to evaluate the safety and efficacy of P. trimera-derived compounds in animal cancer models. Moreover, elucidating the precise molecular mechanisms underlying the anticancer activity of the plant's constituents is crucial for optimizing their therapeutic efficacy. Further thorough research on their toxicity and safety is also ultimately important to assess their therapeutic potential.

In this review, we also collected phytochemical data on P. trimera. To date, 146 phytochemical compounds from parts of P. trimera have been isolated and identified including coumarins, flavonoids, terpenoids, and several other compounds. We provide a data table with the structures of the compounds represented as SMILES. This data file can be convenient for molecular mechanism prediction studies and pharmacokinetic or structure-activity relationship analysis. Based on this compound data, future research can focus on evaluating the cytotoxic and antitumor activities of these compounds. Last but not least, an ethnopharmacological survey can be conducted to identify remedies containing P. trimera used for cancer patients, providing stronger ethnopharmacological evidence.

Conclusion

The available evidence strongly supports the proposition that Paramignya trimera is a valuable source of anticancer compounds. The plant's broad-spectrum cytotoxicity, coupled with a favorable safety profile, makes it a promising candidate for further in vivo studies. Continued research is essential to translate these preclinical findings into clinical applications.

Supplemental Material

sj-docx-1-npx-10.1177_1934578X251315038 - Supplemental material for A Review of Anticancer Properties and Phytochemicals from Xao tam phan (Paramignya trimera (Oliv.) Guillaum)

Supplemental material, sj-docx-1-npx-10.1177_1934578X251315038 for A Review of Anticancer Properties and Phytochemicals from Xao tam phan (Paramignya trimera (Oliv.) Guillaum) by Pham Nguyen Bao Tran, Nghiem Dinh Van An, Tran Hoang Bao Chau, Nguyen Le Linh Chi, Thai Minh Hoang, Truong Van Dat and Vo Linh Tu in Natural Product Communications

Footnotes

Conflict of Interest Statement

The author(s) declared no potential conflicts of interest concerning the review research, authorship, and/or publication of this review article.

Ethical Approval

Ethical approval is not applicable for this review article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Truong Van Dat

Vo Linh Tu

Statement of Human and Animal Rights

This review article does not contain any studies with human or animal subjects.

Statement of Informed Consent

This review article does not involve human subjects, and informed consent is not applicable.

Supplemental Material

Supplemental material for this article is available online.

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Supplementary Material

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A Review of Anticancer Properties and Phytochemicals from Xao tam phan ( Paramignya trimera (Oliv.) Guillaum)

Abstract

Keywords

Introduction

Materials and Methods

Search Strategy

Analysis of Literature

Collection of Phytochemical Data of P. trimera

Results

Search Results

Anticancer Properties of Paramignya trimera

Phytochemicals from Paramignya trimera

Discussion

Conclusion

Supplemental Material

sj-docx-1-npx-10.1177_1934578X251315038 - Supplemental material for A Review of Anticancer Properties and Phytochemicals from Xao tam phan (Paramignya trimera (Oliv.) Guillaum)

Footnotes

Conflict of Interest Statement

Ethical Approval

Funding

ORCID iDs

Statement of Human and Animal Rights

Statement of Informed Consent

Supplemental Material

References

Supplementary Material