Chemical Constituents From the Leaves of Grewia bulot Gagn. and Their Cytotoxic Activity

Abstract

Objective: The ultimate objective of this study was to isolate bioactive compounds from Grewia bulot Gagn. leaves and evaluate their cytotoxicity against a panel of human cancer cell lines. Methods: Compounds were isolated by column chromatography, whereas their chemical structures were elucidated by NMR spectroscopic data, and literature comparison. The cytotoxic activity of the isolated compounds was assessed using SRB assay against 4 cancer cell lines, including MCF-7 (human breast carcinoma), Hep-G2 (human hepatocellular carcinoma), KB (human carcinoma in the mouth), and SK-LU-1 (human lung carcinoma). Results: From the n-hexane extract, 4 compounds were isolated and identified as taraxerol (1), 3-(E)-coumaroyltaraxerol (2), 3-(Z)-coumaroyltaraxerol (3), and lupeol (4). Additionally, 6 compounds were isolated from the ethyl acetate extract and identified as daucosterol (5), trans-tiliroside (6), inugalactolipid A (7), (3S,5R,6S,7E,9R)-7-megastigmene-3,6,9-triol (8), biphenyl-3,3′,4,4′-tetrol (9), and smiglabrone B (10). Among these isolates, only compound 9 exhibited moderate cytotoxic activity against all tested cancer cell lines with the IC₅₀ values ranging from 31.67 to 63.15 µM. Conclusion: All these compounds have been detected from G bulot for the first time, biphenyl-3,3′,4,4′-tetrol (9) emerged as a promising candidate for cancer drug development. This study contributes to the growing body of knowledge regarding natural compounds with anticancer properties.

Keywords

anticancer chemical constituent biphenyl-3,3′,4,4′-tetrol cytotoxic activity

Introduction

As can be seen, drug discovery and development have been basically relied on natural products, particularly in the treatment of cancer and infectious diseases.¹ Moreover, the global utilization of medicinal plants for diseases has seen a notable surge in recent decades.² The genus Grewia, encompasses about 325 shrubs and small trees in the family Malvaceae, which is widely distributed in tropical and subtropical regions of Africa, Asia, and Australia.³ Grewia species have traditionally valued for health care benefits, in which they were used to treat diarrhea, coughs, inflammation, and bacterial infections.³ In addition, Grewia significantly contributed to the food processing sector, particularly in the productions of preserves, fruit juices, and teas.⁴ It is found that plants of this genus served as a reservoir of diverse phytochemicals,⁴ including flavonoids,^3,5 alkaloids,^3,6,7 triterpenoids,^3,8 phenols,^3,8,9 polysaccharides,^10,11 and others.^7,12–16 These compounds manifest a spectrum of bioactivities, such as antioxidant, anti-inflammatory, anticancer, antidiabetic, antibacterial, antispasmodic, antiviral, antimicrobial, and antimalarial properties.^3,4 The diverse repertoire of bioactive compounds present in Grewia has piqued the interest of researchers delving into the pharmaceutical and functional food potential inherent within these plants.¹⁷ Nonetheless, it is imperative to undertake further investigations in order to comprehensively fathom the activities and potential applications of these constituents.¹⁸

Among the 24 species of Grewia genus distributed in Vietnam, Grewia bilamellata Gagn. and Grewia bulot Gagn. have undergone detailed scrutiny.^15,19,20 Previously, we have disseminated findings regarding the volatile compounds and the anti-inflammatory, antioxidant, and cytotoxic activities of extracts and oils derived from the leaves of G bulot.^21,22 In the present study, our research wishes to report chromatographic isolation, and structural elucidation for the isolates from G bulot leaves, and subsequently evaluate their cytotoxic potentials against several cancer cell lines.

Results and Discussion

Through employing a comprehensive array of chromatographic separation techniques, we successfully isolated ten pure compounds (1-10) from the leaves of G bulot. This isolation yielded 4 compounds from the n-hexane extract and 6 compounds from the ethyl acetate extract, as illustrated in Figure 1.

Figure 1.

Chemical structures of the isolated compounds (1-10).

The structural elucidation of these compounds, namely taraxerol (1),²³ 3-(E)-coumaroyltaraxerol (2),²³ 3-(Z)-coumaroyltaraxerol (3),²³ lupeol (4),²⁴ daucosterol (5),²⁵ trans-tiliroside (6),²⁶ inugalactolipid A (7),²⁷ (3S,5R,6S,7E,9R)-7-megastigmene-3,6,9-triol (8),²⁸ biphenyl-3,3′,4,4′-tetrol (9),²⁹ and smiglabrone B (10),³⁰ was accomplished through meticulous 1D and 2D NMR spectroscopy, coupled with comparative analysis with reported data in the literature. This study unveiled the isolation of these compounds for the first time from the Grewia genus, comprising novel additions such as 3-(E)-coumaroyltaraxerol, 3-(Z)-coumaroyltaraxerol, trans-tiliroside, inugalactolipid A, (3S,5R,6S,7E,9R)-7-megastigmene-3,6,9-triol, smiglabrone B, and biphenyl-3,3′,4,4′-tetrol. Noteworthy is the inclusion of lupeol, daucosterol, and taraxerol, identified in various plants within the Grewia genus, thereby expanding the knowledge of their botanical sources such as G asiatica L., G damine Gaertn., G hexamita Burret, G bilamellata Gagnep., G optiva J.R.Drumm. ex Burret, G tiliaefolia Vahl., G flava DC., and G tenax (Forssk.) Fiori.^31–35 trans-Tiliroside has been previously identified in various botanical sources, including Buddleja officinalis Maxim., Potentilla chinensis Ser., Rosa canina L., and Rubus fruticosus L.^36–38 Inugalactolipid A, a rarely isolated compound from plants, was successfully obtained from G bulot, with its conventional sources being bacteria, microbial organisms, and marine sponges. Smiglabrone B was previously characterized in the rhizomes of Smilax glabra Roxb. The phenolic derivative biphenyl-3,3′,4,4′-tetrol found in 3 Erythroxylum species was analyzed using liquid chromatography coupled with electrospray ionization mass spectrometry (ESI-MSn) and high-resolution electrospray ionization mass spectrometry (HRESIMS).³⁹ Additionally, the isolation of (3S,5R,6S,7E,9R)-7-megastigmene-3,6,9-triol was established in G bulot, with prior reports indicating its presence in Mitrephora teysmannii Scheff., Hosta longipes (Franch. & Sav.) Matsum., and Cinnamomum cassia Siebold.^40–42

All isolates (1-10) underwent cytotoxicity evaluation against MCF-7, Hep-G2, SK-LU-1, and KB cell lines using a sulforhodamine B assay, with ellipticine employed as the positive control. The results, detailed in Table S1, indicate that only biphenyl-3,3′,4,4′-tetrol (9) demonstrated notable cytotoxic effects, presenting IC₅₀ values ranging from 31.67 to 63.15 µM. With consistent evidence, compound 9 (biphenyl-3,3′,4,4′-tetrol) displayed cytotoxic activity against MCF-7, Hep-G2, SK-LU-1, and KB cells, as evidenced by IC₅₀ values of 63.15 ± 5.09 µM, 53.34 ± 5.00 µM, 44.91 ± 3.71 µM, and 31.67 ± 1.33 µM, respectively. These values were lower than those of the positive control (Ellipticine), with compound 9 exhibiting IC₅₀ values 47 times lower for MCF-7 cells, 41 times lower for Hep-G2 cells, 26 times lower for KB cells, and 24 times lower for SK-LU-1 cells. Notably, compound 9 demonstrated the strongest cytotoxicity against KB and SK-LU-1 cells among the tested cell lines.

Previously, we reported the cytotoxicity profiles of n-hexane (GBH), dichloromethane (GBD), ethyl acetate (GBE), methanol (GBM), and water (GBW) extracts of G bulot against MCF-7, Hep-G2, SK-LU-1, and KB cell lines.²² The GBH and GBD samples exhibited cytotoxic activity against selected cell lines, with IC₅₀ values ranging from 90.60 to 98.27 μg/mL, while the remaining samples displayed no such activity at the tested concentrations. In a separate publication, the cytotoxic potential of G bulot leaf oil against KB, Hep-G2, MCF-7, and SK-LU-1 cell lines was elucidated, revealing IC₅₀ values ranging from 44.04 ± 1.47 to 74.20 ± 3.71 μg/mL.²¹ Collectively, these findings underscore the substantial promise of biphenyl-3,3′,4,4′-tetrol (9) from the G bulot plant, suggesting its potential as a lead compound for anticancer applications. This contributes meaningfully to the expanding database on medicinal plants and their pharmacological attributes. In this study, due to the limitation of condition, we did not test other biological activities of the isolated compounds to have an overall view of the bioactivity of these compounds as well as this species.

Conclusion

In this study, 7 compounds were isolated for the first time from the Grewia genus and identified as 3-(E)-coumaroyltaraxerol, 3-(Z)-coumaroyltaraxerol, trans-tiliroside, inugalactolipid A, (3S,5R,6S,7E,9R)-7-megastigmene-3,6,9-triol, biphenyl-3,3′,4,4′-tetrol, and smiglabrone B, in addition to daucosterol, lupeol, and taraxerol. All isolated compounds underwent anticancer testing, revealing that only biphenyl-3,3′,4,4′-tetrol exhibited moderate anticancer activity against all 4 tested cancer cell lines. The IC₅₀ values for biphenyl-3,3′,4,4′-tetrol ranged from 31.67 to 63.15 µM, indicating its potent cytotoxicity. These findings contribute significantly to the understanding of the phytochemical composition of G bulot and highlight the plant's potential as a valuable resource for the discovery of new anticancer agents.

Materials and Methods

Plant Materials

Grewia bulot leaves were harvested from Quang Tri Province, Vietnam, with geographical coordinates 16°29'30.0"N 107°01'18.4"E in January 2022. The botanical identification was conducted by Dr Nguyen Sinh Khang, a botanist affiliated with the Vietnam Academy of Science and Technology. A voucher specimen (Hue.22-01) has been securely deposited at the Faculty of Chemistry, University of Education, Hue University, Vietnam.

Extraction and Isolation

The dried leaves of G bulot (4.2 kg) underwent an initial process of pulverization, followed by extraction with methanol (5 times, 5.0 L each) at room temperature. Subsequently, the resulting extract underwent concentration under low pressure, yielding 175.42 g of a black solid extract with a percentage yield of 4.2% (w/w). This extract was then subjected to aqueous distribution, alternately partitioned with n-hexane, dichloromethane (CH₂Cl₂), and ethyl acetate (EtOAc) (5.0 L, 3 times each). The partitioning resulted in distinct layers: n-hexane (GBH, 29.94 g), CH₂Cl₂ (GBD, 21.33 g), EtOAc (GBE, 38.22 g), and the residual water layer (GBW, 85.93 g) after removal of solvents under low pressure.

The GBH extract was subjected to fractionation, yielding 8 subfractions (H1-H8) through chromatography on a silica gel column with n-hexane:acetone (1:0-0:1, v/v) as the elution solvent. Subsequently, the H2 and H3 fractions (4.0 g) underwent further chromatography on a silica gel column using a solvent system of n-hexane:acetone (20:1, 1.68 L; 10:1, 1.65 L), resulting in the generation of 9 subfractions labeled H2.1 to H2.9. The H2.5 fraction (800 mg) was purified using Sephadex LH-20 column chromatography with a CH₂Cl₂:MeOH (1:1) solvent mixture, leading to the isolation of 5 smaller subfractions labeled H2.5.1 to H2.5.5. Subfraction H2.5.4 (100 mg) underwent additional purification through YMC RP-18 column chromatography, utilizing a MeOH:water (4:1) solvent system, resulting in the isolation of 5 even smaller subfractions (H2.5.4.1-H2.5.4.5). Subfraction H2.5.4.2 (15.3 mg) underwent chromatography on a silica gel column with an n-hexane:EtOAc (10:1) solvent system, leading to the isolation of compounds 2 (5.0 mg) and 3 (4.5 mg). Similarly, subfraction H2.5.4.4 (20.0 mg) underwent chromatography on a silica gel column (n-hexane:EtOAc 10:1), resulting in the isolation of compounds 4 (6.0 mg) and 1 (7.5 mg).

The GBE extract was initially fractionated into 8 subfractions (E1-E6) using chromatography on a silica gel column, with elution using CH₂Cl₂:EtOAc (12.5:1, v/v) as the solvent mixture. Fraction E2 (790 mg) yielded a precipitate, which, after filtration and methanol washing, was recrystallized in CH₂Cl₂:MeOH (1:1, v/v) to produce 5 (50 mg). Fraction E3 (870 mg) was subjected to chromatography on a Sephadex LH-20 column, using 100% MeOH as the eluent, resulting in 3 subfractions, E3.1 to E3.6. Subfraction E3.1 (60 mg) was subsequently purified by chromatography on a YMC RP-18 column, using MeOH:water (1:2, v/v) as the eluent, yielding 8 (17.5 mg). Compound 6 (18 mg) was obtained by filtering and washing the precipitate that appeared in fraction E4 (1.49 g). The filtrate was then purified by a Sephadex LH-20 column, eluted with 100% MeOH, to generate 4 subfractions, E4.1 to E4.4. Subfraction E4.2 (95 mg) was further separated on a YMC RP-18 column, eluted with MeOH:water (2:3, v/v), resulting in 10 (23 mg). Similarly, the third subfraction, E4.3 (57 mg), was chromatographed on a YMC RP-18 column, eluted with the same mobile phase, and yielded 9 (13 mg). Fraction E8 (580 mg) was loaded onto a Sephadex LH-20 column and eluted with 100% MeOH, yielding 3 subfractions, E8.1 to E8.3. Fraction E8.2 (161 mg) was then subjected to chromatography on a silica gel column, with CH₂Cl₂:MeOH (7:1, v/v) as the elution system, ultimately providing 7 (47 mg). Compound 7 (1 mg) was dissolved in 0.2 mL of toluene. Subsequently, 1.5 mL of MeOH and 0.3 mL of 8% HCl (dissolved in MeOH) were sequentially added. The mixture was incubated for approximately 2 h at 45 °C. After cooling to room temperature, 1.0 mL of n-hexane and 1.0 mL of distilled water were added for extraction of the methyl ester derivative (FAME), forming compound.²⁷ Using the GC-MS method, the acyl groups were identified as palmitoyl and linolenoyl, with corresponding retention times of 21.04 and 26.67 min on the GC-MS chromatogram.

Taraxerol (1): A white amorphous solid; ¹H-NMR (600 MHz, CDCl₃) and ¹³C-NMR (150 MHz, CDCl₃): see Table S2.

3-(E)-coumaroyltaraxerol (2): A white amorphous solid; ¹H-NMR (600 MHz, CDCl₃) and ¹³C-NMR (150 MHz, CDCl₃): see Table S3.

3-(Z)-coumaroyltaraxerol (3): A white amorphous solid; ¹H-NMR (600 MHz, CDCl₃) and ¹³C-NMR (150 MHz, CDCl₃): see Table S4.

Lupeol (4): A white amorphous solid; ¹H-NMR (600 MHz, CDCl₃) and ¹³C-NMR (150 MHz, CDCl₃): see Table S5.

Daucosterol (5): A white amorphous solid; HRESIMS m/z 599.4239 [M + Na]⁺ (calcd. for C₃₅H₆₀O₆Na⁺, 599.4288); ¹H-NMR (600 MHz, CDCl₃+ CD₃OD) and ¹³C-NMR (150 MHz, CDCl₃+ CD₃OD): see Table S6.

trans-Tiliroside (6): A bright yellow powder; HRESIMS m/z 595.1425 [M + H]⁺ (calcd. for C₃₀H₂₇O₁₃⁺, 595.1452); ¹H-NMR (600 MHz, CD₃OD) and ¹³C-NMR (150 MHz, CD₃OD): see Table S7.

Inugalactolipid A (7): A white amorphous solid; HRESIMS m/z 915.6023 [M + H]⁺ (calcd. for C₄₉H₈₇O₁₅⁺, 915.6045); ¹H-NMR (600 MHz, CD₃OD) and ¹³C-NMR (150 MHz, CD₃OD): see Table S8.

(3S,5R,6S,7E,9R)-7-megastigmene-3,6,9-triol (8): A white amorphous solid; HRESIMS m/z 251.1599 [M + Na]⁺ (calcd. for C₁₃H₂₄O₃Na⁺, 251.1623); ¹H-NMR (600 MHz, CD₃OD) and ¹³C-NMR (150 MHz, CD₃OD): see Table S9.

Biphenyl-3,3′,4,4′-tetrol (9): A muddy brown solid; HRESIMS m/z 218.0545 [M]⁺ (calcd. for C₁₂H₁₀O₄⁺, 218.0579); ¹H-NMR (600 MHz, CD₃OD) and ¹³C-NMR (150 MHz, CD₃OD): see Table S10.

Smiglabrone B (10): A white amorphous solid; HRESIMS m/z 467.1316 [M + H]⁺ (calcd. for C₂₅H₂₃O₉⁺, 467.1342); ¹H-NMR (600 MHz, CD₃OD) and ¹³C-NMR (150 MHz, CD₃OD): see Table S11.

Cytotoxicity Assays

Cytotoxicity of isolated compounds against the growth of human cancer cell lines (SK-LU-1, Hep-G2, MCF-7, and KB) was determined by the Sulforhodamine B assay. The details of the protocols have been carefully described in our previous reports.^21,22

Supplemental Material

sj-docx-1-npx-10.1177_1934578X241250251 - Supplemental material for Chemical Constituents From the Leaves of Grewia bulot Gagn. and Their Cytotoxic Activity

Supplemental material, sj-docx-1-npx-10.1177_1934578X241250251 for Chemical Constituents From the Leaves of Grewia bulot Gagn. and Their Cytotoxic Activity by Ty Viet Pham, Duc Viet Ho, Y Duy Ngo, Nhan Thanh Thi Dang, Thang Quoc Le, Ninh The Son, Anh Tuan Le and Bao Chi Nguyen in Natural Product Communications

Footnotes

Acknowledgments

The authors are grateful to Mr Luong Vu Dang (Institute of Chemistry, VAST, Hanoi, Vietnam) for recording the NMR spectra.

Authors’ Contributions

Ty Viet Pham, Duc Viet Ho, Anh Tuan Le, and Bao Chi Nguyen conceived and designed research. Ty Viet Pham, Duc Viet Ho, Y Duy Ngo, Nhan Thanh Thi Dang, Thang Quoc Le, Son The Ninh, Anh Tuan Le, and Bao Chi Nguyen conducted experiments and analyze data. Ty Viet Pham, Duc Viet Ho, and Bao Chi Nguyen wrote the manuscript. All authors read and approved the manuscript.

Declaration of Conflicting Interests

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

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Ministry of Education and Training under grant (number B2022-DHH-13) and the partial support of Hue University under the Core Research Program (ID No. NCM.DHH.2023.02).

ORCID iDs

Ty Viet Pham

Duc Viet Ho

Ninh The Son

Bao Chi Nguyen

Supplemental Material

Supplemental material for this article is available online.

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