Fused Tricyclic Naphthalene Lactones and a Xanthone from Ventilago maingayi and their Anti-HIV-1 Activity

• Abstract
• Introduction
• Results and Discussion
• Materials and Methods
• General experimental procedures
• Plant material
• Extraction and isolation
• Physical and spectroscopic data of compounds 1 – 3
• X-ray crystal structure analysis
• Anti-HIV-1 reverse transcriptase assay
• Syncytium reduction assay
• Contributorsʼ Statement
• References

Abstract

Three previously undescribed compounds, including two fused tricyclic naphthalene lactones (ventilaganones A and B, 1 and 2) and a xanthone (ventilagoxanthone, 3), along with eight known compounds (4–11), were isolated from the bark of Ventilago maingayi. Their structures were elucidated by extensive analysis of their spectroscopic data and by comparison with those of related compounds reported in the literature. The absolute configuration of ventilaganone A (1) was established by single-crystal X-ray analysis. Anti-HIV-1 activity of the isolated compounds was evaluated with a reverse transcriptase (RT) assay and a syncytium reduction assay using the ^ΔTat/RevMC99 virus in the 1A2 cell line. Compounds 1, 2, 4, 5, and 8–11 showed inhibitory activity against syncytium formation, while most compounds were found to be inactive in the reverse transcriptase assay.

Introduction

The genus Ventilago belongs to the Rhamnaceae family and comprises more than 40 species distributed in India, South Asia, and Thailand [1], [2]. In Thailand, nine species have been reported [3]. Among them, Ventilago denticulata Willd. has been used to promote granulation of wounds [4]. Previous phytochemical investigations of plants from the genus Ventilago revealed that they are rich sources of various types of secondary metabolites such as anthraquinones [5], naphthalenes [6], pyranonaphthoquinones [7], flavonoids [8], xanthones [9], and triterpenes [10]. Several compounds isolated from the Ventilago species showed significant biological activities such as antioxidant, cytotoxic, anti-inflammatory, antibacterial, antifungal, and phosphodiesterase inhibitory activities [5], [6], [7], [8], [9], [10]. Ventilago maingayi M. A. Lawson is a vine wood plant with climbing and hanging branches. It is a native plant in Indonesia, Malaya, Myanmar, and Thailand [2]. To the best of our knowledge, V. maingayi has never been investigated. In the course of our continuing search for biologically active substances in plants from the genus Ventilago, we observed in a preliminary biological screening that the methanol extract of the barks of V. maingayi possessed anti-HIV-1 activity in a syncytium reduction assay (see Supporting Information). Detailed investigation of this extract resulted in the isolation of two new fused tricyclic naphthalene lactones (1−2), one new xanthone (3) and eight known compounds (4−11). We herein report the structure elucidation and anti-HIV-1 activity of these compounds. It should be mentioned that compounds 1 and 3 reported in the present work were previously studied by high-resolution mass spectrometry coupled with ion mobility [11]. This provided detailed information including accurate mass measurements, MS/MS spectra, and a collision cross-section. However, the isolation, structure elucidation, and complete spectroscopic information (NMR, IR, UV, and MS) of 1 and 3 are reported here for the first time. The structure and absolute configuration of compound 1 were confirmed by X-ray diffraction analysis. The absolute configuration of compound 2 was established by comparison of its spectroscopic data and ECD patterns with those of compound 1. The anti-HIV-1 activity of the isolated compounds was evaluated in a reverse transcriptase (RT) assay and a syncytium reduction assay using the ^ΔTat/RevMC99 virus in the 1A2 cell line.

Results and Discussion

Phytochemical investigation of the methanol extract from the bark of V. maingayi led to the isolation of eleven compounds including two new fused tricyclic naphthalene lactones (1−2), one new xanthone (3), and eight known compounds (4−11) ([Fig. 1]). The known compounds were identified as 8-dihydroxy-6-methyl-9-oxo-9H-xanthene-1-carboxylate (4) [12], conioxanthone A (5) [13], chrysophanol (6) [14], physcion (7) [14], emodin (8) [14], ventilanone K (9) [15], 2-hydroxyemodin 1-methyl ether (10) [16], and questin (11) [17].

Compound 1 was obtained as brown needles. Its molecular formula was established as C₁₅H₁₄O₅ by HR-ESI-MS, which showed an [M + H]⁺ ion peak at m/z 275.0912 (calcd. for C₁₅H₁₅O₅, 275.0919). The IR spectrum showed major absorptions at ν _max 3244 cm⁻¹ (O−H stretching of phenol) and 1760 cm⁻¹ (C=O stretching of lactone) together with 1275 and 1156 cm⁻¹ (C−O stretching of lactone). Major peaks in the IR spectrum indicated the presence of γ-lactone carbonyl and hydroxy groups in the structure. The UV absorption bands at λ _max (log ε) 218 (4.71), 247 (5.03), 258 (4.98), and 352 (4.32) nm supported the presence of a conjugated carbonyl group in a naphthalene lactone chromophore [18]. The combination of ¹³C NMR and DEPT-135 data ([Table 1]) revealed resonances at δ _C 170.6, 149.1, 147.6, 143.0, 131.4, 127.4, 123.9, and 120.7 for eight non-protonated carbons; δ _C 62.2, 56.8, and 19.2 for three methyl carbons, and δ _C 127.4, 117.1, 115.6, and 77.2 for four methine carbons. In addition, the ¹H NMR data ([Table 1]) revealed three aromatic proton resonances at δ _H 7.35 (1H, d, J = 9.2 Hz, H-7), 7.76 (1H, d, J = 9.2 Hz, H-8), and 7.89 (1H, s, H-9). According to the HMQC spectrum, these resonances were correlated to the resonances at δ _C 115.6 (C-7), 127.4 (C-8), and 117.1 (C-9), respectively. The connectivity of a quartet signal at 5.72 (1H, J = 6.6 Hz, H-3) and a doublet signal at δ _H 1.77 (3H, J = 6.6 Hz, 3-CH₃) was confirmed by ¹H-¹H COSY correlation. These resonances were connected to carbons at δ _C 77.2 (C-3) and 19.2 (3-CH₃), respectively, in the HMQC spectrum. A hydroxy [δ _H 9.95 (1H, s, 4-OH)] and two methoxy groups [δ _H 4.13 (3H, s, 5-OCH₃)/δ _C 62.2 and δ _H 4.04 (3H, s, 6-OCH₃)/δ _C 56.8] were located at C-4 (δ _C 147.6), C-5 (δ _C 143.0), and C-6 (δ _C 149.1), as supported by the HMBC data [(δ _H 9.95 (4-OH) with δ _C 147.6 (C-4), δ _C 127.4 (C-4a), δ _C 123.9 (C-9a); δ _H 4.13 (5-OCH₃) with δ _C 143.0 (C-5); δ _H 4.04 (6-OCH₃) with δ _C 149.1 (C-6)] (see [Table 1]). The ¹H and ¹³C NMR data of 1 were similar to those of ventilagodenin A [5]. However, while ventilagodenin A possesses a methylene carbon at δ _C 71.8/δ _H 5.05 and 5.19, compound 1 contains a carbonyl carbon at δ _C 170.6, which was assigned as C-1 according to its HMBC correlations with δ _H 5.72 (H-3) and δ _H 7.89 (H-9). Furthermore, the numbers of substituents on the naphthalene core are different. Ventilagodenin A exhibited two aromatic resonances at δ _H 7.02 (1H, s, H-8) and 6.96 (1H, s, H-9), while compound 1 showed two doublet signals at δ _H 7.35 (1H, d, J = 9.2 Hz, H-7) and 7.76 (1H, d, J = 9.2 Hz, H-8) and a singlet signal at δ _H 7.89 (1H, s, H-9). The locations of the aromatic protons H-7, H-8, and H-9, two methoxy groups at 5-OCH₃ and 6-OCH₃, and a hydroxy group at 4-OH were confirmed on the basis of NOESY data ([Fig. 2]). The R configuration at C-3 of 1 was primarily deduced by comparison of its optical rotation value [[α]_D ²⁷ + 80.0 (c 1.0, CHCl₃)] with that of ventilagodenin A ([α]_D ²⁵ + 8.02 (c 0.4, CHCl₃), which is of the same sign despite being different in magnitude to that of compound 1. This similarity suggested that 1 and ventilagodenin A possess the same absolute configuration. The chemical structure and absolute configuration of 1 were eventually confirmed by single-crystal X-ray crystallographic analysis using Cu Ka radiation ([Fig. 3]). Thus, compound 1 was identified as (3R)-4-hydroxy-5,6-dimethoxy-3-methylnaphtho[2,3-c]furan-1(3H)-one and named ventilaganone A.

Compound 2 was obtained as colorless rods. The molecular formula of compound 2, C₁₆H₁₆O₆, was established by HR-ESI-MS, which showed a [M + H]⁺ peak at m/z 327.0840 (calcd. for C₁₆H₁₆O₆Na: 327.0845). The UV and FTIR patterns, as well as the ¹H and ¹³C NMR data ([Table 1]) of 2, showed close similarity to those of 1. The key differences between compounds 1 and 2 included the replacement of an aromatic resonance at δ _H 7.35 (1H, d, J = 9.2 Hz, H-7) in 1 by a hydroxy group at δ _H 6.25 (1H, s, 7-OH) in 2. This was further supported by the HMBC cross-peak between δ _H 6.25 (7-OH) and δ _C 149.1 (C-7) and the aromatic resonance at δ _H 7.25 (1H, s, H-8) as a singlet in 2. Additionally, 1 had a phenol proton at δ _H 9.95 (1H, s) at C-4, while 2 had a methoxy group at δ _H 3.95 (3H, s)/δ _C 62.6 at this position, as supported by the HMBC correlation of δ _H 3.95 (4-OCH₃) to δ _C 133.7 (C-4). Full assignments of ¹H and ¹³C NMR data ([Table 1]) were established based on HMBC ([Table 1]) and NOESY ([Fig. 2]) information. The optical rotation values of 1 and 2 were of the same sign despite being different in magnitude. Finally, the absolute configuration of 2 was established by comparison of its experimental ECD spectrum with that of 1 ([Fig. 4]). Therefore, compound 2, named as ventilaganone B, was identified as (3R)-7-hydroxy-4,5,6-trimethoxy-3-methylnaphtho[2,3-c]furan-1(3H)-one.

Compound 3 was obtained as orange rods. Its molecular formula, C₁₈H₁₆O₇, was determined by HR-ESI-MS, which showed a sodium adduct ion peak at m/z 367.0787 [M + Na]⁺ (calcd. for C₁₈H₁₆O₇Na: 367.0794). The IR spectrum showed absorptions at ν _max 3470 cm⁻¹ (OH stretching of phenol), together with 1745 and 1655 cm⁻¹ (C=O stretching of conjugated ester). The UV spectrum showed absorption bands at λ _max (log ε) 234 (4.46), 254 (4.53), 268 (4.39), 300 (4.27), and 359 (3.59) nm. The characteristic IR and UV spectra of 3 suggested the presence of a xanthone chromophore [13]. The ¹³C NMR data of 3 ([Table 2]), in combination with DEPT-135 experiments, showed resonances at δ _C 179.1, 167.1, 161.3, 159.0, 155.8, 154.1, 148.4, 143.3, 126.6, 110.8, and 106.4 for eleven non-protonated carbons, δ _C 62.2, 56.5, 53.1, and 22.6 for four methyl carbons, and δ _C 111.6, 107.1, and 101.0 for three methine carbons. The ¹H NMR spectrum of 3 showed three aromatic resonances at δ _H 6.92 (1H, s), 6.69 (1H, br s), and 6.60 (1H, br s). These resonances were connected to ¹³C NMR signals at δ _C 101.0 (C-4), 107.1 (C-5), and 111.6 (C-7), respectively, in the HMQC spectrum. In addition, the HMBC correlations (from H-4 to C-1, C-2, C-3, C-4a, C-9, C-9a; from H-5 to C-5a, C-7, C-8a, C-9; and from H-7 to C-5, C-8, C-8a, C-9) confirmed their locations at C-4, C-5, and C-7, respectively. The chelated hydroxy proton at δ _H 12.26 (1H, s, 8-OH) was located at C-8 (δ _C 161.3) on the basis of HMBC correlations from 8-OH to C-8 and C-7. The ¹H NMR and ¹³C NMR spectra also revealed resonances for a methyl ester at δ _H 4.05 (3H, s, 10-OCH₃) and δ _C 53.9, respectively, with a cross-peak observed between 10-OCH₃ and C-10 in the HMBC spectrum. The HMBC correlations from 6-CH₃ to C-5, C-6, and C-7 also supported the location of a methyl group at C-6 (δ _H 2.42, 3H, s; δ _C 148.4) ([Table 2]). The spectroscopic data of 3 closely resemble those of 3,8-dihydroxy-6-methyl-9-oxo-9H-xanthene-1-carboxylate, as previously reported [18]. The key difference was the presence of two singlet signals for methoxy groups at δ _H 3.89 (3H, s, 2-OCH₃) and 4.02 (3H, s, 3-OCH₃) in 3. This assumption was confirmed by HMBC correlations (2-OCH₃/C-2; 3-OCH₃/C-3). On the basis of these data, compound 3 was identified as methyl 8-hydroxy-2,3-dimethoxy-6-methyl-9-oxo-9H-xanthene-1-carboxylate and named ventilagoxanthone.

The isolated compounds were evaluated for their anti-HIV-1 activity employing a syncytium reduction assay using the ^ΔTat/RevMC99 virus in the 1A2 cell line system ([Table 3]) and a reverse transcriptase (RT) assay ([Table 4]). Compounds 1, 2, 4, 5, and 8 – 11 significantly reduced the number of syncytium formations in the syncytium reduction assay with EC₅₀ values in the range of 19.4 to 172 µM (SI 1.42 to > 8.65). Compound 10 showed the most potent anti-HIV-1 activity with EC₅₀ 19.4 µM (95% CI 14.2 to 21.0; SI 8.65). Compounds 8 and 10 exhibited moderate activity against RT enzyme at 200 µg/mL (65.1% inhibition at 740 µM for 8 and 70.1% inhibition at 666 µM for 10), whereas the other tested compounds were found inactive in the anti-HIV-1 RT assay.

Materials and Methods

General experimental procedures

Melting points (uncorrected) were recorded on a digital Sanyo Gallenkamp melting point apparatus. IR spectra were obtained on a Perkin Elmer EX FT-IR spectrometer or a Bruker FT-IR spectrometer, model ALPHA. UV absorption spectra were recorded on a JASCO V-530 spectrometer in EtOH. ECD spectra were recorded on a JASCO J-810 spectrometer. Optical rotations were measured on a JASCO DIP-370 digital polarimeter by using 10 and 50 mm microcells. High-resolution mass spectra (HR-ESI-MS) were recorded on a Bruker Micromass model VQ-TOF spectrometer. ¹H NMR and ¹³C NMR spectra were recorded on a Bruker DPX-400 or a Bruker Avance-500 spectrometer using tetramethylsilane (TMS) or residual non-deuterated solvent peak as an internal reference. Chromatographic separations were performed by using silica gel 60 (70 – 230 mesh, Merck) for column chromatography (CC), silica gel plates (Silica gel 60 PF₂₅₄, Merck) for preparative TLC, and Sephadex LH-20 (Merck) for gel filtration. Anisaldehyde was used as a spray reagent for monitoring spots on TLC after visualization under ultraviolet light. All solvents used for extraction and isolation were distilled prior to use.

Plant material

The bark of Ventilago maingayi was collected from Nakornratchasima province in the northeastern part of Thailand in April 1999. The plant material was identified by one of the authors (N. N.). A voucher specimen (BKF No. 084 548) has been deposited at the Forest Herbarium, Royal Forestry Department, Ministry of Agriculture and Cooperatives, Bangkok, Thailand.

Extraction and isolation

The air-dried powdered barks (18.6 kg) of V. maingayi were percolated with methanol (6 × 70 L, over the period of 60 days) at room temperature, followed by filtration. The extracts were evaporated under reduced pressure (aspirator) to dryness followed by freeze-drying to afford the crude MeOH extract (859 g) as a sticky solid. A portion of the MeOH extract (390 g) was subjected to CC on silica gel (70 – 230 mesh ASTM, 1400 g, 7.5 × 36 cm). Elution was initially conducted using hexane gradually enriched with acetone, followed by an increasing amount of methanol in acetone and finally with methanol. Fractions (250 mL each) were collected and combined on the basis of their TLC profiles to afford 14 main fractions (F1−F14). Compounds 1 (27.5 mg), 2 (37.2 mg), 3 (27.3 mg), 4 (52.5 mg), 5 (242 mg), 6 (122 mg), 7 (55.5 mg), 8 (282 mg), 9 (25.8 mg), 10 (121 mg), and 11 (45.0 mg) were obtained from fractions F2 to F12 after purification using column chromatography, preparative thin layer chromatography, and crystallization (for details, see Supporting Information).

Physical and spectroscopic data of compounds 1 – 3

Compound 1 ((3R)-4-hydroxy-5,6-dimethoxy-3-methylnaphtho[2,3-c]furan-1(3H)-one, ventilamainganone A): brown needles from CH₂Cl₂-hexane; m. p. 151.4 – 152.4 °C; [α]_D ²⁷ + 80.0 (c 1.0, CHCl₃); UV (EtOH) λ _max nm (log ε) 218 (4.71), 247 (5.03), 258 (4.98), 352 (4.32); FTIR (KBr) ν _max · cm⁻¹ 3244, 2985, 2949, 1760, 1618, 1603, 1519, 1475, 1465, 1402, 1364, 1350, 1275, 1156, 1086, 1053, 1035, 968, 899, 709.; ¹H and ¹³C NMR data see [Table 1]; HR-ESI-MS m/z 275.0912 [M + H]⁺ (calcd. for C₁₅H₁₅O₅, 275.0919).

Compound 2 ((3R)-7-dihydroxy-4,5,6-trimethoxy-3-methylnaphtho[2,3-c]furan-1(3H)-one, ventilamainganone B): colorless rods from CH₂Cl₂-hexane; mp 169.3 – 170.2 °C; [α]_D ²⁷ + 36.0 (c 1.0, CHCl₃); UV(EtOH) λ _max nm (log ε) 232 (4.15), 259 (4.44), 301 (3.57), 363 (3.22); FTIR (KBr) ν _max · cm⁻¹ 3475, 3006, 2936, 1768, 1629, 1592, 1508, 1472, 1440, 1339, 1273, 1164, 1113, 1082, 1005, 898, 776, 688; ¹H and ¹³C NMR data see [Table 1]; HR-ESI-MS m/z 327.0840 [M + Na]⁺ (calcd. for C₁₆H₁₆O₆Na: 327.0845).

Compound 3 (methyl 8-hydroxy-2,3-dimethoxy-6-methyl-9-oxo-9H-xanthene-1-carboxylate, ventilamaingaxanthone): orange rods from CH₂Cl₂-hexane; mp 162.8 – 163.3 °C; UV (EtOH) λ _max nm (log ε) 234 (4.46), 254 (4.53), 268 (4.39), 300 (4.27), 359 (3.59); FTIR (KBr) ν _max · cm⁻¹ 3470, 3024, 2949, 1745, 1655, 1602, 1577, 1478, 1468, 1435, 1376,1318, 1277, 1246, 1212, 1124, 1027, 975, 833, 755; ¹H and ¹³C NMR data see [Table 2]; HR-ESI-MS m/z 367.0787 [M + Na]⁺, calcd. for C₁₈H₁₆O₇Na, 367.0794.

X-ray crystal structure analysis

X-ray crystallographic data for 1 (C₁₆H₁₈O₅), MW = 290.32, 0.35 × 0.30 × 0.30 mm, monoclinic, space group P21 (No. 4). a = 4.7635(1) Å, 14.3742(4) Å, 9.6197(3) Å, β = 95.734(1) °, V = 655.38(3) Å3, Z = 2, T = 273(2) K, µ(Cu Kα) = 0. 878 mm⁻¹, Dx = 1.390 g/g/mm³, reflections collected/unique: 6701/6499, number of observations [I > 2σ(I)]: 2490, R1 = 0.0278, wR2 = 0.0 762(all data), Flack parameter = 0.13(5). X-ray crystallographic data were measured on a Bruker APEX2 diffractometer equipped with a graphite monochromated Cu Kα radiation source (λ = 1.54 178 Å). The structure was solved by using Olex2 [19] and refined with the Olex2.refine refinement package using Gauss–Newton minimization [20], [21]. The crystallographic data were deposited at the Cambridge Crystallographic Data Centre under the reference numbers CCDC 2 382 581. Copies of the data can be obtained, free of charge, upon application to the Director, CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK (e-mail: deposit@ccdc.cam.ac.uk).

Anti-HIV-1 reverse transcriptase assay

For crude extracts and fractions, tannins were removed by following the procedure described by Tan et al. [22]: 100 µL of a 20 mg/mL stock solution in DMSO were treated with approximately 100 mg of polyvinylpyrrolidone in a microcentrifuge tube. The mixture was shaken and centrifuged at 300 g for 5 – 10 min at 10 °C. Then, the supernatant was collected for testing. Pure compounds were dissolved in DMSO to obtain a final concentration of 0.2 mg/mL [23].

In 96-well plate, 0.1 U/reaction of HIV-1 reverse transcriptase (Amersham Pharmacia Biotech Asia Pacific Ltd.) and the sample (0.2 mg/mL) were added to the reaction mixture containing radiolabeled thymidine triphosphate ([³H]TTP) (0.5 µCi/reaction) and polyadenylic acid (polyA) (40 µM/reaction), which served as a reverse transcriptase (RT) enzyme substrate and RNA template, respectively. HIV-1 RT activity was detected by measuring the incorporation of [³H]TTP to the polyA template. Positive controls included the known RT inhibitors fagaronine chloride (purity > 98%, Sigma) and nevirapine (purity > 98%, Sigma), whereas negative controls consisted of wells without test samples. RT enzyme activity was standardized with fagaronine chloride. The experiments were done in three duplicates. The data were averaged, and the percent inhibition compared with the negative control was calculated. For the samples with more than 70% inhibition, the 50% inhibitory concentrations (IC₅₀) were further determined by testing RT activities in the presence of various concentrations of the samples. The IC₅₀ values were then estimated from the dose-response curves using GraphPad Prism 9.0.0 software.

Syncytium reduction assay

The syncytium reduction assay was carried out using the ^ΔTat/RevMC99 virus and 1A2 cell line system obtained from Dr. D. J. Clanton [24]. Briefly, 1A2 cells prepared in 96-well plates were infected with the ^ΔTat/RevMC99 virus in the presence of various concentrations of compounds, ranging from 3.9 to 250 mg/mL. The syncytia formed were counted after incubation at 37 °C for three days. The results were expressed as 50% effective concentration (EC₅₀) or as concentration that inhibited syncytia formation by 50% [24]. Each data point was determined in triplicate. Controls included cells-only control, no-compound control, and no-virus control. A known HIV-1 replication inhibitor, zidovudine (azidothymidine, AZT, purity > 98%, Sigma), was used as a positive control. The cytotoxicity of the compounds was also assessed in parallel using a colorimetric XTT assay in duplicate. Cytotoxicity was expressed as the concentration that inhibited formazan formation in uninfected cells by 50% (IC₅₀) [24] using GraphPad Prism 9.0.0 software. The selectivity index (SI) was calculated using equation SI = IC₅₀/EC₅₀.

Contributorsʼ Statement

Conception and design of the work: V. R., S. H., C. K.; data collection: P. L., S. H., S. T.; plant collection, taxonomic identification and processing plant sample: N. N.; analysis and interpretation of the spectroscopic data: P. L., S. H., S. T.; biological experiments and analysis: R. A., A. C.; theoretical study: R. I., S. J.; drafting the manuscript: S. H. V. R.; critical revision of the manuscript: S. H., V. R., C. K.; V. R. and S. H. contributed equally as corresponding authors.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Correspondence

Publication History

Received: 28 October 2024

Accepted after revision: 16 April 2025

Accepted Manuscript online:
16 April 2025

Article published online:
08 May 2025

© 2025. Thieme. All rights reserved.

Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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  PubMedSearch in Google Scholar
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  PubMedSearch in Google Scholar
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  PubMedSearch in Google Scholar

• Supplementary Material