A prenylated acridone alkaloid and ferulate xanthone from barks of Citrus medica (Rutaceae)
-
Marie Fomani
,
Kouam
Abstract
A new prenylated acridone alkaloid, medicacridone (1), and a new ferulate xanthone, medicaxanthone (5), together with 11 known compounds were isolated from the methanol extract of the bark of the Cameroonian medicinal plant Citrus medica. The structures of all compounds were determined by comprehensive analyses of their 1D and 2D NMR, mass spectral (EI and ESI) data, chemical reactions, and comparison with previously known analogues. The agar diffusion test delivered low to missing antimicrobial activities, corresponding with MICs > 1 mg mL–1, while compounds 1–6 and atalantoflavone (9) displayed weak cytotoxic activity against the human Caucasian prostate adenocarcinoma cell line PC-3, with IC50 values ranging from 60.5 to 80.0 μm versus doxorubicine with IC50=0.9 μm.
1 Introduction
Citrus medica and other species of the genus are native to parts of India, China, and northern Australia [1]. Belonging to the family of Rutaceae, Citrus species are small to medium-size shrubs or trees that are cultivated throughout the tropics and subtropics for medicinal, herbal and agricultural purposes. The stem and root bark are reported to be used against stomach ache, edema, headache, rheumatism, infectious hepatitis, and arthritis in Taiwan [2]. Both the leaves and juice are commonly employed by the Yoruba people of southwestern Nigeria for the treatment of febrile illness [3]. Fruits are applied by the Malayali in Kottur Hills, Dharmapuri district, Tamil Nadu, against fungal nail infections and elsewhere in India for the treatment of gastric ulcers [4, 5]. In Chinese traditional herbal medicine, the fruit is used to treat distension and pain of the chest in combination with the rhizomes of Cyperus rotundus and Curcuma longa, while the fruit is applied against bloated stomach, anorexia, belching, and vomiting in combination with the root of Aucklandia lappa and the fruit of Citrus aurantium. In addition, the fruit is used against cough, copious sputum, and chest pain mixed with the fruit sponge of Luffa cylindrica, and the leaf of Eriobtory japonica [6].
Previous phytochemical investigations revealed coumarins, acridone alkaloids, limonoids, xanthones, flavonoids, and steroids. Some of these compounds exhibited potent antibacterial, fungicidal, anticancer, anti-inflammatory, antiulcer, antidiabetic, hypocholesterolemic, hypolipidemic, and algicidal properties [7–12]. Widespread traditional medicinal use and significant biological activities of compounds investigated so far justified continued investigation of C. medica. This paper reports the isolation and structure elucidation of a new prenylated acridone alkaloid (1) and a ferulate xanthone (5), together with low antimicrobial and cytotoxic activities of isolated compounds.
2 Results and discussion
The methanol extract of the bark of C. medica were extracted with methanol. The extract was separated using repeated column chromatography and preparative TLC to afford two new and 11 known compounds (Fig. 1).
Structures of some of the isolated compounds.
Medicacridone 1 was obtained as a yellow powder. The molecular composition was found by ESI-MS and HR-ESI-MS ([M]+ at m/z=362.1368, calcd. 362.1370) to be C20H21NO4. The UV spectrum showed a highly conjugated system with absorption bands characteristic of a 1-hydroxy-9-acridone skeleton in the molecule [13]. A positive reaction with ferric chloride (FeCl3), an infrared (IR) band at 3300 cm–1, and a 1H NMR signal at δ=14.90 ppm (s) of a chelated hydroxyl group, which disappeared with deuterium oxide (D2O), indicated the presence of a phenolic hydroxyl group [13].
Analysis of the 1H NMR data (Table 1) of compound 1 revealed characteristic resonances of ABC-type aromatic protons at δ=7.98 (dd, J=8.2; 2.5 Hz, H-8), 7.38 (dd, J=8.2; 2.5 Hz, H-6) and 7.25 ppm (dd, J=8.2; 8.2 Hz, H-7), a singlet at δ=6.51 ppm (s, H-2), an N–CH3 unit at δ=3.94 ppm (s), a methoxy group at δ=4.01 ppm (s), and a prenyl unit at δ= 5.32 (t, J=8.2 Hz, H-2′), 3.38 (d, J=8.2 Hz, H-1′), 1.80 (s, CH3-4′), and 1.66 ppm (s, CH3-5′). These findings are in agreement with the prenylated acridone skeleton [13]. The presence of a prenyl group was further confirmed by the 13C NMR spectrum (Table 1) displaying characteristic signals at δ=131.2 (C-3′), 123.7 (C-2′), 25.9 (C-5′), 21.9 (C-1′), and 17.9 ppm (C-4′).
1H (500 MHz) and 13C (125 MHz) assignments for 1 (in [D6]acetone) and 5 (in CD3OD)a.
| Attribution | 1 | 5 | ||
|---|---|---|---|---|
| 13C | 1H (m, J in Hz) | 13C | 1H (m, J in Hz) | |
| 1 | 163.1 | 14.90 (s) | 165.5 | – |
| 2 | 91.8 | 6.51 (s) | 97.0 | 6.26 (d, 2.1) |
| 3 | 162.7 | – | 167.0 | – |
| 4 | 105.4 | – | 92.8 | 6.40 (d, 2.1) |
| 4a | 146.7 | – | 156.5 | – |
| 5 | 150.6 | – | 99.4 | 6.78 (d, 2.3) |
| 6 | 116.9 | 7.38 (dd, 8.2; 2.5) | 159.1 | – |
| 7 | 122.7 | 7.25 (dd, 8.2; 8.2) | 116.3 | 6.70 (d, 2.3) |
| 8 | 118.6 | 7.98 (dd, 8.2; 2.5) | 143.1 | – |
| 8a | 124.3 | – | 113.9 | – |
| 9 | 181.0 | – | 183.5 | – |
| 9a | 109.0 | – | 104.8 | – |
| 10a | 135.9 | – | 156.3 | – |
| CH3 | – | – | 23.5 | 2.80 (s) |
| 1′ | 21.9 | 3.38 (d, 8.2) | 170.4 | – |
| 2′ | 123.7 | 5.32 (t, 8.2) | 115.1 | 6.21 (d, 15.8) |
| 3′ | 131.2 | – | 146.6 | 7.53 (d, 15.8) |
| 4′ | 17.9 | 1.66 (s) | 128.4 | – |
| 5′ | 25.9 | 1.80 (s) | 114.9 | 7.00 (d, 1.7) |
| 6′ | – | – | 144.3 | – |
| 7′ | – | – | 146.8 | – |
| 8′ | – | – | 116.4 | 6.77 (d, 8.2) |
| 9′ | – | – | 122.8 | 6.91 (dd, 8.2; 1.7) |
| OH | – | 14.90 | – | – |
| O–CH3 | 56.9 | 4.01 (s) | 56.2 | 3.86 (s) |
| O–CH3 | – | – | 56.4 | 3.89 (s) |
| N–CH3 | 42.0 | 3.94 (s) | – | – |
| O–CH2 | – | – | 64.4 | 4.14 (t, 7.2) |
| CH2 | – | – | 29.9 | 1.58 (m) |
| (CH2)21 | – | – | 29.9 | 1.25 (brs) |
| CH3 | – | – | 14.1 | 0.88 (t, 6.9) |
aAssignments were based on HMQC, HMBC and NOESY experiments.
The complete assignment of compound 1 was based on COSY, NOESY, HMQC, and HMBC experiments. In the HMBC spectrum, correlations between the proton H-1′ (δ=3.38 ppm) and the carbons C-4a (δ=146.7 ppm), C-3 (δ=162.7 ppm), and C-3′ (δ=131.2 ppm) and between the proton H-2 (δ=6.51 ppm) and the carbons C-9a (δ=109.0 ppm) and C-4 (δ=105.4 ppm) suggested the prenyl group to be at C-4 position. The position of the methoxy group was determined by a cross-peak observed in the NOESY spectrum between the N-Me (δ=3.94 ppm) and the OMe group (δ=4.01 ppm). From the above spectroscopic data, the structure of compound 1 was deduced as 1,3-dihydroxy-10-methyl-5-methoxy-4-prenylacridone and was given the trivial name medicacridone.
Medicaxanthone 5 was obtained as a yellow amorphous powder and gave a positive reaction with FeCl3 indicating its phenolic nature. The presence of hydroxyl, carbonyl, and ester functions was indicated by three IR bands at 3400, 1660, and 1650 cm–1, respectively. From the HR-ESI-MS, the molecular composition was found to be C49H68O8Na by [M+Na]+ at m/z=807.4810 (calcd. 807.4810).
The 1H NMR spectrum of 5 displayed characteristic resonances of two AB-type aromatic protons at δ=6.26 ppm (d, J=2.1 Hz, H-2), 6.40 ppm (d, J=2.1 Hz, H-3), and at δ=6.70 ppm (d, J=2.3 Hz, H-7), 6.78 ppm (d, J=2.3 Hz, H-5), one methoxy at δ=3.86 ppm, and one methyl at δ=2.80 ppm indicating the presence of a lichexanthone moiety [14, 15]. Furthermore, the 1H NMR spectrum indicated the presence of feruloyl moiety by an ABX system of aromatic protons at δ=7.00 ppm (d, J=1.7 Hz, H-5′), 6.91 ppm (dd, J=1.7; 8.2 Hz, H-9′) and 6.77 ppm (d, J=8.2 Hz, H-8′), two olefinic protons at δ=6.21 ppm (d, J=1.5 Hz, H-3′), 7.53 ppm (d, J=1.5 Hz, H-2′), and a methoxy group at δ=3.89 ppm. A terminal methyl at δ=0.88 ppm (t, J=6.9 Hz) and methylenes at δ=1.25 (brs, nH), 1.58 (m, CH2-CH2O-) and 4.14 ppm (t, J=7.2 Hz, -CH2O-) were also observed. These data suggested the presence of a long chain linked to feruloyle and lichenxanthone moieties which was confirmed by characteristic signals in the 13C NMR spectrum at δ=170.4 (C-1′); 146.8 (C-7′); 146.6 (C-3′); 144.3 (C-6′); 128.4 (C-4′); 122.8 (C-9′); 116.4 (C-8′); 115.1 (C-2′); 114.9 (C-5′); and at δ=14.1 (CH3), 29.9 ((CH2)n), 64.3 ppm (CH2-O-).
The linkage among the lichenxanthone, the feruloyle, and the long chain was determined by an HMBC experiment and by hydrolysis. Correlation of H-1″ (δ=4.14 ppm) with C-7′ (δ=146.8 ppm); (CH2)n (δ=29.9 ppm), and of H-5′ (δ=7.00 ppm) with C-7′ (δ=146.8 ppm) and C-4′ (δ=128.4 ppm) in the HMBC spectrum revealed that the long chain is linked to the feruloyle moiety by an ether function at C-7′. The hydrolysis of 5 yielded 7-tetracosyloxyferuloïc acid, identified by ESI-MS, which indicated a pseudomolecular ion at m/z=553 [M+Na]+, corresponding to a molecular formula C34H58O4, together with 1,6-dihydroxy-3-methoxy-8-methylxanthone 5a. From these spectroscopic data, medicaxanthone 5 was characterized as 3-tetracosyloxyferulate of 1,6-dihydroxy-3-methoxy-8-methylxanthone.
Furthermore, the known compounds citracridone-I (2), 5-hydroxynoracronycine (3), citracridone-III (4), lichenxanthone (6), bergaptene (7), 5,8-dimethoxypsoralene (8), atalantoflavone (9), limonin (10), lupeol (11), stigmasterol (12), and β-sitosterol (13) [13, 16] were identified by comparison of their spectroscopic data with those of authentic samples or published data.
Tests of pure compounds on paper disk diffusion agar against the bacteria Bacillus subtilis, Staphylococcus aureus, and Escherichia coli, the fungi Mucor miehei and Candida albicans, and the plant pathogen oomycetes Aphanomyces cochlioides, Pythium ultimum, and Rhizoctonia solani resulted in missing or low activities.
Compounds 1–6 and atalantoflavone (9) displayed weak cytotoxic activity against the human Caucasian prostate adenocarcinoma cell line PC-3 with IC50 ranging from 60.5 to 80.0 μm, compared with the standard doxorubicine with IC50=0.9 μm (Table 2).
Cytotoxicity against human prostate adenocarcinoma cell line PC-3.
| Compounds | IC50 (μm) |
|---|---|
| 1 | 60.5±1.5 |
| 2 | 80.0±1.5 |
| 3 | 79.5±1.8 |
| 4 | 68.5±1.7 |
| 5 | 65.0±2.5 |
| 6 | 70.2±1.5 |
| 9 | 65.1±1.8 |
| Doxorubicinea | 0.9±0.1 |
aStandard used in the assay.
3 Experimental section
3.1 General
Ultraviolet spectra were recorded on a Hitachi UV 3200 spectrophotometer in MeOH. Infrared spectra were recorded on a JASCO 302-A spectrophotometer. ESI-HR mass spectra were recorded on a Bruker FTICR 4.7 T mass spectrometer. EI-MS were recorded on a Finnigan MAT 95 spectrometer (70 eV) with perfluorokerosene as reference substance for EI-HR-MS. The 1H and 13C NMR spectra were recorded at 500 and 125 MHz, respectively, on Bruker DRX 500 spectrometers. Methyl, methylene, and methine carbons were distinguished by DEPT experiments. Homonuclear 1H connectivities were determined by using the COSY experiment. One-bond 1H-13C connectivities were determined with HMQC gradient pulse factor selection. Two- and three-bond 1H-13C connectivities were determined by HMBC experiments. Chemical shifts are reported in δ (ppm) using TMS as internal standard, and coupling constants (J) were measured in hertz. Column chromatography was carried out on silica gel (70–230 mesh, Merck). TLC was performed on Merck precoated silica gel 60 F254 aluminum foil, and spots were detected using ceric sulfate spray reagent. Phenolic compounds were detected using FeCl3 reagent. The purity of the compounds was investigated by means of 1H NMR and ESI-MS experiment. The degree of purity of the tested compounds was > 95 %, and of the positive control (doxorubicin) 99.9 %. All other substances, if otherwise not specified, were purchased from Sigma-Aldrich (Germany). All reagents used were of analytical grade.
3.2 Collection and identification
The bark of C. medica was collected at the Nkondjock locality in a littoral region of Cameroon in May 2013 and identified by Mr. Nana Victor of the National Herbarium, Yaoundé, Cameroon, where a voucher specimen (ref. 65105 SRF/CAM) has been deposited.
3.3 Extraction and isolation
The air-dried and powdered bark (5.5 kg) of C. medica was extracted with methanol at room temperature for 72 h. After filtration and evaporation under reduced pressure, 155.6 g of the crude extract obtained was purified by column chromatography over silica gel 60 (230–400 mesh) and preparative TLC using a gradient system of hexane, CH2Cl2, AcOEt, and MeOH. One hundred twenty subfractions (ca. 250 mL each) were collected and pooled on the basis of TLC analysis leading to four main fractions (A–D).
Fraction A (11.2 g, combined from sub-fractions 1–25) was chromatographed over a silica gel 60C column with a hexane-CH2Cl2 gradient. A total of 20 fractions of ca. 100 mL each was collected and combined on the basis of TLC. Fractions 4–8 precipitated to give a colorless powder, lupeol (11) (35.2 mg). Fractions 9–25 were further chromatographed over a a silica gel 60H column with a mixture of hexane-CH2Cl2 (1:1) to yield bergaptene (7) (11.3 mg), 5,8-dimethoxypsoralene (8) (7.0 mg), and a mixture of steroids. Fraction B (25.4 g, combined from sub-fractions 26–55) was chromatographed over a silica gel 60C column with a hexane-CH2Cl2 gradient. A total of 50 fractions of ca. 100 mL each was collected and combined on the basis of TLC. Fractions 11–25 were further chromatographed over a silica gel 60H column with a mixture of CH2Cl2-AcOEt (9:1) to yield medicacridone (1) (13.1 mg), medicaxanthone (5) (6.2 mg), lichenxanthone (6) (4.5 mg), limonin (10) (8.2 mg), and atalantoflavone (9) (22.1 mg). Fraction C (16.5 g, combined from sub-fractions 56–90) was chromatographed over a silica gel 60C column with a hexane-CH2Cl2 gradient. A total of 34 fractions of ca. 100 mL each was collected and combined on the basis of TLC. Fractions 10–25 were further chromatographed over a silica gel 60H column with a mixture of CH2Cl2-AcOEt (4:1) to yield citracridone I (2) (10.5 mg), 5-hydroxynoracronycine (3) (15.3 mg), and citracridone III (4) (21.5 mg). Fraction D (32.5 g, combined from sub-fractions 91–120) was not further studied.
3.4 Medicacridone (1)
Yellow powder (Aceton); Rf=0.67, silica gel 60 F254, CH2Cl2· – UV (MeOH): λmax (log ε)=375 (3.30), 330 (3.23), 290 (3.13), 260 (3.45) nm. – IR (CH2Cl2): νmax=3300, 2960, 1650, 1500, 1445 cm–1. – 1H NMR and 13C NMR data see Table 1. – MS ((+)-ESI): m/z (%)=362 (100) [M+Na]+. – HRMS ((+)-ESI): m/z=362.1368 (calcd. 362.1370 for C20H21NaNO4, [M+Na]+).
3.5 Medicaxanthone (5)
Yellow powder (MeOH); Rf=0.72, silica gel 60 F254, CH2Cl2. – UV (MeOH): λmax (log ε)=340 (3.50), 308 (3.80), 244 (4.00), 235 (4.00), 209 (3.70) nm. – IR (CH2Cl2): νmax=3449, 2925, 1655, 1609 cm–1. – 1H NMR and 13C NMR data see Table 1. – MS ((+)-ESI): m/z (%)=807 (100) [M+Na]+. – HRMS ((+)-ESI): m/z=807.4810 (calcd. 807.4812 for C49H68NaO8, [M+Na]+).
3.6 Hydrolysis
Compound 5 (3.5 mg) was added to an aqueous solution of KOH (10%) and refluxed for 16 h with magnetic stirring. Then HCl (5%) was added to the mixture, which was extracted with n-hexane (3 × 5 mL). 1,6-Dihydroxy-3-methoxy-8-methylxanthone (5a, 2.0 mg) and 7-tetracosyloxyferuloic acid (0.5 mg) were obtained.
3.7 Biological activities
3.7.1 Antimicrobial assays
Agar diffusion test plates with the bacteria Bacillus subtilis and Escherichia coli (on peptone agar), Staphylococcus aureus (Bacto nutrient agar), and the fungi Mucor miehei and Candida albicans (Sabouraud agar) as test strains were performed as previously described [17]. For the plant pathogen oomycetes Aphanomyces cochlioides, Pythium ultimum, and Rhizoctonia solani, squares of 0.5×0.5 cm2 were cut with a microbiological hook from the growth margins of mycelial mats grown on PDA plates, inoculated onto the centers of fresh plates, and cultivated for 24 h at 28 °C to initiate radial growth.
Compounds were dissolved in CH2Cl2-MeOH (9:1), and paper disks (Ø 9 mm) were impregnated with 40.0 μg, dried for 1 h under sterile conditions, and arranged evenly on the premade agar test plates, whereas for oomycete plates, the disks were placed around the mycelia squares at a distance of 30 mm. Bacteria and fungi plates were kept in an incubator at 37 °C for 15 h, oomycetes at 28 °C for 48 h. Plates were evaluated macroscopically for the prence of the inhibition zones. Nystatin (Maneesh Pharmaceutic, Govandi, Mumbai, India) was used as positive control for fungi and gentamycin (Jinling Pharmaceutic (Group), Zhejang Tieng Feng Pharmaceutic Factory, Huzhou, Zhejang, China) for bacteria.
3.7.2 Cytotoxicity assay
Cytotoxic activities of the compounds were evaluated against the human Caucasian prostate adenocarcinoma cell line PC3 by the MTT method according to a reported protocol [18]. Freshly trypsinized cell suspensions were seeded into 96-well microtiter plates at densities of 1×104 cells per well, and the test compounds were added from DMSO-diluted stock. After 3 days, the attached cells were incubated with MTT and subsequently solubilized in DMSO. The absorbance at 550 nm was measured by using a microplate reader. The IC50 is the concentration of agent that reduced cell growth under experimental conditions by 50 %, with doxorubicin as positive control (IC50=0.9 μm).
Acknowledgments
J.D.W. wishes to thank the Alexander von Humboldt Foundation (AvH, Germany) for the generous support with laboratory equipment.
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©2015 by De Gruyter
Articles in the same Issue
- Frontmatter
- In this Issue
- Editorial
- Zeitschrift für Naturforschung B now being published by De Gruyter
- Original Communications
- “Naked” S2O72– ions – the serendipitous formation of the disulfates [HPy]2[S2O7] and [bmim][HPy][S2O7] (HPy = pyridinium; bmim = 1-Butyl-3-methylimidazolium)
- Orthoamide und Iminiumsalze, LXXXVIII. Synthese N,N,N′,N′,N″,N″-persubstituierter Guanidiniumsalze aus N,N′-persubstituierten Harnstoff/Säurechlorid-Addukten**
- The acidic ionic liquid [BSO3HMIm]HSO4: a novel and efficient catalyst for one-pot, three-component syntheses of substituted pyrroles
- The influence of alkali-metal ions on the molecular and supramolecular structure of manganese(II) complexes with tetrachlorophthalate ligands
- New triazolothiadiazole and triazolothiadiazine derivatives as kinesin Eg5 and HIV inhibitors: synthesis, QSAR and modeling studies
- Two copper(I) complexes of bi- (or tri-)pyrazolyl ligands featuring Cu3pz3 or Cu4pz4 motifs
- Synthesis of ferrocenyl aryl ethers via Cu(I)/phosphine catalyst systems
- A prenylated acridone alkaloid and ferulate xanthone from barks of Citrus medica (Rutaceae)
- Synthesis and structural characterization of substituted phenols with a m-terphenyl backbone 2,4,6-R3C6H2OH (R=2,4,6-Me3C6H2, Me5C6)
- 2-Ethyl-1-phenylindazolium hexafluorophosphate. N-heterocyclic carbene formation, rearrangement, ring-cleavage reactions, and rhodium complex formation
Articles in the same Issue
- Frontmatter
- In this Issue
- Editorial
- Zeitschrift für Naturforschung B now being published by De Gruyter
- Original Communications
- “Naked” S2O72– ions – the serendipitous formation of the disulfates [HPy]2[S2O7] and [bmim][HPy][S2O7] (HPy = pyridinium; bmim = 1-Butyl-3-methylimidazolium)
- Orthoamide und Iminiumsalze, LXXXVIII. Synthese N,N,N′,N′,N″,N″-persubstituierter Guanidiniumsalze aus N,N′-persubstituierten Harnstoff/Säurechlorid-Addukten**
- The acidic ionic liquid [BSO3HMIm]HSO4: a novel and efficient catalyst for one-pot, three-component syntheses of substituted pyrroles
- The influence of alkali-metal ions on the molecular and supramolecular structure of manganese(II) complexes with tetrachlorophthalate ligands
- New triazolothiadiazole and triazolothiadiazine derivatives as kinesin Eg5 and HIV inhibitors: synthesis, QSAR and modeling studies
- Two copper(I) complexes of bi- (or tri-)pyrazolyl ligands featuring Cu3pz3 or Cu4pz4 motifs
- Synthesis of ferrocenyl aryl ethers via Cu(I)/phosphine catalyst systems
- A prenylated acridone alkaloid and ferulate xanthone from barks of Citrus medica (Rutaceae)
- Synthesis and structural characterization of substituted phenols with a m-terphenyl backbone 2,4,6-R3C6H2OH (R=2,4,6-Me3C6H2, Me5C6)
- 2-Ethyl-1-phenylindazolium hexafluorophosphate. N-heterocyclic carbene formation, rearrangement, ring-cleavage reactions, and rhodium complex formation
