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Acetylcholinesterase Inhibitors from the Leaves of Macaranga kurzii Van Trinh Thi Thanh,† Huong Doan Thi Mai,*,† Van Cuong Pham,*,† Marc Litaudon,‡ Vincent Dumontet,‡ Françoise Guéritte,‡ Van Hung Nguyen,† and Van Minh Chau† †
Institute of Marine Biochemistry of the Vietnam Academy of Science and Technology (VAST), 18 Hoang Quoc Viet Road, Cau Giay, Hanoi, Vietnam ‡ Institut de Chimie des Substances Naturelles, Gif-sur Yvette, France S Supporting Information *
ABSTRACT: Bioassay-guided fractionation of an extract of leaves of Macaranga kurzii yielded four new compounds, a stilbene (furanokurzin, 1) and three flavonoids (macakurzin A−C, 2−4). Nine known compounds were also isolated (5− 13). Their structures were determined by spectroscopic analyses including MS and 2D NMR. The isolates were all evaluated for acetylcholinesterase inhibitory activity. Compound 6 (trans-3,5-dimethoxystilbene) exhibited the greatest activity (IC50 9 μM). Cytotoxic evaluation against KB cells showed that compound 7 had an IC50 of 4 μM, followed by 11 (IC50 10 μM) and 3 (IC50 13 μM).
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residue of 100.8 g. The EtOAc solubles were fractionated by column chromatography (CC) on silica gel. The fractions were tested for their AChE inhibitory activity, and the active fractions were then purified by repeated open CC to afford compounds 1−13.
cetylcholinesterase (AChE) inhibitors are considered to be promising therapeutic agents for the treatment of neurological disorders such as Alzheimer′s disease (AD), senile dementia, ataxia, myasthenia gravis, and Parkinson′s disease. AD is the most common cause of senile dementia in later life. Besides the neuropathologic hallmarks of this disease, namely, neurofibrillary tangles and neuritic plaques, it is characterized neurochemically by a consistent deficit in cholinergic neurotransmission, particularly affecting cholinergic neurons in the basal forebrain.1,2 Hypothetically, AChE inhibitors should increase the efficiency of cholinergic transmission by preventing the hydrolysis of released ACh, thus making more ACh available at the cholinergic synapse.3−5 As part of our search for new bioactive compounds from plants of Vietnam, an extract of the leaves of Macaranga kurzii Pax & K.Hoffm. (Euphorbiaceae) collected from Yen-Bai, Vietnam, was found to inhibit 40% of AChE at a concentration of 10 μg/mL. The genus Macaranga comprises more than 300 species distributed mainly in Southern Asia.6 Sixteen different species of this genus occur in Vietnam, and M. kurzii has been used for scabies treatment in traditional medicine.7,8 An overview of the literature indicated that the genus Macaranga was a rich source of isoprenylated and geranylated flavonoids and stilbenes, many of which have cytotoxic and antioxidant activity.9−15 In this paper, we describe the bioassay-guided isolation and structural elucidation of four new compounds, furanokurzin (1) and macakurzin A−C (2−4), from the leaves of M. kurzii. Nine known compounds, cis-3,5-dimethoxystilbene (5), trans-3,5dimethoxystilbene (6), trans-3,5-dimethoxy-2-prenylstilbene (7), 5,7-dihydroxy-6-prenylflavanone (8), glabranin (9), izalpinin (10), glepidotin A (11), 8-prenylgalangin (12), and galangin (13), were also isolated and tested (see Supporting Information for the structures of compounds 5−13). Dried and ground leaves of M. kurzii (1.8 kg) were extracted with ethyl acetate (4 × 4 L) at room temperature. The EtOAc solution was concentrated under reduced pressure to give a © XXXX American Chemical Society and American Society of Pharmacognosy
Compound 1 was obtained as a white, microcrystalline solid. A molecular formula of C16H12O2 was deduced from the HRESI mass spectrum of 1, which presented the protonated molecular ion at m/z 237.0911 [M + H]+ (calcd 237.0916 for C16H13O2). The 1H NMR spectrum indicated the presence of a phenyl ring [δH 7.55 (d, J = 8.0 Hz, H-2′ and H-6′), 7.39 (t, J = 8.0 Hz, H-3′ and H-5′), and 7.30 (t, J = 8.0 Hz, H-4′)], two olefinic protons with trans-configuration at δH 7.20 (d, J = 16.5 Hz, H-β) and 7.31 (d, J = 16.5 Hz, H-α), and four aromatic protons at δH 6.93 (d, J = 2.0 Hz, H-4), 6.96 (d, J = 2.0 Hz, H7′), 7.01 (d, J = 2.0 Hz, H-6), and 7.58 (d, J = 2.0 Hz, H-8′). The 13C NMR spectrum displayed 16 sp2 carbon signals including 11 methine and five quaternary carbons. The chemical shifts of carbons at δC 156.2 (C-3), 153.7 (C-5), and 144.3 (C-8′) suggested their linkage to oxygen. These data and the HMBC spectrum confirmed that 1 was a stilbene derivative. Cross-peaks at δC 119.9 (C-2) with H-α, H-6, and H-7′, and that of carbon C-3 with H-8′, revealed the presence of a furan ring (C-ring). Thus, compound 1 was identified as 5hydroxyfuro[3,2-h]stilbene and named furanokurzin. Many furanocoumarins and furanoflavonoids have been isolated Received: September 25, 2012
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from plants;16−19 however, this appears to be the first example of a furanostilbene from a natural source. Compound 2 was obtained as a yellow, microcrystalline solid (mp 209−210 °C). The IR spectrum of 2 indicated the presence of conjugated carbonyl (1641 cm−1) and OH (3293 cm−1) groups. Its HRESI mass spectrum gave a pseudomolecular ion [M + Na]+ at m/z 377.1002 (calcd 377.1001 for C20H18NaO6) consistent with the molecular formula C20H18O6. Analysis of the 1H NMR spectrum revealed a methyl singlet at δH 1.75 (CH3-11′), a methylene (CH2-7′) at δH 2.75 (dd, J = 7.0 and 13.0 Hz, Ha-7′) and 2.83 (dd, J = 7.0 and 13.0 Hz, Hb7′), an oxymethine at δH 4.31 (t, J = 7.0 Hz H-8′), two olefinic protons as broad signlets at δH 4.62 and 4.65 (CH2-10′), a phenyl ring [δH 8.14 (d, J = 7.5 Hz, H-2′ and H-6′), 7.55 (t, J = 7.5 Hz, H-3′ and H-5′), and 7.49 (t, J = 7.5 Hz, H-4′)], a singlet aromatic proton at δH 6.51 (H-8), and a chelated OH proton at δH 12.65 (OH-5). The 13C NMR and DEPT spectra of 2 displayed carbon signals corresponding to the groups observed in the 1H NMR spectrum with additional signals of a conjugated carbonyl at δC 176.2 (C-4) and nine aromatic quaternary carbons. The signals from 1D NMR spectra strongly suggested that 2 was a flavonol derivative. The linkage of a side chain to C-6 of the flavonol skeleton of 2 was established by cross-peaks of the carbon at δC 108.3 (C-6) with CH2-7′, H-8′, and the chelated proton OH-5, and those of carbons at δC 73.3 (C-8′) and 147.9 (C-9′) with the methyl protons CH3-11′ and olefinic protons CH2-10′. Careful analysis of 2D NMR spectra established the structure of 2 as 5,7-dihydroxy-6-(2-hydroxy-3methyl-3-butenyl)flavonol. This is the first report of a compound with this structure, and compound 2 has been named macakurzin A. Compound 3 was obtained as a yellow, microcrystalline solid (mp 198−199 °C). The IR spectrum indicated the presence of conjugated carbonyl (1657 cm−1) and OH (3401 cm−1) groups, and the molecular formula C20H18O6 was assigned for 3 from analysis of its HRESI mass spectrum. Twelve degrees of unsaturation were thus deduced. Comparison of the 1D NMR spectrum of 3 with that of 2 revealed significant differences as follows: signals of the C-9′−C-10′ double bond in 2 were replaced by signals corresponding to a singlet methyl group at δC 1.38 (CH3-10′) and an oxygenated sp3 quaternary carbon at δC 78.7 (C-9′). Also, the proton chemical shift of CH3-11′ at δH 1.75 of 2 was displaced upfield to δH 1.42 in the 1H NMR spectrum of 3. This suggested that 3 was a derivative of 2, and this suggestion was supported by analyses of 2D NMR spectra of 3. The side chain connecting to C-6 of the flavonol skeleton of 3 was confirmed by correlations of the carbon at δC 102.6 (C-6) with protons at δH 2.79 (dd, J = 5.5 and 17.0 Hz, Ha-7′), 3.01 (dd, J = 5.5 and 17.0 Hz, Hb-7′), 3.90 (t, J = 5.5 Hz, H-8′), and the chelated proton OH-5 at δH 11.95, and cross-peaks of the carbons at δC 68.9 (C-8′) and 78.7 (C-9′) with the protons of two methyl groups at δH 1.38 (CH3-10′) and 1.42 (CH311′). Taking into account the molecular formula established above, the pyran D-ring was defined. The proton H-8′ was observed as a triplet with two gauche coupling constants (J = 5.5 Hz). It was thus equatorially oriented on the D-ring. Compound 3 was named macakurzin B. Biosynthesis of 3 in the plant could involve an additive cyclization of the OH group at C-7 to the C-9′−C-10′ double bond of 2 to form the pyran D-ring. Compounds 2 and 3 were both optically inactive, suggesting that they were racemic. This was confirmed by their esterification with the Mosher′s reagent (R-MTPA). Analysis
of 1H NMR spectra of the resulting esters indicated the presence of two diastereoisomers each for compounds 2 and 3. Compound 4 was isolated as a yellow microcrystalline material (mp 168−170 °C). The IR spectrum had conjugated carbonyl (1651 cm−1) and OH (3305 cm−1) bands, and the HRESI mass spectrum yielded the molecular formula of C20H16O5. The NMR spectra of 4 were similar to those of 3, except for the presence of a double bond instead of signals of a methylene and an oxymethine. This suggested that compound 4 was a dehydration product of 3. Analyses of 2D NMR spectra confirmed the structure of 4. This compound was previously synthesized,20 but had not been reported from a natural source. It was named macakurzin C. The isolates (1−13) were evaluated for their acetylcholinesterase inhibitory activity. Compound 6 (trans-3,5-dimethoxystilbene) had an IC50 of 9 μM, followed by 8 (IC50 18 μM), 7 (IC50 19 μM), 4 (IC50 20 μM), 9 (IC50 23 μM), and 1 (IC50 42 μM). Tacrine, used as positive control, had an IC50 of 50 nM. Compound 6 has been found elsewhere; however, this is the first report for its AChE inhibitory activity. Comparison of activity between 5 and 6 suggested that trans-configuration of the double bond may be an important factor for activity of 6, as cis-3,5-dimethoxystilbene (5) was less active. Also, the double bond of the pyran ring of 4 increased activity in comparison with 3 (which gave no inhibition at 50 μM). In addition to antioxidant activity, flavonoids were found to be promising natural compounds for treating AD due to their AChE inhibition,21 and flavonoids have been of interest in AD research and treatment due to their free radical scavenging properties. The cytotoxicity of compounds 1−13 against KB cells was also examined. Compound 7 had an IC50 of 4 μM, while 11 and 3 displayed IC50 values of 10 and 13 μM, respectively. The other compounds were noncytotoxic at 20 μM. Thus, the active compounds against AchE had weak or no cytotoxicity toward the KB cell line.
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EXPERIMENTAL SECTION
General Experimental Procedures. Melting points were recorded on a Buchi B-545 instrument and are uncorrected. Optical rotations were recorded on a Polax-2L polarimeter in MeOH. UV spectra were recorded on an UV-1601 spectrometer. IR spectra were measured on a Nicolet Impact-410 FT-IR spectrometer. NMR spectra were recorded on a Bruker AM500 FT-NMR spectrometer operating at 500.13 and 125.76 MHz for 1H NMR and 13C NMR spectra, respectively. Chemical shifts are recorded in parts per million (δ) in CDCl3, CD3OD, or DMSO-d6 with TMS as an internal standard. The HMBC measurements were optimized to 7.0 Hz long-range couplings, and NOESY experiments were run with a 150 ms mixing time. Highresolution ESIMS were measured on a Varian 910 spectrometer. Plant Material. Leaves of M. kurzii were collected at Tram Tau, Yen Bai, Vietnam, in March 2001. The plant material was identified by Dr. Nguyen Quoc Binh, and a voucher specimen (VN 0810) has been deposited at the Herbarium of the Institute of Ecology and Biological Resources of the Vietnam Academy of Science and Technology, Hanoi, Vietnam. Extraction and Isolation. Dried and ground leaves of M. kurzii (1.8 kg) were extracted with ethyl acetate (4 × 3 L) at room temperature. The EtOAc extract was concentrated under reduced pressure to give a residue of 100.8 g, which was subjected to CC on silica gel and eluted with n-hexane/EtOAc (from 0% to 100% EtOAc in n-hexane) and then with EtOAc/MeOH (95:5) to yield 15 fractions, which were evaluated against AchE. Fractions 2, 3, and 6−11 were active at a concentration of 10 μg/mL. Fractions 2 and 3 were combined and subjected to CC on silica gel, eluted with gradient of nhexane/acetone, to yield cis-3,5-dimethoxystilbene (5, 8 mg). Fractions 6−8 were combined and separated on a silica gel column, eluting with B
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MHz) δ 176.4 (C, C-4), 158.7 (C, C-7), 155.4 (C, C-9), 154.6 (C, C5), 146.2 (C, C-2), 137.1 (C, C-3), 130.7 (C, C-1′), 129.9 (CH, C-4′), 128.9 (CH, C-8′), 128.4 (CH, C-3′ and C-5′), 127.5 (CH, C-2′ and C-6′), 114.3 (CH, C-7′), 104.1 (C, C-6), 104.0 (C, C-10), 94.5 (CH, C-8), 77.9 (C, C-9′), 27.8 (CH3, C-10′ and C-11′); HRESIMS m/z 337.1072 [M + H]+ (calcd 337.1076 for C20H17O5). Acetyl Cholinesterase Inhibitory Activity Testing. AChE from Electrophorus electricus (C2888) was purchased from Sigma. Inhibition of AChE activity was determined by the spectroscopic method of Ellman, using acetylthiocholine iodide as substrate, in 96-well microtiter plates. All solutions were brought to room temperature prior to use. Aliquots of 200 μL of a solution containing 640 μL of 10 mM 5,5′-dithio-bis-2-nitrobenzoic acid (DTNB) in 0.1 M sodium phosphate, pH 8.0, 19.2 mL of the same buffer, and 13 μL of a solution of AChE (100 U/mL) in water were added to each well, followed by 2 μL of a DMSO solution of the inhibitor (0.9% final volume). The reaction was initiated by adding 20 μL of acetylthiocholine iodide (7.5 mM) to each well and was followed by monitoring the appearance of the thiolate dianion produced by the reduction of DTNB at 412 nm every 13 s for 120 s at 25 °C in a Molecular Devices Spectra Max 384 Plus plate reader. Each compound was evaluated at 10 concentrations (ranging from 1 mg/mL to 0.05 μg/mL by diluting by a factor of 3). Percentage inhibition was calculated relative to a control sample of DMSO (% inhibition = [1 − (slope compd/slope DMSO)] × 100) with SoftMax Pro software. Cytotoxic Activity Assay. The human KB tumor (oral epidermoid carcinoma) cell line was obtained originally from ATCC (Manassas, VA, USA). KB cells were maintained in Dulbecco′s DMEM medium, supplemented with 10% fetal calf serum, L-glutamine (2 mM), penicillin G (100 IU/mL), streptomycin (100 μg/mL), and gentamicin (10 μg/mL). Stock solutions of compounds were prepared in DMSO/H2O (1:9), and the cytotoxicity assays were carried out in 96-well microtiter plates against KB cells (3 × 103 cells/mL). After 72 h incubation at 37 °C in air/CO2 (95:5) with or without test compounds, cell growth was estimated by colorimetric measurement of stained living cells by neutral red. Optical density was determined at 540 nm with a Titertek Multiscan photometer. The percentage cell growth inhibition or percentage cytotoxicity was calculated by the following formula: % growth inhibition = [100 − (mean OD of individual test group/mean OD of control group) × 100].
a gradient of n-hexane/acetone, to provide 10 subfractions. Subfraction 1 was subjected to CC on silica gel, using a stepwise gradient of acetone in n-hexane, to afford trans-3,5-dimethoxystilbene (6, 10 mg). Subfraction 2 was recrytallized in a mixture of n-hexane/acetone to give 3 (6 mg). Fraction 9 was crystallized from a mixture of n-hexane/ EtOAc, affording izalpinin (10, 15 mg). The filtrate was concentrated under reduced pressure, and the residue was subjected to CC on silica gel, using a stepwise gradient of MeOH in CH2Cl2, to yield 1 (9 mg), 5,7-dihydroxy-6-prenylflavanone (8, 7 mg), and glabranin (9, 5 mg). Fractions 10 and 11 were combined and recrystallized in a mixture of n-hexane/EtOAc, giving glepidotin A (11, 20 mg). The filtrate was concentrated under reduced pressure and chromatographed on a silica gel column, eluting with 5−50% MeOH in CH2Cl2 to afford 2 (5 mg), 4 (6 mg), trans-3,5-dimethoxy-2-prenylstilbene (7, 5 mg), 8prenylgalangin (12, 7 mg), and galangin (13, 10 mg). Furanokurzin (1): white, microcrystalline solid; mp 157−158 °C; UV (MeOH) λmax (log ε) 250.7 (3.62), 310.4 (3.82) nm; IR (KBr) νmax 3312, 1610, 1499, 1424, 1387, 1278, 1147, 944, 832, 743, 620, 560 cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.58 (1H, d, J = 2.0 Hz, H-8′), 7.55 (2H, d, J = 8.0 Hz, H-2′ and H-6′), 7.39 (2H, t, J = 8.0 Hz, H-3′ and H-5′), 7.31 (1H, d, J = 16.5 Hz, H-α), 7.30 (1H, t, J = 8.0 Hz, H4′), 7.20 (1H, d, J = 16.5 Hz, H-β), 7.01 (1H, d, J = 2.0 Hz, H-6), 6.96, (1H, d, J = 2.0 Hz, H-7′), 6.93, (1H, d, J = 2.0 Hz, H-4), 4.83 (1H, s, OH); 13C NMR (CDCl3, 125 MHz) δ 156.2 (C, C-3), 153.7 (C, C-5), 144.3 (CH, C-8′), 137.2 (C, C-1′), 131.2 (C, C-1), 130.9 (CH, C-β), 128.8 (CH, C-3′ and C-5′), 128.0 (CH, C-4′), 126.7 (CH, C-2′ and C-6′), 125.7 (CH, C-α), 119.9 (C, C-2), 108.8 (CH, C-6), 105.1 (CH, C-7′), 97.9 (CH, C-4); ESIMS m/z 237.0911 [M + H]+ (calcd 237.0916 for C16H13O2). Macakurzin A (2): yellow, microcrystalline solid; mp 209−210 °C; [α]30D 0.0 (c 0.6, MeOH); UV (MeOH) λmax (log ε) 270.4 (3.51), 323.2 (3.31), 361.6 (3.26) nm; IR (KBr) νmax 3293, 2918, 1641, 1599, 1481, 1311, 1167, 1056, 894, 768, 616, 465 cm−1; 1H NMR (DMSOd6, 500 MHz) δ 12.65 (1H, s, OH-5), 10.84 (1H, s, OH-7), 9.55 (1H, s, OH-3), 8.14 (2H, d, J = 7.5 Hz, H-2′ and H-6′), 7.55 (2H, t, J = 7.5 Hz, H-3′ and H-5′), 7.49 (1H, t, J = 7.5 Hz, H-4′), 6.51 (1H, s, H-8), 4.97 (1H, br s, OH-8′), 4.65 (1H, br s, Hb-10), 4.62 (1H, br s, Ha-10), 4.31 (1H, t, J = 7.0 Hz, H-8′), 2.83 (1H, dd, J = 7.0 and 13.0 Hz, Hb7′), 2.75 (1H, dd, J = 7.0 and 13.0 Hz, Ha-7′), 1.75 (3H, s, CH3-11′); 13 C NMR (DMSO-d6, 125 MHz) δ 176.2 (C, C-4), 162.8 (C, C-7), 158.3 (C, C-5), 154.3 (C, C-9), 147.9 (C, C-9′), 145.5 (C, C-2), 136.9 (C, C-3), 130.9 (C, C-1′), 129.8 (CH, C-4′), 128.4 (CH, C-3′ and C5′), 127.4 (CH, C-2′ and C-6′), 109.7 (CH2, C-10′), 108.3 (C, C-6), 102.8 (C, C-10), 92.9 (CH, C-8), 73.3 (CH, C-8′), 28.7 (CH2, C-7′), 17.1 (CH3, C-11′); HRESIMS m/z 377.1002 [M + Na]+ (calcd 377.1001 for C20H18NaO6). Macakurzin B (3): yellow, microcrystalline solid; mp 198−199 °C; [α]30D 0.0 (c 0.8, MeOH); UV (MeOH) λmax (log ε) 269.3 (3.37), 320.5 (3.15), 365.9 (3.16) nm; IR (KBr) νmax 3401, 2981, 2924, 1657, 1600, 1551, 1485, 1327, 1138, 1054, 767, 687, 611, 526 cm−1; 1H NMR (CDCl3, 500 MHz) δ 11.95 (1H, s, OH-5), 8.17 (2H, dd, J = 1.5 and 8.5 Hz, H-2′ and H-6′), 7.51 (2H, dt, J = 1.5 and 8.5 Hz, H-3′ and H-5′), 7.46 (1H, dt, J = 1.5 and 8.5 Hz, H-4′), 6.65 (1H, s, OH-3), 6.48 (1H, s, H-8), 3.90 (1H, t, J = 5.5 Hz, H-8′), 3.01 (dd, J = 5.5 and 17.0 Hz Hb-7′), 2.79 (dd, J = 5.5 and 17.0 Hz Ha-7′), 1.82 (1H, br s, OH-8′), 1.42 (3H, s, CH3-11′), 1.38 (3H, s, CH3-10′); 13C NMR (CDCl3, 125 MHz) δ 175.5 (C, C-4), 159.8 (C, C-7), 158.5 (C, C-5), 155.2 (C, C-9), 145.2 (C, C-2), 136.3 (C, C-3), 131.0 (C, C-1′), 130.2 (CH, C-4′), 128.6 (CH, C-3′ and C-5′), 127.7 (CH, C-2′ and C-6′), 103.1 (C, C-10), 102.6 (C, C-6), 95.2 (CH, C-8), 78.7 (C, C-9′), 68.9 (CH, C-8′), 25.4 (CH2, C-7′), 25.0 (CH3, C-10′), 22.0 (CH3, C-11′); HRESIMS m/z 335.1177 [M + H]+ (calcd 335.1182 for C20H20O6). Macakurzin C (4): yellow, microcrystalline solid; mp 168−170 °C; UV (MeOH) λmax (log ε) 288.5 (3.93), 346.7 (3.57) nm; IR (KBr) νmax 3305, 2926, 2983, 1651, 1592, 1551, 1484, 1310, 1163, 1037, 769, 600, 434 cm−1; 1H NMR (DMSO-d6, 500 MHz) δ 12.75 (1H, s, OH5), 9.76 (1H, s, OH-3), 8.16 (2H, d, J = 7.5 Hz, H-2′ and H-6′), 7.56 (2H, t, J = 7.5 Hz, H-3′ and H-5′), 7.50 (1H, t, J = 7.5 Hz, H-4′), 6.63 (1H, d, J = 10.0 Hz, H-7′), 6.57 (1H, s, H-8), 5.81 (1H, d, J = 10.0 Hz, H-8′), 1.44 (6H, s, CH3-10′ and CH3-11′); 13C NMR (DMSO-d6, 125
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ASSOCIATED CONTENT
S Supporting Information *
IR, UV, HRESIMS, and NMR spectra of the new compounds 1−4, Figures 1 and 2, and structures of compounds 5−13. This material is available free of charge via the Internet at http:// pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*Tel: 84 (0)4 37564995. Fax: 84 (0)4 37917054. E-mail:
[email protected] (H.D.T.M.);
[email protected] (V.C.P.). Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The authors thank Dr. N. Quoc Binh and Mc.S. D. D. Cuong, (VAST-Vietnam) for plant collection and botanical determination. The Centre National de la Recherche Scientifique (CNRS, France) is gratefully acknowledged for the FrancoVietnamese Cooperation Program and the L′Oréal-UNESCO for Women in Science Program for financial support.
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