Quinoline Alkaloids and Anti-Platelet Aggregation Constituents from the Leaves of Melicope semecarpifolia

• Abstract
• Introduction
• Materials and Methods
• General experimental procedures
• Plant material
• Extraction and isolation
• Isolates
• Anti-platelet aggregation test
• Results and Discussion
• Acknowledgements
• References

Abstract

Three new quinoline alkaloids, melisemine, confusadine, and melicarpinone, together with twelve known compounds have been isolated from the leaves of Melicope semecarpifolia. The structures of these three compounds were determined through spectral analyses. Confusadine was demonstrated to be an anti-platelet aggregation constituent.

Introduction

Melicope semecarpifolia (Merr.) T. Hartley [Evodia merrillii Kanehira & Sasaki ex Kanehira; Melicope confusa (Merr.) Liu] is a small-to-medium-sized evergreen trifoliated tree, distributed in Taiwan and Philippines [1]. The leaves of this plant were rich in furoquinoline alkaloids, and among these alkaloids, only confusameline and evomerrine were isolated as new compounds at that time [2], [3], [4], [5]. The roots of this plant have been used as a carminative in folk medicine [6]. The major anti-platelet aggregation constituents were proved to be some furoquinolines, skimmianine (4), confusameline (5), kokusaginine (6), and haplopine (7) [5], [7]. Investigation of minor constituents and their anti-platelet aggregation activity led to the isolation and characterization of three new alkaloids, melisemine (1), confusadine (2), and melicarpinone (3), together with twelve known compounds. This paper describes the structural elucidation of 1-3 and the anti-platelet aggregation activity of the minor isolates.

Materials and Methods

General experimental procedures

All melting points were determined on a Yanaco micro-melting point apparatus and are uncorrected. IR spectra (KBr or neat) were taken on a Perkin Elmer system 2000 FT-IR spectrometer. UV spectra were obtained on a Shimadzu UV-160A spectrophotometer in EtOH. EI-mass spectra were recorded on a VG Biotech Quattro 5022 spectrometer. HR-mass spectra were recorded on a JEOL JMX-HX 110 spectrometer. NMR spectra including COSY, NOESY, HMBC and HMBC experiments were recorded on a Varian Unity 400 and Varian Inova 500 spectrometer either at 400 or 500 MHz (¹H) and 100 or 125 MHz (¹³C), and chemical shifts are given in ppm (δ) with TMS as internal standard. Silica gel (60 - 230, 230 - 400 mesh) (Merck) was used for CC and silica gel 60 F-254 (Merck) for TLC and prep. TLC. Optical rotations were measured using a Jasco DIP-370 polarimeter in CHCl₃ or MeOH.

Plant material

The leaves of M. semecarpifolia were collected from Lai-I, Pingtung County, Taiwan, in April 1998 and identified by Dr. I. S. Chen. A voucher specimen (Chen 5685) was deposited in the herbarium of the School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan, Republic of China.

Extraction and isolation

The dried leaves (11.2 kg) were extracted with cold MeOH and the extract concentrated under reduced pressure. The MeOH extract was partitioned between H₂O-CHCl₃ (1 : 1) to afford a CHCl₃-soluble fraction. Bases in the CHCl₃-soluble fraction were extracted with 2 % H₂SO₄. The acid-soluble part was basified with NH₄OH and extracted with CHCl₃ to give the basic fraction (fr. A, 32.1 g). Fr. A was washed with MeOH to yield 5 (7.5 g). The MeOH washing (19.7 g) was chromatographed over silica gel (658 g) (column 6 × 47 cm) eluting with CHCl₃, gradually increasing the solvent strength with MeOH to obtain 13 frs: fr. A1 (2500 ml, CHCl₃), fr. A2 (2500 ml, CHCl₃-MeOH, 9 : 1), fr. A3 (2500 ml, CHCl₃-MeOH, 4 : 1), fr. A4 (1000 ml, CHCl₃-MeOH, 4 : 1), fr. A5-A9 (each 1000 ml, CHCl₃-MeOH, 1 : 1), fr. A10 - A12 (each 1000 ml, MeOH), fr. A13 (5000 ml, MeOH). Fr. A3 (72.4 mg) was purified by preparative TLC (CHCl₃) to obtain 8 (6.9 mg) (R_f = 0.51). Fr. A4 (1.47 g) was rechromatographed on silica gel (48 g) eluting with CHCl₃-MeOH (1 : 0 - 1 : 1) to obtain 7 frs (each 500 ml, fr. A4 - 1 - fr. A4 - 7). Fr. A4 - 3 (267 mg) was rechromatographed on silica gel (9.3 g) using CHCl₃-MeOH (20 : 1) as eluent to give 8 frs (each 300 ml, fr. A4 - 3-1 - fr. A4 - 3-8). Fr. A4 - 3-1 (267 mg) was further purified by preparative TLC (CHCl₃-Me₂CO, 10 : 1) to obtain 13 (9.1 mg) (R_f = 0.74), 12 (6.4 mg) (R_f = 0.69) and 1 (4.5 mg) (R_f = 0.09). Fr. A4 - 3-3 (39 mg) was further purified by preparative TLC (CHCl₃-Me₂CO, 5 : 1) to obtain 11 (8.7 mg) (R_f = 0.66). Fr. A4 - 4 (285 mg) was further purified by preparative TLC (CHCl₃-MeOH, 25 : 1) to obtain 4 (28.7 mg) (R_f = 0.49) and 10 (7.5 mg) (R_f = 0.49). Fr. A5 (2.37 g) was rechromatographed on silica gel (74 g) eluting with CHCl₃-Me₂CO (5 : 1) to obtain 8 frs (each 800 ml, fr. A5 - 1 - fr. A5 - 8). Fr. A5 - 2 (276 mg) was further separated by preparative TLC (CHCl₃-Me₂CO, 10 : 1) to obtain 6 (10.8 mg) (R_f = 0.77). Fr. A5 - 4 (179 mg) was further purified by preparative TLC (benzene-EtOAc, 1 : 1) to obtain 2 (2.1 mg) (R_f = 0.76). Fr. A5 - 5 (258 mg) was further purified by preparative TLC (benzene-MeOH, 10 : 1) to obtain 7 (6.7 mg) (R_f = 0.38). Fr. A7 (927 mg) was rechromatographed on silica gel (28 g) eluting with CHCl₃-Me₂CO (1 : 0-1 : 1) to obtain 8 frs (each 500 ml, fr. A7 - 1 - fr. A7 - 8). Fr. A7 - 6 (126 mg) was further purified by preparative TLC (EtOAc-MeOH, 10 : 1) to afford 14 (4.4 mg) (R_f = 0.41). Part (208 mg) of fr. A13 (1.72 g) was further purified by preparative TLC (CHCl₃-MeOH, 3 : 1) to yield 3 (5.8 mg) (R_f = 0.53), 9 (4.6 mg) (R_f = 0.82), and 15 (5.3 mg) (R_f = 0.86).

Isolates

Melisemine (1): Pale yellow needles from CHCl₃-MeOH, m. p. 189 - 191 °C. UV: λ_max (log ε) = 219 (4.32), 235 (4.38), 260 (sh, 4.12), 316 (3.90), 387 nm (3.78). IR: ν_max = 3422 (NH), 1672 (C = O), 1626 cm^-1 (C = O). EI-MS: m/z (rel. int.) = 263 (M⁺, 77), 235 (56), 234 (100), 220 (65), 206 (54), 205 (75), 189 (15), 148 (10), 57 (15). HR-EI-MS: C₁₃H₁₃O₅N, found: 263.0796 [M]⁺, calcd: 263.0794. ¹H-NMR (CDCl₃, 400 MHz): δ = 3.96 (3H, s, OMe-6), 4.02 (3H, s, OMe-7), 4.19 (3H, s, OMe-4), 6.71 (1H, s, H-8), 7.33 (1H, s, H-5), 10.49 (1H, s, CHO-3), 11.20 (1H, br. s, NH, exchangeable with D₂O).

Confusadine (2): Colorless needles from MeOH, m. p. 144 - 146 °C. UV: λ_max (log ε) = 246 (4.83), 309 (4.03), 320 (4.05), 333 nm (sh, 3.95). IR: ν_max = 3423 (OH), 1623, 1587, 1505, 1459 cm^-1 (aromatic ring C = C stretch). FAB-MS: m/z (rel. int.) = 300 ([M + H]⁺, 81); HR-FAB-MS: C₁₇H₁₈O₄N, found: 300.1230 [M + H]⁺, calcd: 300.1236. ¹H-NMR (CDCl₃, 400 MHz): δ = 1.86 (3H, s, Me-3′), 2.42 (1H, br.s, OH-2′, exchangeable with D₂O), 4.09 (1H, dd, J = 9.6, 8.0 Hz, H-1′), 4.22 (1H, dd, J = 9.6, 3.2 Hz, H-1′), 4.44 (1H, s, OMe-4), 4.57 (1H, br.d, J = 8.0 Hz, H-2′), 5.04 (1H, s, H-4′), 5.19 (1H, s, H-4′), 7.06 (1H, d, J = 2.8 Hz, H-3), 7.13 (1H, dd, J = 9.2, 2.4 Hz, H-6), 7.33 (1H, d, J = 2.4 Hz, H-8), 7.58 (1H, d, J = 2.8 Hz, H-2), 8.17 (1H, d, J = 9.2 Hz, H-5). [α]_D ²⁷: -22.4 (c 0.11, MeOH).

Melicarpinone (3): Pale yellow needles from CHCl₃-MeOH, m. p. 145 - 147 °C. UV: λ_max (log ε) = 204 (4.32), 234 (4.42), 276 (4.48), 320 (3.86), 339 (3.61), 399 nm (4.11). IR: ν_max = 1643 cm^-1 (C = O). FAB-MS: m/z (rel. int.) = 230 ([M + H]⁺, 17); HR-FAB-MS: C₁₃H₁₂NO₃, found: 230.0810 [M + H]⁺ (100), calcd: 230.0817. ¹H-NMR (CDCl₃, 400 MHz): δ = 3.95 (3H, s, N-Me), 4.45 (3H, s, OMe-4), 6.58 (1H, d, J = 2.0 Hz, H-8), 6.96 (1H, dd, J = 9.6, 2.0 Hz, H-6), 7.12 (1H, d, J = 2.4 Hz, H-3), 7.48 (1H, d, J = 2.4 Hz, H-2), 7.97 (1H, d, J = 9.6 Hz, H-5); (CD₃OD + acetone-d₆, 500 MHz): δ = 4.04 (3H, s, N-Me), 4.57 (3H, s, OMe-4), 6.52 (1H, d, J = 1.6 Hz, H-8), 6.81 (1H, dd, J = 7.6, 1.6 Hz, H-6), 7.55 (1H, d, J = 2.0 Hz, H-3), 7.89 (1H, d, J = 2.0 Hz, H-2), 7.97 (1H, d, J = 7.6 Hz, H-5). ¹³C-NMR (CD₃OD + acetone-d₆, 125 MHz): δ = 33.5 (N-Me), 61.0 (OMe-4), 99.8 (C-3a), 100.5 (C-8), 107.4 (C-4a), 109.0 (C-3), 126.0 (C-6), 126.3 (C-5), 142.1 (C-2), 143.2 (C-8a), 158.3 (C-8b), 162.9 (C-4), 179.8 (C-7).

Edulinine (9): [α]_D ²⁵: + 25.9 (c 0.11, MeOH).

(S)-(-)-7,8-Dimethoxyplatydesmine (10): [α]_D ²⁴: -18.5 (c 0.15, CHCl₃).

Isoplatydesmine (14): [α]_D ²⁶: + 79.5 (c 0.12, CHCl₃).

Anti-platelet aggregation test

Blood was collected from the rabbit marginal vein, anticoagulated with EDTA (6 mM) and centrifuged for 10 min at 90 × g and room temperature. Platelet suspension was prepared from this EDTA-anticoagulated platelet-rich plasma according to the washing procedures described previously [8]. Platelet numbers were counted by a Coulter counter (Model ZM) and adjusted to 4.5 × 10⁸ platelets/ml. The platelet pellets were finally suspended in Tyrode’s solution of the following composition (mM): NaCl (136.8), KCl (2.8), NaHCO₃ (11.9), MgCl₂ (2.1), NaH₂PO₄ (0.33), CaCl₂ (1.0) and glucose (11.2), containing bovine serum albumin (0.35 %). Platelet aggregation was measured at 37 °C by the turbidimetric method as described by O’Brien [9] using a Chrono-log Lumi-aggregometer. The platelet suspensions were stirred at 1200 rpm. Washed rabbit platelets were preincubated with DMSO (0.5 %, control) or various concentrations of the tested compounds at 37 °C for 3 min. The inducer [thrombin (0.1 U ml^-1), arachidonic acid (AA, 100 μM), collagen (10 μg ml^-1), and PAF (2 ng/ml)] was then added to trigger the aggregation. The extent of platelet aggregation was measured as the increase of light transmission at 5 min after the addition of inducers. In order to eliminate the effect of the solvent on the aggregation, the final concentration of dimethyl sulfoxide (DMSO) was fixed at 0.5 %. Percentages of aggregation were calculated using the absorbance of platelet suspension to represent 0 % aggregation and the absorbance of Tyrode’s solution as 100 % aggregation. The Student’s t-test was used to test the significance of differences between the tested compounds and control.

Results and Discussion

Melisemine (1) was isolated as pale yellow needles. The EI-MS afforded the positive ion at m/z = 263 [M]⁺, implying a molecular formula of C₁₃H₁₃O₅N, which was confirmed by the HR-EI-MS ([M]⁺ found: 263.0796, calcd: 263.0794). The presence of a 2-quinolone system in the molecule was indicated by the UV absorptions at 219, 235, 260 sh, 316, and 387 nm [10] and an IR band at 1626 cm^-1. The IR spectrum also showed a band at 3422 cm^-1 indicating an NH group and a band at 1672 cm^-1 suggesting the presence of an α,β-unsaturated aldehyde, which was confirmed by a formyl signal at δ = 10.49 in the ¹H-NMR. The ¹H-NMR spectrum of 1 also included signals at δ = 4.19, 3.96, and 4.02, which were assigned to OMe-4, OMe-6 and OMe-7, respectively. Two singlet signals at δ = 7.33 and 6.71 were attributed to H-5 and H-8, respectively. The ¹H-NMR resonance signal for the NH group was at δ = 11.20 (1H, br. s, disappeared on addition of D₂O) and the existence of hydrogen-bonding with the neighbouring carbonyl group was further suggested. According to the above data and NOESY experiment (Fig. [1]), the structure of 1 was elucidated as 3-formyl-4,6,7- trimethoxy-2-quinolone, and named melisemine. This is the first report of the occurrence of 1 in a natural source, although it has been obtained due to autooxidation of kokusaginine by Rios et al. [10].

Confusadine (2) was obtained as colorless needles, [α]²⁵: -22.4°. The FAB-MS afforded the molecular ion [M + H]⁺ at m/z = 300, implying a molecular formula of C₁₇H₁₇O₄N which was confirmed by HR-FAB-MS ([M + H]⁺ found: 300.1230, calcd: 300.1236). The UV absorptions at 246, 309, 320 and 333 sh were similar to those of evolitrine and were characteristic of a furoquinoline nucleus [2]. The presence of a hydroxy group in the molecule was revealed by a band at 3423 cm^-1 in the IR spectrum, which was confirmed by a signal at δ = 2.42 (br.s, disappeared on addition of D₂O) in the ¹H-NMR spectrum. The ¹H-NMR spectrum of 2 was very similar to that of evolitrine except that the methoxy group (C-7) of evolitrine was replaced by a 2-hydroxy-3-methyl-3-butenyloxy group in 2. The presence of a 2-hydroxy-3-methyl- 3-butenyloxy group was clearly demonstrated from a pairs of double doublets at δ = 4.09 (J = 9.6, 8.0 Hz) and 4.22 (J = 9.6, 3.2 Hz) corresponding with the AB-part of an ABX system in a -O-CH₂-CH(OH)- moiety, and a double doublet at δ = 4.56 (J = 8.0, 3.2 Hz) showing the X-portion of the same system. In addition, the ¹H-NMR spectrum exhibited two broad singlet signals at δ = 5.04 and 5.19, typical of terminal vinylic protons, and a singlet signal at δ = 1.86 (3H) characteristic of a methyl group, suggesting the presence of a CH₂ = C(CH₃)- group. Finally, the chemical shifts of H-5 (δ = 8.17), H-6 (δ = 7.13), and H-8 (δ = 7.33) of 2 were similar to those [H-5 (δ = 8.15), H-6 (δ = 7.09), and H-8 (δ = 7.32)] of evolitrine, and different from those of pteleine [12]. Thus the inference of the side chain (2-hydroxy-3-methyl-3-butenyloxy group) being attached to C-7 was reasonable. On the basis of the above results and the NOESY experiments (Fig. [2]), the structure of this compound was elucidated as 2.

Melicarpinone (3) was isolated as pale yellow needles. The HR-FAB-MS gave an [M + H]⁺ ion peak at m/z = 230.0810 (calcd. 230.0817), consistent with a molecular formula of C₁₃H₁₁O₃N. The presence of a furoquinolinoid skeleton was indicated by the UV spectrum owning absorptions at 204, 234, 276, 320, 339 and 399 nm [2]. The presence of a conjugated carbonyl group was revealed by IR absorption at 1643 cm^-1, along with a resonance signal in the ¹³C-NMR spectrum at δ = 179.8. The ¹H-NMR spectrum (CDCl₃) of 3 showed three resonances for protons of an ABX system at δ = 7.97 (1H, d, J = 9.6 Hz), 6.96 (1H, dd, J = 9.6, 2.0 Hz), and 6.58 (1H, d, J = 2.0 Hz), which were assigned to H-5, H-6, and H-8, respectively. Two singlets at δ = 4.45 and 3.95 (each 3H) were attributed to OMe-4 and N-Me, respectively. In addition, a pair of ortho-coupled protons at δ = 7.48 and 7.12 (each 1H, d, J = 2.4 Hz) were characteristic of H-2 and H-3, respectively. On the basis of the above results, ¹H-¹H COSY and NOESY experiments (Fig. [3]), the structure of this compound was elucidated as 3, named melicarpinone. The assignment of ¹³C-NMR resonances were confirmed by the DEPT, HMQC, HMBC (Fig. [4]) techniques which also supported the structure of 3.

The known compounds including six furoquinoline alkaloids, skimmianine (4) [2], confusameline (5) [2], kokusaginine (6) [2], haplopine (7) [7], dutadrupine (8) [11], (S)-(-)-7,8-dimethoxyplatydesmine (10) [12], [13], two 2-quinolone alkaloids, edulinine (9) [14], glycocitridine (11) [15], two secofuroquinoline alkaloids, Z-dimethyl rhoifolinate (12) [16], E-dimethyl rhoifolinate (13) [16], one furoquinolin-4-one alkaloid, isoplatydesmine (14) [17] and one benzenoid, trans-methyl p-coumarate (15) [18] were readily identified by comparison of physical and spectroscopic data (UV, IR, ¹H-NMR, [α]_D, and mass spectrometry data) with the literature values.

The anti-platelet aggregation effects (Table [1]) of the isolates including 10 compounds were tested in vitro using a turbidimetric method [8], [9]. In washed rabbit platelets, thrombin (0.1 U ml^-1), arachidonic acid (AA, 100 μM), collagen (10 μg ml^-1), and PAF (2 ng/ml) all caused about 87 - 92 % aggregation. In the previous paper, it was demonstrated that the major isolates skimmianine (4) [5], [19], confusameline (5) [5], kokusaginine (6) [5], and haplopine (7) [7] possessed marked anti-platelet aggregation effects. In this study, it was found that among the tested compounds, only confusadine (2) at 50 and 100 μg ml^-1 showed marked inhibition of platelet aggregation induced by AA, collagen and PAF, and the other compounds all showed no obvious activity. This could support that the anti-platelet activity of M. semecarpifolia leaves was due to the major isolates.

Acknowledgements

This work was supported by grants from the National Science Council of the Republic of China (NSC 89-2320-B-127-009) and Tajen Institute of Technology (89 008).

References

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Prof. Dr. I. S. Chen

Graduate Institute of Pharmaceutical Sciences

Kaohsiung Medical University

Kaohsiung, Taiwan

Republic of China

Email: m635013@cc.kmu.edu.tw

Fax: +886-7-3210683

References

• 1 Chang C E, Hartley T G. Rutaceae in Flora of Taiwan. 2nd edition. Editorial Committee of the Flora of Taiwan Taipei, Taiwan; 1993 Vol. 3: 510-44
  Search in Google Scholar
• 2 Yang T H, Lu S T, Wang S J, Wang T W, Lin J H, Chen I S. Alkaloids of Melicope confusa .  Yakugaku Zasshi. 1971;  91 782-6
  PubMedSearch in Google Scholar
• 3 Tsai I L, Wu S J, Ishikawa T, Seki H, Yan S T, Chen I S. Evomerrine from Melicope semecarpifolia .  Phytochemistry. 1995;  40 1561-2
  CrossrefPubMedSearch in Google Scholar
• 4 Kang S S, Woo W S. Furoquinoline alkaloids from the leaves of Melicope confusa .  Archives of Pharmacological Research. 1986;  9 11-3
  PubMedSearch in Google Scholar
• 5 Chen K S, Chang Y L, Teng C M, Chen C F, Wu Y C. Furoquinolines with antiplatelet aggregation activity from leaves of Melicope confusa .  Planta Medica. 2000;  66 80-1
  PubMedSearch in Google Scholar
• 6 Kan W S. Manual of Medicinal Plants in Taiwan. National Research Institute of Chinese Medicine Taipei, Taiwan; 1970 Vol. 2: 374
  Search in Google Scholar
• 7 Chen I S, Wu S J, Lin Y C, Tsai I L, Seki H, Ko F N, Teng C M. Dimeric 2-quinolone alkaloid and antiplatelet aggregation constituents of Zanthoxylum simulans .  Phytochemistry. 1994;  36 237-9
  CrossrefPubMedSearch in Google Scholar
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  PubMedSearch in Google Scholar
• 9 O’Brien J R. Platelet aggregation II. Some results from a new method of study.  Journal of Clinical Pathology. 1962;  15 452-5
  PubMedSearch in Google Scholar
• 10 Rios M Y, Delgado G. Terpenoids and alkaloids from Esenbeckia belizencis. Spontaneous oxidation of furoquinoline alkaloids.  Journal of Natural Products. 1992;  55 1307-9
  CrossrefPubMedSearch in Google Scholar
• 11 Tillequin F, Baudouin G, Koch M. Synthesis of dutadrupine.  Heterocycles. 1982;  19 507-9
  PubMedSearch in Google Scholar
• 12 Chen I S, Chen H F, Cheng M J, Chang Y L, Teng C M, Ishikawa T, Chen J J, Tsai I L. Quinoline alkaloids and other constituents of Melicope semecarpifolia with antiplatelet aggregation activity.  Journal of Natural Products. 2001;  64 1143-7
  CrossrefPubMedSearch in Google Scholar
• 13 Muyard F, Bevalot F, Laude B, Vaquett J. Alkaloids from stem bark of Dutaillyea baudouinii .  Phytochemistry. 1992;  31 1087-9
  PubMedSearch in Google Scholar
• 14 Higa T, Scheuer P J. Alkaloids from Ptelea barbigera .  Phytochemistry. 1974;  13 1269-72
  CrossrefPubMedSearch in Google Scholar
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Prof. Dr. I. S. Chen

Graduate Institute of Pharmaceutical Sciences

Kaohsiung Medical University

Kaohsiung, Taiwan

Republic of China

Email: m635013@cc.kmu.edu.tw

Fax: +886-7-3210683