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Metabolites of isocorynoxeine in rats after its oral administration a

b

a

a

Ya-Ping Chen , Min-Nan Lu , Jing-Chao Hao , Mei-Hong Li , Masao c

Hattori & Wei Wang

ac

a

School of Pharmaceutical Sciences and Yunnan Provincial Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming 650500, China b

Experiment Center for Medical Science Research, Kunming Medical University, Kunming 650500, China

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c

Division of Metabolic Engineering, Institute of Natural Medicine, University of Toyama, Sugitani 2630, Japan Published online: 30 Jan 2015.

To cite this article: Ya-Ping Chen, Min-Nan Lu, Jing-Chao Hao, Mei-Hong Li, Masao Hattori & Wei Wang (2015) Metabolites of isocorynoxeine in rats after its oral administration, Journal of Asian Natural Products Research, 17:4, 384-390, DOI: 10.1080/10286020.2014.1003182 To link to this article: http://dx.doi.org/10.1080/10286020.2014.1003182

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Journal of Asian Natural Products Research, 2015 Vol. 17, No. 4, 384–390, http://dx.doi.org/10.1080/10286020.2014.1003182

Metabolites of isocorynoxeine in rats after its oral administration Ya-Ping Chena, Min-Nan Lub, Jing-Chao Haoa, Mei-Hong Lia, Masao Hattoric* and Wei Wangac* a School of Pharmaceutical Sciences and Yunnan Provincial Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming 650500, China; bExperiment Center for Medical Science Research, Kunming Medical University, Kunming 650500, China; cDivision of Metabolic Engineering, Institute of Natural Medicine, University of Toyama, Sugitani 2630, Japan

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(Received 8 October 2013; final version received 25 December 2014) This work presents the metabolites of isocorynoxeine (ICOR), which is one of four bioactive tetracyclic oxindole alkaloids isolated from Uncaria hooks used commonly in the traditional Chinese medicines and Kampo medicines. After oral administration of 40 mg kg21 ICOR to rats, bile was drained and analyzed by LC-MS. Two phase I metabolites, namely 11-hydroxyisocorynoxeine (M1) and 10-hydroxyisocorynoxeine (M2), and two phase II metabolites, namely 11-hydroxyisocorynoxeine 11-O-b-D glucuronide (M3) and 10-hydroxyisocorynoxeine 10-O-b-D -glucuronide (M4), were isolated from rat excreta and bile, respectively, whose structures were elucidated on the basis of CD, NMR, and MS. Keywords: isocorynoxeine; metabolites; structure elucidation

1.

Introduction

Isocorynoxeine (ICOR, Figure 1(a), (b)) is one of the bioactive tetracyclic oxindole alkaloids identified in Uncaria stems and hooks, along with corynoxeine, rhynchophylline, and isorhynchophylline. The hooks are applied widely in traditional Chinese medicines formulations and Kampo medicines characterized by Chotosan and Yokukansan. It was found that ICOR is one of the active compounds reducing glutamate-induced neuronal death in cultured cerebellar granule cells.[1] ICOR was also reported to reduce the head-twitch response in reserpinized mice [2] and inhibit lipopolysaccharide-induced NO release in primary cultured rat cortical microglia.[3] Recently, ICOR was detected to be able to cross brain endothelial cells in culture conditions in vitro.[4] Lots of contributions presented LC-MS identification and determination of the alkaloids including ICOR in Uncaria plants, bio-

fluids, and tissues.[5–12] We have investigated the metabolism and pharmacokinetics of rhynchophylline and isorhynchophylline, and metabolites of corynoxeine in rats detected by LC-MS.[13–15] Until now, the biotransformation of ICOR in vivo has not been illustrated. This paper describes the metabolites of ICOR in rats after oral administration detected by optimized LCESI-ion trap MS method, and its phases I and II metabolites’ structures were elucidated by CD, NMR, and high-resolution mass spectra (HRMS).

2.

Results and discussion

Both 11-hydroxyisocorynoxeine (M1) and 10-hydroxyisocorynoxeine (M2) with molecular fragments at m/z 399 [M þ H] þ got 16 Da higher than that of ICOR. It suggested that ICOR might be monohydroxylated. The molecular formula C22H26N2O5 was assigned to M1 by HR-

*Corresponding authors. Emails: [email protected]; [email protected] q 2015 Taylor & Francis

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Journal of Asian Natural Products Research FAB-MS. The 1H and 13C NMR spectra of M1 (Table 1) resembled those of ICOR except for an aromatic region, in which an ABX-type signal appeared. M1 was determined as 11-hydroxyisocorynoxeine (Figure 1(c)) based on the HMBC spectrum, in which the proton at d 7.26 (1H, d, H-9) correlated with the carbon signal at d 55.5 (C-7). Similarly, M2 was assigned the molecular formula C22H26N2O5 based on HR-FAB-MS. The 1H and 13C NMR spectra of M2 (Table 1) were similar to those of M1 with an ABX-type signal in the aromatic region. Couplings between H-9 at d 7.24 (1H, d, J9,11 ¼ 1.2 Hz) and H-11 at d 7.10, H-11 (1H, d, J11,12 ¼ 7.6 Hz,) and H12 at d 6.84 deduced that a hydroxy group attached at C-10 in the aromatic ring. M2 was determined as 10-hydroxyisocorynoxeine (Figure 1(d)). 11-Hydroxyisocorynoxeine 11-O-b-D -glucuronide (M3) and 10hydroxyisocorynoxeine 10-O-b-D -glucuronide (M4) were speculated to be glucuronides of M1 and M2, respectively, due to LC-MS analysis which showed that the m/z difference between M3/4 and M1/2 was just the value of glucuronic acid residue C6H8O6. M3 was assigned the molecular formula C28H34N2O11 by HR-FAB-MS. The 1H and 13C NMR spectra of M3 and M4 (Table 1) resembled those of M1 and M2, respectively, except for the presence of signals due to the glucuronide moiety. The appreciable correlation between a proton signal at d 4.98 (1H, d, J ¼ 7.6 Hz, H-10 ) and a carbon signal at d 154.1 (C-11) in the HMBC experiment of M3 indicated that a glucuronic acid residue is attached to C-11 of M1. From the coupling constant 7.6 Hz of the anomeric proton, the structure of M3 was determined as 11-hydroxyisocorynoxeine 11-O-b-D -glucuronide (Figure 1(e)). Similarly, M4 was assigned the molecular formula C28H34N2O11 by HR-FAB-MS. The appreciable correlation of a proton signal at d 4.99 (1H, d, J ¼ 7.6 Hz, H-10 ) and a carbon signal at d 151.7 (C-10) in the HMBC experiment of M4 showed that a glucuronic acid residue was attached to C-

385

10 of M2. Based on the coupling constant J10 ,20 ¼ 7.6 Hz of the anomeric proton, M4 was determined as 10-hydroxyisocorynoxeine 10-O-b-D -glucuronide (Figure 1(f)). With comparison of CD spectra of ICOR and its metabolites, the absolute configurations of the asymmetric centers at C-3 and C-7 for M1 –4 were assigned to be S and S, respectively.[3,14] 3. Experimental 3.1. General experimental procedures Optical rotation was measured using a Jasco DIP-140 digital polarimeter (Jasco Co., Tokyo, Japan). Melting points were determined on a Yanaco micro-melting point apparatus (Yanaco Co., Kyoto, Japan) without correction. 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were recorded using a Jeol ECX400P spectrometer (Jeol Co., Tokyo, Japan) with CD3OD as the solvent and tetramethylsilane (TMS) as the internal standard. Chemical shifts are shown as d values in ppm relative to TMS. Coupling constants (J) are described in hertz (Hz). Singlet, doublet, multiplet, and broad types of multiplicity are shown as s, d, m, and br, respectively. High-resolution fast atom bombardment mass spectrometry (HR-FAB-MS) proceeded using a Jeol JMS-AX505HAD mass spectrometer (Jeol Co.). Circular dichroic (CD) spectra (cell length of 1 cm, volume of 2 mL, 258C) were recorded on a Jasco J-805 spectropolarimeter (Jasco Co.). 3.2. Reagents and chemicals Elution solvents for LC-MS were of HPLC grade purchased from Tedia Company, Inc., OH, USA. We isolated ICOR (1.9 g) from stems and hooks of a mixture (2 kg) of U. species including U. rhynchophylla Miquel, U. sinensis Haviland, and U. macrophylla Wallich (Rubiaceae) (Juhuacun traditional medicines market, Kunming) which were authenticated by Prof. Yi Liu in Kunming

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Intens. x10 6

EIC 383; 399; 575 ± All MS

(a) M4

0.8

M3

M2

M1

ICOR

0.6 0.4 0.2 0.0 2

0

Intens. x10 5

4

6

9

(b)

8

10

6

13 12

N1 H

16

18

H

20

O 14

CH3O

Time [min]

+MS

18

CH2

19

CH

23

1.0

14

21

3

15

1.5

12

383.0

N4 2

11

2.0

10

5

H

7

S

2.5

8

22

OCH3

16

ICOR

17

0.5

408.1

491.8 519.9

400

500

O

764.8

595.0

0.0

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100

Intens. x10 4

200

300

600

700

800

900

+MS

(c)

H

399.1 N

4 H HO

N H

3

CH2

O CH OCH3

CH3O

2

M1 O

1

335.0 367.0

175.5 0 100

Intens. x10 5 2.0

(d)

200

300

400

600

700

800

900

+MS

H

HO

500

399.1

N H

1.5

N H

1.0

CH2

O CH OCH3

CH3O

M2 0.5

O

367.0

282.8

216.6 0.0 100

Intens. x10 5

200

300

400

500

600

H

(e) 6' 5'

3'

O

O 2'

OH

N H

92.6

m/z

+MS

CH2

O CH

1'

224.8

OCH3

CH3O

M3

0.5 156.7

900

H

HOOC HO 4' HO

1.0

800

575.0

N

1.5

700

O

369.0

0.0 100

Intens. x10 5

200

300

400

500

600

700

800

900

HOOC

(f)

HO HO

0.8

O

m/z

+MS 574.9

H

O

N

OH H

0.6

N H

M4

0.4

CH2

O CH OCH3

CH3O

256.7

0.2

O

92.6

417.9 458.9518.0

650.0

0.0 100

200

300

400

500

600

700

800

900

m/z

Figure 1. ICOR and M1– 4 detected by LC-MS in rat bile collected 2– 3 h after administration (a), and their MS (b –f), respectively.

Medical University, and a portion of samples kept in the laboratory. ICOR was isolated by refluxing Uncaria hooks with

CHCl3 and purified by repeated silica gel column chromatography,[6] followed by preparative HPLC. The isolated ICOR was

182.9 74.8 57.6

35.2

55.5 129.1 121.4 110.4 153.5 109.7 140.5 28.8

42.6 116.1 161.5 134.7 143.1 42.2 58.1

171.8 49.6 63.6

6

7 8 9 10 11 12 13 14

15 16 17 18 19 20 21

22 23 – OCH3 10 20 30 40 50 60

dC

13

3.58 (3H, s) 3.78 (3H, s)

7.30 (1H, s) 4.98 (2H, dd) 5.49– 5.51 (1H, m) 2.20– 2.26 (1H, br m) 2.06 (a, 1H, dd) 3.22 (b, 1H, dd)

2.28– 2.30 (a, 1H, m) 1.12– 1.14 (b, 1H, m) 2.27– 2.29 (1H, m)

6.87 (1H, d, 1.2)

7.26 (1H, d, 8.0) 7.06 (1H, dd, 8.0, 1.2)

2.37– 2.39 (1H, m) 2.47– 2.49 (a, 1H, m) 3.25– 3.27 (b, 1H, m) 2.04– 2.07 (a, 1H, m) 2.47– 2.50 (b, 1H, m)

171.7 49.5 63.7

42.7 116.2 161.6 134.8 143.2 42.2 58.0

55.5 126.5 106.9 151.0 118.2 124.3 143.6 28.6

35.1

182.9 74.9 57.3

dC

3.62 (3H, s) 3.76 (3H, s)

7.26 (1H, s) 4.98 (2H, dd) 5.50– 5.52 (1H, m) 2.19– 2.25 (1H, br m) 2.08 (a, 1H, dd) 3.23 (b, 1H, dd)

2.29– 2.31 (a, 1H, m) 1.11– 1.14 (b, 1H, m) 2.25– 2.28 (1H, m)

7.10 (1H, dd, 1.2, 7.6) 6.84 (1H, d, 7.6)

7.24 (1H, d, 1.2)

2.38– 2.41 (1H, m) 2.49– 2.51 (a, 1H, m) 3.26– 3.28 (b, 1H, m) 2.09– 2.11 (a, 1H, m) 2.45– 2.47 (b, 1H, m)

dH (J, Hz)

M2

C (100 MHz) NMR spectral data of M1 – 4 in CD3OD.

dH (J, Hz)

M1

H (400 MHz) and

1

2 3 5

Position

Table 1.

171.8 49.6 63.6 100.8 75.1 79.0 71.7 78.5 176.6

42.6 116.2 161.5 134.7 143.1 42.4 58.2

55.5 129.2 121.2 110.6 154.1 109.9 140.3 28.8

35.2

182.9 74.8 57.6

dC

3.58 (3H, s) 3.78 (3H, s) 4.98 (1H, d, 7.6) 3.31– 3.33 (1H, m) 3.42– 3.44 (1H, m) 3.44– 3.46 (1H, m) 3.68 (1H, d, 7.6)

7.30 (1H, s) 4.98 (2H, dd) 5.49– 5.51 (1H, m) 2.20– 2.24 (1H, br m) 2.05 (a, 1H, dd) 3.22 (b, 1H, dd)

2.28– 2.30 (a, 1H, m) 1.12– 1.14 (b, 1H, m) 2.26– 2.29 (1H, m)

6.88 (1H, d, 1.2)

7.25 (1H, d, 8.0) 7.07 (1H, dd, 8.0, 1.2)

2.38– 2.40 (1H, m) 2.48– 2.51 (a, 1H, m) 3.25– 3.27 (b, 1H, m) 2.05– 2.07 (a, 1H, m) 2.47– 2.49 (b, 1H, m)

dH (J, Hz)

M3

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171.7 49.5 63.7 100.7 75.2 78.8 71.8 78.6 176.6

42.7 116.2 161.6 134.8 143.2 42.4 58.0

55.5 126.3 106.6 151.7 118.5 124.5 143.8 28.6

35.3

182.9 74.9 57.3

dC

(1H, m) (a, 1H, m) (b, 1H, m) (a, 1H, m) (b, 1H, m)

3.62 (3H, s) 3.76 (3H, s) 4.99 (1H, d, 7.6) 3.30–3.33 (1H, m) 3.43–3.45 (1H, m) 3.45–3.47 (1H, m) 3.66 (1H, d, 7.6)

7.26 (1H, s) 4.98 (2H, dd) 5.50–5.52 (1H, m) 2.19–2.24 (1H, br m) 2.07 (a, 1H, dd) 3.23 (b, 1H, dd)

2.30–2.33 (a, 1H, m) 1.10–1.13 (b, 1H, m) 2.26–2.28 (1H, m)

7.12 (1H, dd, 1.2, 7.6) 6.83 (1H, d, 7.6)

7.25 (1H, d, 1.2)

2.37–2.39 2.50–2.52 3.26–3.28 2.09–2.11 2.45–2.47

dH (J, Hz)

M4

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identified by comparing its retention time on HPLC, NMR, LC-MS, and CD spectra. ICOR (.99.0% purity confirmed by HPLC) was applied for all experiments.

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3.3.

Animals and ICOR administration

Male Wistar rats aged 9 weeks and weighing 220 ^ 5 g were obtained from the Animal Experimental Center, Kunming Medical University. The animal husbandry and experiments proceeded in this paper were approved by the Animal Care and Use Committee in Kunming Medical University. ICOR was dissolved in DMSO at a concentration of 12.0 mg mL21. The solution was administered orally to a rat at a dosage of 40.0 mg kg21 for ICOR. No appreciable side effects were evident in the rats throughout the study. 3.4. Bile drainage and preparation of biliary samples after oral administration The rats were fed for 3 days in metabolic cages with 12-h light intervals. They were fasted overnight with free access to drinking water and the fast was continued for 3 h after administration. The rats were anesthetized with 12 mg (64.8 mg mL21) of pentobarbital sodium intraperitoneally when rats were cannulated (PortexTM fine bore polythene tubing, 0.28 mm i.d. £ 0.61 mm o.d., Smiths Medical International Ltd., Kent, UK, made in Belgium).[16– 17] After the animal came back to normal physiological state, 40.0 mg kg21 ICOR was dosed by gavage. The bile was drained to sealed vials kept in an ice-water bath for 8 h after administration, during which the biliary sample was collected at 1-h interval (ca 0.6 mL h21). At each interval, 0.4 mL bile was treated, respectively, or stored at 2 228C until analysis. A 3-mL Waters Sep-Pakw Vac cartridge was washed with methanol (3.0 mL) followed by water (6.0 mL). The biliary sample was then

passed through the cartridge eluted with 3.0 mL of methanol. The eluate was concentrated under vacuum at room temperature to yield a light yellow-green residue, which was dissolved in methanol (4.0 mL) and analyzed by LC-MS. Rat bile was collected as control after administration of DMSO vehicle and processed as described above.

3.5.

Isolation of phase I metabolites

ICOR (60.0 mg kg21 at the interval of 8 h) was administered orally to four rats for 1 week. The collected feces (ca 20 g per rat in 24 h) were ground and extracted with methanol under sonication (120 W, 15 min). The methanol extract was combined with urine samples (ca 18 mL per rat in 24 h) and applied to a Diaion HP-20 column (6 cm £ 40 cm). The column was eluted with 5 L methanol and the methanol eluate was concentrated. The residues were separated by a Sephadex LH-20 column (2.5 cm £ 30 cm) eluted with methanol and purified by preparative HPLC with the following conditions: Cosmosil column, 5C18-AR-II, Waters type, 20 i.d. £ 250 mm; flow rate, 3.0 mL min21; temperature, 308C; detection, UV at 254 nm; stepwise gradient of increasing solvent B (0.01% v/v acetic acid in acetonitrile) in solvent A (0.01% v/v acetic acid) from 10% to 25% in 50 min, 25 –100% in 50 min, and kept 100% for another 20 min for elution. M1 and M2 were obtained in amounts of 8.0 mg (solvent B: 91– 95%) and 7.0 mg (solvent B: 88 –91%), respectively.

3.5.1.

Metabolite M1

>White amorphous solid, m.p. 230– 2328C (uncorrected). ½a20 D þ 110.2 (c 0.58, MeOH). For 1H and 13C NMR spectral data, see Table 1. CD (c 0.2, MeOH): D1285nm 2 3.8, D1258nm 2 10.0, D 1226nm þ 8.6. HR-FAB-MS: m/z

Journal of Asian Natural Products Research 399.1915 [M þ H] þ (calcd for C22H27N2O5, 399.1920).

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3.5.2. Metabolite M2 White amorphous solid, m.p. 226–2288C (uncorrected). ½a20 D þ 99.6 (c 0.65, MeOH). For 1H and 13C NMR spectral data, see Table 1. CD (c 0.2, MeOH): D1285nm 2 6.2, D1260nm 2 7.9, D1225nm þ 9.2. HR-FABMS: m/z 399.1914 [M þ H] þ (calcd for C22H27N2O5, 399.1920). 3.6. Isolation of phase II metabolites Rat bile was collected from 10 rats after oral ICOR administration at a dose of 60.0 mg kg21 at 8-h intervals for 24 h. The pooled bile was applied to an LH-20 column (2.5 cm £ 30 cm). The methanol eluate was subjected to preparative HPLC under the same conditions described above. M3 and M4 were obtained in amounts of 6.0 mg (solvent B: 84– 87%) and 9.0 mg (solvent B: 79 –82%), respectively. 3.6.1. Metabolite M3 White amorphous solid, m.p. 281–2838C (uncorrected). ½a22 D þ 26.8 (c 0.60, MeOH). For 1H and 13C NMR spectral data, see Table 1. CD (c 0.2, MeOH): D1286nm 2 8.6, D1258nm 2 7.8, D1224nm þ9.9. HR-FABMS: m/z 575.2239 [M þ H] þ (calcd for C28H35N2O11, 575.2241). 3.6.2. Metabolite M4 White amorphous solid, m.p. 277–2808C (uncorrected). ½a22 D þ 21.3 (c 0.65, MeOH). For 1H and 13C NMR spectral data, see Table 1. CD (c 0.2, MeOH): D1283nm 2 7.3, D1260nm 2 8.2, D1227nm þ10.5. HR-FABMS: m/z 575.2238 [M þ H] þ (calcd for C28H35N2O11, 575.2241). 3.7. LC-ESI-ion trap MS measurements Samples were analyzed by an Agilent 1100 series HPLC system coupled with a

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Bruker Daltonicsw Esquire 3000plus mass spectrometer (Bruker Daltonic Inc., Boston, MA, USA). Agilent ChemStation for the LC-MS system and Bruker Daltonics Esquire 5.1 (Esquire Control Version 5.1 and DataAnalysis Version 3.1) were applied for integrated LC-MS control and data processing. A Cosmosil packed column (5C18-MS-II, 4.6 i.d. £ 150 mm) at 308C was utilized for separation with UV detection set at 208, 230, and 254 nm simultaneously. The elution system comprised an increment of solvent B (0.01% v/v acetic acid in CH3CN) from 10% to 25% in solvent A (0.01% v/v acetic acid) within 40 min, 25– 65% within 10 min, and then to 100% within 10 min at a flow rate of 1.0 mL min21. All samples were passed through a 0.2- mm filter before analysis. The injection volume was set at 2.0 mL for LC-MS. Through a splitting device, 20% of the eluate from a diode array detector was introduced to electrospray ionization (ESI) for monitoring. The fragmentation cut-off was set at 27% of the precursor mass. The scan range of the ion trap was from m/z 50 to 1000 in the positive ion mode, setting the nebulizer at 50 psi, dry gas at 10.0 L min21, and the dry temperature at 3608C.

Funding This work was sponsored by the 44th Batch of Scientific Research Foundation for the Returned Overseas Chinese Scholars (to WW), State Education Ministry, China, also financially supported by Yunnan Provincial Research Program of Application Foundation [general grant number 2012FB154], [general grant number 2013FZ061], [general grant number 2013FB121]; Yunnan Provincial Education Bureau Research Foundation [grant number 2014Y158], [2013Y296].

Disclosure statement No potential conflict of interest was reported by the authors.

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Metabolites of isocorynoxeine in rats after its oral administration.

This work presents the metabolites of isocorynoxeine (ICOR), which is one of four bioactive tetracyclic oxindole alkaloids isolated from Uncaria hooks...
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