The synthesis of the metabolites of 21,31,51-Tri-O-acetyl-N6-(3-hydroxyphenyl) adenosine (WS070117)

Article abstract of DOI:10.3390/molecules21010008

Seven metabolites of 21,31,51-tri-O-acetyl-N6-(3-hydroxyphenyl) adenosine (WS070117) were synthesized by deacetylation, hydrolysis, cyclization, sulfonylation and glycosylation reactions, respectively. All these compounds, which could be useful as material standards for metabolic research, were characterized by NMR and HPLC-MS (ESI) analyses.

Full text of DOI:10.3390/molecules21010008

Article
The Synthesis of the Metabolites of
21,31,51-Tri-O-acetyl-N6-(3-hydroxyphenyl)
Adenosine (WS070117)
Wen-Xuan Zhang, Hong-Na Wu, Bo Li, Hong-Lin Wu, Dong-Mei Wang and Song Wu *
Received: 9 November 2015 ; Accepted: 16 December 2015 ; Published: 28 December 2015
Academic Editor: Maria Emília de Sousa
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica,
Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China;
wxzhang@imm.ac.cn (W.-X.Z.); hongnawu@imm.ac.cn (H.-N.W.); bolee@imm.ac.cn (B.L.);
redwoods86@sina.com (H.-L.W.); wangdmchina@imm.ac.cn (D.-M.W.)
*
Correspondence: ws@imm.ac.cn; Tel.: +86-10-63162291
Abstract: Seven metabolites of 21,31,51-tri-O-acetyl-N6-(3-hydroxyphenyl) adenosine (WS070117)
were synthesized by deacetylation, hydrolysis, cyclization, sulfonylation and glycosylation reactions,
respectively. All these compounds, which could be useful as material standards for metabolic research,
were characterized by NMR and HPLC-MS (ESI) analyses.
Keywords: WS070117; metabolites; synthesis
1. Introduction
21,31,51-Tri-O-acetyl-N6-(3-hydroxyphenyl) adenosine (also known as WS070117) is a new
adenosine analog anti-hyperlipidemic drug candidate currently in many preclinical studies [
Guo and coworkers have investigated and elucidated the in vivo metabolites of WS070117 in rat urine
after oral administration of WS070117 by HPLC-DAD, ESI-MS and Off-Line Microprobe NMR [ ].
In the study, seven metabolites of WS070117 were observed in the HPLC trace (the metabolites
are ranked M2 M8 according to the retention time; Figure 1). The structure elucidation results
1–5].
6
–
unambiguously revealed that there are two phase I metabolites, including a deacetylation product
of WS070117 (M8) and an adenine derivative formed by the loss of ribofuranose (M7). In addition,
there are five phase II metabolites: M6 is the oxidation product of M7 at C-8; M2 and M4 are the
glycosylation products of M7 and M8 on the phenolic hydroxyl groups, respectively; M3 and M5 are
the sulfonylation products of M6 and M8, respectively. Herein, the synthesis of the above metabolites
was carried out to provide metabolites material standards for preclinical pharmacokinetic studies.
2. Results and Discussion
The metabolite M8 was prepared in quantitative yield by the hydrolysis of the acetyl groups in
WS070117 with NaOH [
7
] (Scheme 1). Treatment of WS070117 with chlorosulfonic acid [
8] afforded
the corresponding sulphonate
1, which was converted to the desired product M5 by subsequent
deacetylation with Na2CO3. Direct hydrolysis of the glycosidic bond in WS070117 with concentrated
hydrochloric acid and 95% ethanol solution at reflux smoothly afforded M7.
We initially attempted to synthesize M6 by bromination and hydrolysis reactions at C-8
of M7
Then 4,5-diamino-6-chloropyrimidine
synthesize 8-hydroxy-6-chloroadenine (
[9], but liquid bromine and NaH did not afford the needed C8-brominated adenine.
2
3
and N,N1-carbonyldiimidazole (CDI) were employed to
) [10], which could be ammoniated at C-6 to prepare M6
(Scheme 2). The amination was catalyzed by hydrochloric acid to afford the desired product in 70%
Molecules 2016, 21, 8; doi:10.3390/molecules21010008
www.mdpi.com/journal/molecules

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˝
yield at 120 C in a microwave reactor. Subsequent sulfonylation of M6 with sulfur trioxide-pyridine
complex gave the target metabolite M3.
HN
HN
OH
OH
HN
OH
OH
HN
OH
Phase II
HN
OSO3H
OH
N
N
N
N
Phase II
Phase I
N
Phase I
N
N
N
N
N
N
N
N
N
N
H
N
H
N
N
OAc
OH
OH
N
H
N
O
O
M6
M7
OAc
OAc
M3
OH
Phase II
Phase II
WS070117
Phase II
M8
OH
OH
O
HO
O
OH
COOH
HO
O
OH
COOH
HN
OSO3H
OH
HN
N
O
HN
N
N
N
N
N
N
N
N
N
H
N
M2
N
OH
OH
O
O
OH
OH
OH
M5
M4
Figure 1. The structures of the WS070117 metabolites in rat urine.
Reagents and conditions: (a) NaOH, H2O, 2 h, 99%; (b) HSO3Cl, pyridine, r.t., 12 h; (c) Na2CO3, H2O,
12 h, 66.3% for two steps; (d) HCl/95%EtOH, reflux,1 h, 92.5%.
Scheme 1. The synthesis of M5, M7 and M8.
Reagents and conditions: (a) CDI, dioxane, reflux, 6 h; (b) 3-aminophenol, HCl(aq), ethanol, MW 120 ˝C,
4 h, 70%; (c) SO3¨ pyr., pyridine, DMF, 24 h, 67.2%
Scheme 2. The synthesis of M3 and M6.

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Initially, the glycosylation reaction with tetra-O-acetyl-β-D-glucopyranuronic acid methyl ester as
the donor and WS070117 as the receptor was catalyzed by SnCl4 to synthesize M4, but the yield of the
desired product was poor, with the formation of a complex mixture of by-products. The Koenigs–Knorr
glycosylation reaction with acetobromo-α-D-glucuronic acid methyl ester as the donor was then
employed, but Ag2O failed to catalyze the reaction even at two equivalents, which may be due
to its complexation with the nitrogen-atoms. Afterwards the Schmitt glycosylation reaction was
tried with trichloroacetimidate as donor (Scheme 3). A series of conditions for selective anomeric
deacetylation of
4
were investigated, including benzylamine/DMF [11], FeCl3 6H2O/CH3CN [12]
¨
and Nd(OTf)3/CH3OH [13]. The results showed that Nd(OTf)3/CH3OH gave a cleaner reaction
in quantitative yield and the product could be used directly in the next step without purification.
Under the catalysis of BF3
¨
Et2O, trichloroacetimidate 6 reacted smoothly with WS070117 to give the
desired -glucoside due the neighboring group participation effect. After deacetylation with Cs2CO3,
β
7
M4 was obtained in 83.3% yield. However, the glycosylation reaction of M7 under the same conditions
only afforded the desired product M2 with a 25% conversion because of the poor solubility of the raw
material in dichloromethane. An alternate route such as selective hydrolysis of the N-glycoside bond
of M4 with aqueous hydrochloric acid solution afforded M2 in moderate yield.
Reagents and conditions: (a) Nd(OTf)3/CH3OH, reflux, 6 h; (b) Cl3CCN/DBU/CH2Cl2, 0 ˝C, 2 h;
(c) WS070117, BF3
Et2O, CH2Cl2, 0 ˝C,12 h, 86.7%; (d) Cs2CO3/MeOH/H2O, 40˝C, 0.5 h, 83.3%;
¨
(e) HCl/H2O, reflux, 74.1%.
Scheme 3. The synthesis of M4 and M2.
3. Materials and Methods
3.1. General Information
WS070117 was prepared in our laboratory in 98% purity. Unless otherwise indicated, all
1
commercial reagents and solvents were used without additional purification. H-NMR and 13C-NMR
spectra were recorded on a Mercury-300M (Varian, Salt Lake City, UT, USA,) or Bruker 400M (Varian)
spectrometer. Chemical shifts (in ppm) were referenced to tetramethylsilane (δ = 0) in deuterated
solvent as internal standard. HPLC-mass spectra (ESI) were recorded on an Acquity UPLC-MS system
(Waters, Milford, MA, UK). Optical rotations were recorded on p-2000 polarimeter (Jasco, Tokyo, Japan)
˝
at 20 C in 589 nm.
3.2. Synthesis of N6-(3-Hydroxyphenyl) Adenosine (M8)
NaOH (2.1 g, 52.5 mmol) was added to a stirred suspension of WS070117 (8.0 g, 16.5 mmol) in
H2O (50 mL), and the mixture was stirred at room temperature for 2 h until the disappearance of the

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˝
solid. The solution was cooled to 5 C and the precipitated solid was filtered and washed with water to
20
give M8 (5.90 g, 99%) as a white solid, rαsD
=
´
40.7 (c = 0.4, H2O), ESI/MS: 360.15 [M + H]+, 1H-NMR
(300 MHz, methanol-d4, see Supplementary Materials)
δ 8.34 (d, J = 5.0 Hz, 2H), 7.27 (t, J = 2.1 Hz, 1H),
7.15–6.99 (m, 2H), 6.52 (dt, J = 7.5, 1.8 Hz, 1H), 6.00 (d, J = 6.3 Hz, 1H), 4.77 (dd, J = 6.3, 5.1 Hz, 1H),
4.34 (dd, J = 5.1, 2.6 Hz, 1H), 4.19 (q, J = 2.6 Hz, 1H), 3.90 (dd, J = 12.6, 2.6 Hz, 1H), 3.76 (dd, J = 12.5,
2.8 Hz, 1H). 13C-NMR (100 MHz, methanol-d4)
δ 161.6, 156.5, 155.8, 152.5, 151.9, 144.8, 143.9, 133.1,
115.6, 114.4, 111.6, 93.9, 90.7, 78.1, 75.2, 66.0.
3.3. Synthesis of N6-(3-O-Sulfophenyl) Adenosine (M5)
Chlorosulfonic acid (300
µL, 4.6 mmol) was added dropwise (carefully!) into a stirred solution of
WS070117 (130 mg, 0.27 mmol) in dry pyridine (3 mL) at 0 ˝C under N2. The solution was warmed
to room temperature and stirred for 12 h. Na2CO3 (aq, 0.5 M, 20 mL) was then added to adjust the
pH to 10. The reaction mixture was stirred for another 12 h at room temperature, and the solvent was
removed in vacuo and the remaining solid was purified by Sephadex LH-20 chromatography eluting
20
with water to give M5 (78 mg, 66.3%) as a white solid, rαsD
=
´
33.5 (c = 0.15, H2O), ESI/MS: 440.10
[M + H]+, 1H-NMR (300 MHz, D2O, see Supplementary Materials)
δ
8.28 (s, 1H), 8.21 (s, 1H), 7.50 (t,
J = 3.8 Hz, 1H), 7.40 (t, J = 5.7 Hz, 2H), 7.10 (p, J = 7.7 Hz, 1H), 6.03 (dd, J = 5.9, 2.6 Hz, 1H), 4.76–4.67
(m, 1H), 4.41 (dd, J = 5.4, 3.7 Hz, 1H), 4.28 (dq, J = 6.2, 3.4 Hz, 1H), 3.93 (dd, J = 12.9, 2.94 Hz, 1H), 3.83
(dd, J = 12.9, 3.7 Hz, 1H). 13C-NMR (100 MHz, D2O)
δ180.2, 152.0, 151.5, 148.4, 140.9, 138.6, 130.1, 120.1,
117.7, 115.4, 88.5, 85.8, 73.9, 70.7, 68.0, 61.5.
3.4. Synthesis of N6-(3-Hydroxyphenyl) Adenine (M7)
Concentrated hydrochloric acid (5 mL) was added into a stirred solution of WS070117 (4.85 g,
10 mmol) in 95% ethanol (100 mL). The reaction was refluxed for 1 h and then cooled to room
temperature. The precipitated solid was filtered and washed with water to give M7 (2.1 g, 92.5%) as
a white solid, ESI/MS: 228.05 [M + H]+, 1H-NMR (300 MHz, DMSO-d6, see Supplementary Materials)
δ
11.22 (s, 1H), 9.61 (brs, 1H), 8.74 (s, 1H), 8.70 (s, 1H), 7.42 (s, 1H), 7.31 (d, J = 10.4 Hz, 1H), 7.20 (t,
J = 8.0 Hz, 1H), 6.62 (d, J = 8.0 Hz, 1H). 13C-NMR (100 MHz, DMSO-d6)
δ 158.3, 150.0, 148.9, 148.8,
143.8, 139.1, 130.1, 113.3, 112.6, 112.6, 109.0.
3.5. Synthesis of 8-Hydroxy-N6-(3-hydroxy-phenyl) Adenine (M6)
N,N1-Carbonyldiimidazole (CDI, 1.6 g, 10 mmol) was added into a stirred solution of
4,5-diamino-6-chloropyrimidine ( , 0.76 g, 5.23 mmol) in 1,4-dioxane. The reaction mixture was
refluxed for 6 h and then cooled to room temperature. The precipitated solid was filtered and washed
with water to give 8-hydroxy-6-chloroadenine ( , 700 mg). Concentrated hydrochloric acid (1 mL)
was then added into a stirred solution of intermediate (0.7 g, 4.12 mmol) and 3-aminophenol (0.7 g,
2
3
3
˝
6.42 mmol) in ethanol (20 mL) in a sealed tube, which was irradiated in a microwave reactor at 120 C
for 4 h and then cooled to room temperature. The precipitating solid was filtered and washed with
water to give M6 (0.9g, 70%) as a white solid, ESI/MS: 244.07 [M + H]+, 1H-NMR (400 MHz, DMSO-d6,
see Supplementary Materials)
δ 11.69 (s, 1H), 10.80 (s, 1H), 9.43 (s, 1H), 8.25 (s, 1H), 7.33 (s, 1H),
7.22–7.10 (m, 2H), 6.48 (d, J = 4.0 Hz, 1H). 13C-NMR (100 MHz, DMSO-d6)
δ 158.2, 152.9, 149.5, 148.1,
142.5, 140.9, 129.9, 110.8, 110.2, 107.1, 106.3.
3.6. Synthesis of 8-Hydroxy-N6-(3-O-sulfophenyl) Adenine (M3)
SO3 Pyr complex (9.54 g, 60 mmol) was added into a stirred solution of M6 (2.27 g, 9.3 mmol) in
¨
pyridine (50 mL) and DMF (50 mL) at room temperature. After 24 h, acetone (200 mL) was added and
the precipitated solid was filtered and washed with water to give M3 (2.01 g, 67.2%) as a white solid,
1H-NMR (300 MHz, DMSO-d6)
δ 8.84 (s), 8.20 (s, 1H), 7.61 (dd, J = 8.2, 2.3 Hz, 1H), 7.51 (dd, J = 2.3,
2.2 Hz, 1H), 7.18 (dd, J = 8.2 Hz, 1H), 6.77 (dd, J = 8.2, 2.2 Hz, 1H). 13C-NMR (100 MHz, DMSO-d6)
δ 154.3, 153.5, 150.7, 149.4, 142.4, 141.2, 129.3, 114.5, 114.7, 111.4, 106.3.

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3.7. Synthesis of Intermediate 7
Nd(OTf)3 (0.95 g, 1.6 mmol) was added into a stirred solution of tetra-O-acetyl-
β-
D-glucopyranuronic acid methyl ester ( , 6.0 g, 16 mmol) in methanol (200 mL). The solution was
4
refluxed for 6 h and cooled to room temperature. The solution was then concentrated in vacuo and the
residue was dissolved with CH2Cl2 (30 mL). The organic layer was washed with water, dried with
Na2SO4 and concentrated in vacuo after filtration to give an orange oil of intermediate 5. Next DBU
(0.75 mL, 5 mmol) was added dropwise into a stirred solution of the above product and Cl3CCN (8 mL)
in CH2Cl2 at 0 ˝C. The mixture was stirred for 2 h and concentrated. The residue was purified by
column chromatography (petroleum ether–ethyl acetate = 3:1) to give intermediate 6 (3.45 g).
BF3¨Et2O (1.5 mL, 15.3 mmol) was added dropwise into a stirred mixture of WS070117 (3.64 g,
7.50 mmol), intermediate
6 (5.4 g, 11.3 mmol) and 4 Å molecular sieves in CH2Cl2 (200 mL)
at 0 ˝C. The mixture was stirred for 12 h and neutralized with 2 mL Et3N. The solution was
concentrated in vacuo after filtration and the residue was purified by column chromatography
1
(CH2Cl2–MeOH = 100:1) to give intermediate
7
(5.2 g, 86.7%). ESI/MS:802.53 [M + 1]+, H-NMR
(300 MHz, DMSO-d6, see Supplementary Materials)
δ
: 10.07 (s, 1H), 8.56 (s, 1H), 8.44 (s, 1H), 7.80 (s,
1H), 7.65 (d, J = 8.2 Hz, 1H), 7.28 (t, J = 8.2 Hz, 1H), 6.71 (d, J = 9.8 Hz, 1H), 6.29 (d, J = 5.2 Hz, 1H),
6.06 (t, J = 5.6 Hz, 1H), 5.66 (dd, J = 10.7 Hz, 6.7 Hz, 2H), 5.52 (t, J = 9.6 Hz, 1H), 5.09 (m, 2H), 4.71 (d,
J = 9.9 Hz, 1H), 4.43 (m, 2H), 4.28 (m, 1H), 3.64 (s, 3H), 2.13 (s, 3H), 2.03 (m, 15H).
3.8. Synthesis of N6-(3-O-β-D-Glucuronyphenyl) Adenosine (M4)
Cs2CO3 (2.5 g, 7.7 mmol) was added into a stirred solution of intermediate
7 (4.5 g, 5.6 mmol) in
methanol (20 mL). The mixture was stirred at 40 ˝C for 0.5 h and then cooled to room temperature.
The precipitated solid was filtered, redissolved with water (2 mL), and was then cation exchange resin
was added to adjust the pH to 6–7. The solution was concentrated in vacuo after filtration to give
20
M4 (2.5 g, 83.3%) as a white solid, rαsD
=
´
51.2 (c = 0.1, H2O), ESI/MS:536.40 [M + H]+, 1H-NMR
(400 MHz, methanol-d4, see Supplementary Materials)
δ 8.42 (s, 1H), 8.38 (s, 1H), 7.95 (s, 1H), 7.37
(d, J = 8.2 Hz, 1H), 7.28 (t, J = 8.3 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H), 6.01 (d, J = 6.0 Hz, 1H), 5.01 (d,
J = 6.3 Hz, 1H), 4.77 (t, J = 5.7 Hz, 1H), 4.34 (s, 1H), 4.18 (s, 1H), 4.02 (d, J = 10.0 Hz, 1H), 3.90 (d,
J = 12.6 Hz, 1H), 3.76 (d, J = 12.5 Hz, 1H), 3.62 (d, J = 9.5 Hz, 1H), 3.53 (m, 2H). 13C-NMR (100 MHz,
methanol-d4)
δ 170.9, 158.0, 152.4, 151.8, 148.6, 140.9, 140.1, 129.1, 120.7, 114.2, 111.5, 108.8, 101.1, 89.8,
86.7, 76.0, 75.3, 74.1, 73.1, 71.7, 71.2, 62.0.
3.9. Synthesis of N6-(3-O-β-D-Glucuronyphenyl) Adenine (M2)
Concentrated hydrochloric acid (1 mL) was added into a stirred solution of M4 (1.6 g, 3 mmol)
in water (10 mL). The reaction mixture was refluxed for 1 h and then cooled to room temperature.
The precipitated solid was filtered and washed with water to give M2 (0.89 g, 74.1%) as a white
20
solid, rαsD
=
´
139.8 (c = 0.08, H2O), ESI/MS: 404.33 [M + H]+, 1H-NMR (400 MHz, DMSO-d6, see
Supplementary Materials)
δ 9.95 (brs, 1H), 8.42 (s, 1H), 8.27 (s, 1H), 7.89 (s, 1H), 7.65 (d, J = 7.2 Hz, 1H),
7.23 (t, J = 8.1 Hz, 1H), 6.70 (d, J = 7.9 Hz, 1H), 5.00 (d, J = 7.1 Hz, 1H), 3.88 (d, J = 9.0 Hz, 1H), 3.34 (m,
3H). 13C-NMR (100 MHz, DMSO-d6)
δ 170.6, 157.7, 152.0, 151.5, 141.4, 141.1, 129.6, 114.4, 110.1, 108.7,
100.5, 76.4, 76.1, 73.4, 71.9.
4. Conclusions
Seven metabolites of 21,31,51-tri-O-acetyl-N6-(3-hydroxyphenyl) adenosine (WS070117) were
successfully synthesized by deacetylation, hydrolysis, cyclization, sulfonylation and glycosylation
reactions. All these compounds were characterized by NMR and HPLC-MS (MS) analyses, and the
purities (HPLC) are all higher than 98%, so they could be used as material standards for metabolic
research on WS070117.

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Supplementary Materials: Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/21/
1/8/s1.
Acknowledgments: We thank National Major Scientific and Technological Special Project for “Significant New
Drugs Innovation” (No. 2012ZX09301002-002).
Author Contributions: Study design, experimental work and writing of first draft were performed by
Wen-Xuan Zhang. Hong-Na Wu, Bo Li and Hong-Lin Wu participated in experimental work and revision
of the first draft of paper. DongMei Wang and Song Wu participated in the revision of the manuscript and gave
good suggestions. All authors reviewed and approved the final version.
Conflicts of Interest: The authors declare no conflict of interest.
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2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access
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