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Synlett 2024; 35(06): 728-733
DOI: 10.1055/s-0043-1763629
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Special Issue to Celebrate the Centenary Year of Prof. Har Gobind Khorana

Regio- and Stereoselective Synthesis of 2′-Deoxy-4′-thioguanine Nucleosides: Evaluation of Anti-Hepatitis B Virus Activity and ­Cytotoxicity Leading to Improved Selectivity Index by 4′-C-Cyanation

Hiroki Kumamoto
a   Department of Pharmaceutical Sciences, Nihon Pharmaceutical University, 10281 Komuro, Inamachi, Kita-adachi-gun, Saitama 362-0806, Japan
,
Shuhei Imoto
b   Faculty of Pharmaceutical Sciences, Sojo University, 4022-1 Ikeda, Kumamoto 860-0082, Japan
,
Nobuyo Kuwata-Higashi
c   Center for Clinical Sciences, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinju-ku, Tokyo 162-8655, Japan
,
Hiroaki Mitsuya
c   Center for Clinical Sciences, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinju-ku, Tokyo 162-8655, Japan
d   Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institute of Heath, Bethesda, MD, USA
,
Kazuhiro Haraguchi∗
a   Department of Pharmaceutical Sciences, Nihon Pharmaceutical University, 10281 Komuro, Inamachi, Kita-adachi-gun, Saitama 362-0806, Japan
› Author AffiliationsFinancial support from the Japan Society for the Promotion of Science (KAKENHI No. 24590144 to K.H.) is gratefully acknowledged. The present work was supported in part by the Japan Agency for Medical Research and Development (AMED) for research on innovative development and the practical application of new drugs for hepatitis B under grants numbers JP16fk0310501 and JP19fk0310113 (K.H. and H.M.); a grant from the Japan Society for the Promotion of Sciences (H.M.); a grant from National Center for Global Health and Medicine Research Institute (H.M.); and the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health (H.M.).
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Abstract

An N 9-regio- and β-anomer-selective 4′-thioglycosidation of purine bases has been developed. The reaction between a 2-deoxy-2-iodo-4-thioribofuranosyl glycosyl donor and N-(6-chloro-9H-purin-2-yl)-2-methylpropanamide gave the corresponding 2′-deoxy-4′-thiopurine nucleoside in 87% yield along with its N 7-regioisomer in 6% yield, without the formation of the α-anomer. By using a derivative obtained from 17, a practical chemical synthesis of 2′-deoxy-4′-thioguanosine was developed. 4′-α-C-Cyano-2′-deoxy-4′-thioguanosine was synthesized, starting from a 4-(acetoxymethyl)-2-deoxy-2-iodo-4-thioribofuranose derivative as a glycosyl donor. An evaluation of the anti-hepatitis B virus (HBV) activity and the cytotoxicity toward the host cell revealed that 4'-C-cyano-2'-deoxy-4'-thioguanosine exhibited about 100 times more potent anti-HBV activity than 2′-deoxy-4′-thioguanosine with a comparative cytotoxicity, resulting in the identification of a novel molecule having better selectivity index value than that of 2′-deoxy-4′-thioguanosine. This finding might provide a guideline for the development of the next generation of anti-HBV agents.

Keywords

nucleosides - glycals - deoxythioguanosine - medicinal chemistry - cytotoxicity - hepatitis B virus

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0043-1763629.
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Publication History

Received: 29 July 2023

Accepted after revision: 30 October 2023

Article published online:
05 December 2023

© 2023. Thieme. All rights reserved

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  • 14 Purines 17 and 18 N,O-Bis(trimethylsilyl)acetamide (0.22 mL, 0.90 mmol) was added to a suspension of 16 (215.7 mg, 0.90 mmol) in MeCN (5.0 mL) at rt under Ar, and the mixture was stirred for 1 h. A solution of 15 (360.4 mg, 0.60 mmol) in MeCN (7.0 mL)–CH2Cl2 (4.0 mL) and TMSOTf (0.22 mL, 1.20 mmol) were added sequentially at –10 °C under Ar. The resulting mixture was stirred at –10 °C for 1 h, 0 °C for 1 h, and r.t. overnight. The mixture was then partitioned between CHCl3 and sat. aq NaHCO3, and the organic layer was subjected to column chromatography [silica gel, hexane–EtOAc (7:1)] to give 17 as a colorless foam [yield: 387.6 mg (87%)] and 18 as a colorless syrup [yield: 21.4 mg (6%)]. 17 1H NMR (500 MHz, CDCl3): δ = 0.86–0.90 and 1.07–1.14 (both m, 28 H, Si-i-Pr), 1.32 and 1.33 [both d, J CH,CH3 = 3.5 Hz, 6 H, CH(CH3)2], 3.41–3.42 [br s, 1 H, CH(CH3)2], 3.61 (dd, J 2′,3′ = 4.6 and J 3′,4′ = 8.6 Hz, 1 H, H-3′), 3.76 (ddd, J 3′,4′ = 8.6, J 4′,5′a = 1.7 and J 4′,5′b = 2.9 Hz, 1 H, H-4′), 4.08 (dd, J 4′,5′a = 1.7 and J 5′a,5′b = 12.6 Hz, 1 H, CH2a-5′), 4.18 (dd, J 4′,5′b = 2.9 and J 5′a,5′b = 12.6 Hz, 1 H, CH2b-5′), 4.73 (d, J 2′,3′ = 4.6 Hz, 1 H, H-2′), 6.16 (s, 1 H, H-1′), 8.24 (br s, 1 H, NH), 8.66 (s, 1 H, H-8). NOE experiment: H-8/H-2′ and H-1′/H-4′. 13C NMR (125 MHz, CDCl3): δ = 12.6, 13.1, 13.2, 13.3, 16.88, 16.93, 17.0, 17.31, 17.33, 17.5, 19.1, 19.2, 35.2, 37.7, 53.6, 58.2, 64.6, 71.9, 128.5, 143.3, 151.8, 152.0, 152.2, 176.8. HMBC experiment: C-4/H-1′. ESI-MS: m/z = 762 [M + Na]+. ESI-HRMS: m/z [M + Na]+ calcd for C26H43ClIN5NaO4SSi2: 762.11997; found: 762.11896. UV (MeOH): λmax 290, 263, 230 nm; λmin 272 and 248 nm. 18 1H NMR (500 MHz, CDCl3): δ = 0.79–0.85 and 1.07–1.20 (both m, 28 H, Si-i-Pr), 1.29 [d, J CH,CH3 = 6.9 Hz, 6 H, CH(CH3)2]. 3.12–3.25 [m, 1 H, CH(CH3)2], 3.52 (dd, J 2′,3′ = 4.0 and J 3′,4′ = 9.2 Hz, 1 H, H-3′), 3.74 (dd, J 3′,4′ = 9.2 and J 4′,5′b = 2.3 Hz, 1 H, H-4′), 4.13 (d, J 5′a,5′b = 13.2 Hz, 1 H, CH2a-5′), 4.21 (dd, J 4′,5′b = 2.3 and J 5′a,5′b = 13.2 Hz, 1 H, CH2b-5′), 4.53 (d, J 2′,3′ = 4.0 Hz, 1 H, H-2′), 6.40 (s, 1 H, H-1′), 8.13 (br s, 1 H, NH), 9.25 (s, 1 H, H-8). NOE experiment: H-8/ H-2′ and H-1′/H-4′. 13C NMR (125 MHz, CDCl3): δ = 12.6, 13.1, 13.2, 13.3, 16.8, 16.88, 16.93, 17.27, 17.35, 17.5, 19.19, 19.22, 35.6, 39.4, 53.5, 57.9, 66.5, 71.0, 118.8, 143.2, 149.0, 152.7, 163.9, 176.2. HMBC experiment: C-5/H-1′. ESI-MS: m/z = 762 [M + Na]+. ESI-HRMS: m/z [M + Na]+ calcd for C26H43ClIN5NaO4SSi2: 762.11997; found: 762.11788. UV (MeOH): λmax 298 and 236 nm, λmin 275 nm.
  • 15 Purines 21 and 22 N,O-Bis(trimethylsilyl)acetamide (0.24 mL, 0.99 mmol) was added to a suspension of 16 (237.3 mg, 0.99 mmol) in MeCN (6.0 mL) at r.t. under Ar, and the mixture was stirred for 1 h. A solution of 20 (448.3 mg, 0.66 mmol) in MeCN (5.0 mL)–CH2Cl2 (3.0 mL) and TMSOTf (0.36 mL, 1.98 mmol) were added sequentially at –10 °C under Ar. The resulting mixture was stirred at –10 °C for 1 h, 0 °C for 1 h, and r.t. overnight. The mixture was partitioned between CHCl3 and sat. aq NaHCO3, and the organic layer was subjected to column chromatography [silica gel, hexane–EtOAc (4:1 to 2:1)] to give 21 as a colorless foam [yield: 387.1 mg, (72%)] and 22 as a colorless syrup [yield: 37.2 mg (7%)]. 21 1H NMR (500 MHz, CDCl3): δ = 0.90–0.97 and 1.03–1.12 (both m, 28 H, Si-i-Pr), 1.29 and 1.30 [both d, J CH,Me = 3.5 Hz, 6 H, CH(CH3)2], 2.16 (s, 3 H, Ac), 3.26–3.27 [br s, 1 H, CH(CH3)2], 4.03 (d, J 5′a,5′b = 12.0 Hz, 1 H, CH2a-5′), 4.10 (d, J 5′a,5′b = 12.0 Hz, 1 H, CH2b-5′), 4.30 (d, J 2′,3′ = 6.5 Hz, 1 H, H-3′), 4.57 (d, J CH2a,CH2b = 9.8 Hz, 1 H, CH2aOAc), 5.15 (d, J CH2a,CH2b = 9.8 Hz, 1 H, CH2bOAc), 5.34 (dd, J 1′,2′ = 1.7 and J 2′,3′ = 6.5 Hz, 1 H, H-2′), 6.24 (d, J 1′ 2′ = 1.7 Hz, 1 H, H-1′), 8.12 (br s, 1 H, NH), 8.41 (s, 1 H, H-8). NOE experiment: H-8/H-2′, H-8/H-3′, H-8/CH2a-5′, H-8/CH2b-5′, H-1′/CH2b-OAc, H-2′/CH2a-5′, H-2′/CH2b-5′. 13C NMR (125 MHz, CDCl3): δ = 12.7, 12.9, 13.0, 13.1, 17.0, 17.1, 17.2, 17.3, 17.4, 19.1, 19.2, 21.0, 35.5, 36.0, 63.18, 65.0, 66.0, 67.0, 76.2, 128.7, 143.0, 151.91, 151.98, 152.2, 170.6, 176.1. ESI-MS: m/z = 834 [M + Na]+. FAB-HRMS: m/z [M + Na]+ calcd for C29H47ClIN5NaO6SSi2: 834.14110 found: 834.13980. UV(MeOH) λmax 290, 263 and 230 nm, λmin 272 and 247 nm. 22 1H NMR (500 MHz, CDCl3): δ = 0.83–0.90 and 1.01–1.13 (both m, 28 H, Si-i-Pr), 1.29 [d, J CH,CH3 = 6.9 Hz, 6 H, CH(CH3)2], 2.14 (s, 3 H, Ac), 3.09–3.16. [br s, 1 H, CH(CH3)2], 4.09 (d, J 5′a,5′b = 12.1 Hz, 1 H, CH2a-5′), 4.13 (d, J 5′a,5′b = 12.1 Hz, 1 H, CH2b-5′), 4.16 (d, J 2′,3′ = 6.3 Hz, 1 H, H-3′), 4.53 (d, J CH2a,CH2b = 11.5 Hz, 1 H, CH2aOAc), 4.75 (d, J 2′,3′ = 6.3 Hz, 1 H, H-2’), 5.28 (dd, J CH2a,CH2b = 11.5 Hz, 1 H, CH2bOAc), 6.47 (s, 1 H, H-1′), 8.14 (br s, 1 H, NH), 9.04 (s, 1 H, H-8). NOE experiment: H-8/H-2′, H-8/H-3′, H-8/CH2b-5′, H-1′/CH2b-OAc. 13C NMR (125 MHz, CDCl3): δ = 12.86, 12.90, 13.0, 13.2, 17.0, 17.06, 17.09, 17.2, 17.3, 17.4, 19.2, 20.9, 35.7, 37.2, 62.5, 66.0, 74.9, 118.8, 143.4, 148.1, 152.7, 163.9, 170.4, 175.9. ESI-MS: m/z = 834 [M+ + Na]. FAB-HRMS: m/z [M + Na]+ calcd for C29H47ClIN5NaO6SSi2: 834.14110; found: 834.13938. UV(MeOH) λmax 299 and 237 nm, λmin 275 nm.
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