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

Author:

Haraguchi Kazuhiro1,Kumamoto Hiroki1,Imoto Shuhei2,Kuwata-Higashi Nobuyo3,Mitsuya Hiroaki34

Affiliation:

1. Department of Pharmaceutical Sciences, Nihon Pharmaceutical University

2. Faculty of Pharmaceutical Sciences, Sojo University

3. Center for Clinical Sciences, National Center for Global Health and Medicine

4. Experimental Retrovirology Section, HIV and AIDS Malignancy Branch

Abstract

AbstractAn 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.

Funder

Japan Society for the Promotion of Science

Japan Agency for Medical Research and Development

National Center for Global Health and Medicine Research Institute

Intramural Research Program of the Center for Cancer Research

National Cancer Institute

National Institutes of Health

Publisher

Georg Thieme Verlag KG

Subject

Organic Chemistry

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