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

• Published in: Synlett Vol. 35; no. 6; pp. 728 - 733
• Main Authors: Kumamoto, Hiroki, Imoto, Shuhei, Kuwata-Higashi, Nobuyo, Mitsuya, Hiroaki, Haraguchi, Kazuhiro
• Format: Journal Article
• Language: English; Japanese
• Published: STUTTGART Thieme Medical Publishers 05.12.2023
• Subjects: Chemistry; Chemistry, Organic; Physical Sciences; Science & Technology; nucleosides; POTENT; ANALOGS; hepatitis B virus; deoxythioguanosine; glycals; medicinal chemistry; cytotoxicity
• ISSN: 0936-5214; 1437-2096
• DOI: 10.1055/s-0043-1763629

An N9-regio-and beta-anomer-selective 4 '-thioglycosidation of purine bases has been developed. The reaction between a 2-deoxy-2iodo-4-thioribofuranosyl glycosyl donor and N-(6-chloro-9H-purin-2-yl)-2-methylpropanamide gave the corresponding 2 '-deoxy-4 '-thiopu-rine nucleoside in 87% yield along with its N7-regioisomer in 6% yield, without the formation of the alpha-anomer. By using a derivative obtained from 17, a practical chemical synthesis of 2 '-deoxy-4 '-thioguanosine was developed. 4 '-alpha-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.