Synthesis and antiviral activity of novel acyclic nucleosides: discovery of a cyclopropyl nucleoside with potent inhibitory activity against herpesviruses

Journal of Medicinal Chemistry
T SekiyamaT Tsuji

Abstract

A series of acyclic nucleosides with two hydroxymethyl groups mimicking the 3'- and 5'-hydroxyl groups of the 2'-deoxyribose moiety were prepared and evaluated for their antiherpetic activity. Among those, 9-[[cis-1', 2'-bis(hydroxymethyl)cycloprop-1'-yl]methyl]guanine (3) showed extremely potent antiviral activity against herpes simplex virus type-1 (HSV-1) with good selectivity. Both enantiomers of 3 were synthesized starting from chiral epichlorohydrins, and only one of the enantiomers with 1'S,2'R-configuration (3a) exhibited strong antiherpetic activity (IC50 of 0.020 microg/mL against HSV-1 Tomioka vs 0.81 microg/mL for acyclovir). Enantiomer 3a was also more inhibitory than acyclovir against varicella-zoster virus (VZV) but ineffective against human immunodeficiency virus (HIV). Compound 3a is phosphorylated by HSV-1 thymidine kinase (TK) very efficiently. The relationship between conformation and antiherpetic activity in this series of compounds is discussed.

References

Dec 1, 1977·Proceedings of the National Academy of Sciences of the United States of America·G B ElionH J Schaeffer
Sep 28, 1992·Journal of Medicinal Chemistry·R N ComberJ A Secrist
Jul 1, 1991·Antimicrobial Agents and Chemotherapy·T SakumaM Azuma
Apr 1, 1991·Journal of Medicinal Chemistry·G S BisacchiW A Slusarchyk
Jul 1, 1988·Antimicrobial Agents and Chemotherapy·Y NishiyamaN Shimada
Dec 1, 1988·Antimicrobial Agents and Chemotherapy·K D LakeM R Pritzker
Nov 1, 1986·The Journal of Antibiotics·N ShimadaT Takita
Sep 1, 1987·Journal of Medicinal Chemistry·M R HarndenM R Boyd
Jul 1, 1987·The Journal of Antibiotics·H HoshinoT Takeuchi
May 1, 1983·Journal of Medicinal Chemistry·J C MartinJ P Verheyden
Jul 1, 1983·Proceedings of the National Academy of Sciences of the United States of America·A K FieldR L Tolman

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Citations

Jan 13, 2001·Archives of Pharmacal Research·E Y KwakB G Choi
Oct 17, 2003·Archives of Pharmacal Research·Eun Yee KwakBo Gil Choi
Jan 4, 2003·Archives of Pharmacal Research·Min Chul KookBo Gil Choi
Aug 24, 2005·Archives of Pharmacal Research·Jin Woo KimJoon Hee Hong
Dec 10, 2003·Archives of Pharmacal Research·Min Chul Kook, Bo Gil Choi
Sep 1, 2000·Carbohydrate Research·K W Pankiewicz
Mar 31, 2000·Pharmacology & Therapeutics·J Zemlicka
Feb 12, 2002·Bioorganic & Medicinal Chemistry·Ashok K PrasadVirinder S Parmar
Apr 25, 2000·Nucleosides, Nucleotides & Nucleic Acids·C PierraC K Chu
Jun 8, 2000·Nucleosides, Nucleotides & Nucleic Acids·X F Zhu
Oct 28, 2006·Nucleosides, Nucleotides & Nucleic Acids·Aihong KimChang Hyun Oh
May 5, 2007·Nucleosides, Nucleotides & Nucleic Acids·Chang Hyun Oh, Joon Hee Hong
Dec 7, 2007·Nucleosides, Nucleotides & Nucleic Acids·Hyung Ryong MoonLak Shin Jeong
Dec 11, 2007·Nucleosides, Nucleotides & Nucleic Acids·Hyung Ryong MoonLak Shin Jeong
Mar 26, 2008·Cornea·Motoki ItahashiYoshikazu Shimomura
Jan 5, 2016·The Journal of Organic Chemistry·Piotr SzcześniakSebastian Stecko
Jun 20, 2006·Antiviral Research·Bozenna Golankiewicz, Tomasz Ostrowski
Nov 8, 2005·Nucleosides, Nucleotides & Nucleic Acids·Tomoyuki OnishiTakashi Tsuji
Nov 8, 2005·Nucleosides, Nucleotides & Nucleic Acids·Amel Hadj-BouazzaYves Champavier
Feb 6, 2017·The Journal of Organic Chemistry·Yuka KobayashiMitsuhiro Yoshimatsu
Dec 5, 2014·Acta Crystallographica. Section C, Structural Chemistry·Haozhe YangFrank Seela
May 2, 2017·Chemical & Pharmaceutical Bulletin·Norikazu SakakibaraIkuko Tsukamoto
Dec 29, 2011·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Jamal KrimJoachim W Engels
Feb 23, 2007·Organic & Biomolecular Chemistry·Ah-Young ParkLak Shin Jeong
Jul 7, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Constantin I TănaseAlexander V Slita
Apr 1, 2004·The Korean Journal of Internal Medicine·Soo-Jin ParkDae Sik Hong
Sep 21, 2001·Nucleosides, Nucleotides & Nucleic Acids·B G ChoiC K Lee
May 10, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Izabela Muszalska-KolosAgnieszka Klupczyńska
Sep 21, 2001·Nucleosides, Nucleotides & Nucleic Acids·Y R LeeH D Kim

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