Synthesis and Anti-dengue Virus Activity of 5-Ethynylimidazole-4-carboxamide (EICA) Nucleotide Prodrugs

We previously showed that 5-ethynyl-(1-β-D-ribofuranosyl)imidazole-4-carboxamide (1; EICAR) is a potent anti-dengue virus (DENV) compound but is cytotoxic to some cell lines, while its 4-thio derivative, 5-ethynyl-(4-thio-1-β-D-ribofuranosyl)imidazole-4-carboxamide (2; 4′-thioEICAR), has less cytoto...

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Published in	Chemical & pharmaceutical bulletin Vol. 70; no. 3; pp. 220 - 225
Main Authors	Nakamura, Motoki, Uemura, Kentaro, Saito-Tarashima, Noriko, Sato, Akihiko, Orba, Yasuko, Sawa, Hirofumi, Matsuda, Akira, Maenaka, Katsumi, Minakawa, Noriaki
Format	Journal Article
Language	English
Published	Japan The Pharmaceutical Society of Japan 01.03.2022 Japan Science and Technology Agency
Subjects	4′-thio-modification Antifungal agents Antiviral activity Antiviral Agents - pharmacology Antiviral drugs Bioactive compounds Biological activity Cell Line Cell lines Cytotoxicity Dengue fever dengue virus Dengue Virus - drug effects Drugs Imidazole imidazole nucleoside Imidazoles - pharmacology Kinases Nucleotides Nucleotides - pharmacology Phosphorylation prodrug Prodrugs Prodrugs - pharmacology Toxicity Virus Replication Viruses prodrug 4′-thio-modification antiviral activity dengue virus imidazole nucleoside
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Abstract	We previously showed that 5-ethynyl-(1-β-D-ribofuranosyl)imidazole-4-carboxamide (1; EICAR) is a potent anti-dengue virus (DENV) compound but is cytotoxic to some cell lines, while its 4-thio derivative, 5-ethynyl-(4-thio-1-β-D-ribofuranosyl)imidazole-4-carboxamide (2; 4′-thioEICAR), has less cytotoxicity but also less anti-DENV activity. Based on the hypothesis that the lower anti-DENV activity of 2 is due to reduced susceptibility to phosphorylation by cellular kinase(s), we investigated whether a monophosphate prodrug of 2 can improve its activity. Here, we first prepared two types of prodrug of 1, which revealed that the S-acyl-2-thioethyl (SATE) prodrug had stronger anti-DENV activity than the aryloxyphosphoramidate (so-called ProTide) prodrug. Based on these findings, we next prepared the SATE prodrug of 4′-thioEICAR 18. As expected, the resulting 18 showed potent anti-DENV activity, which was comparable to that of 1; however, its cytotoxicity was also increased relative to 2. Our findings suggest that prodrugs of 4′-thioribonucleoside derivatives such as EICAR (1) represent an effective approach to developing potent biologically active compounds; however, the balance between antiviral activity and cytotoxicity remains to be addressed.
AbstractList	We previously showed that 5-ethynyl-(1-β-D-ribofuranosyl)imidazole-4-carboxamide (1; EICAR) is a potent anti-dengue virus (DENV) compound but is cytotoxic to some cell lines, while its 4-thio derivative, 5-ethynyl-(4-thio-1-β-D-ribofuranosyl)imidazole-4-carboxamide (2; 4'-thioEICAR), has less cytotoxicity but also less anti-DENV activity. Based on the hypothesis that the lower anti-DENV activity of 2 is due to reduced susceptibility to phosphorylation by cellular kinase(s), we investigated whether a monophosphate prodrug of 2 can improve its activity. Here, we first prepared two types of prodrug of 1, which revealed that the S-acyl-2-thioethyl (SATE) prodrug had stronger anti-DENV activity than the aryloxyphosphoramidate (so-called ProTide) prodrug. Based on these findings, we next prepared the SATE prodrug of 4'-thioEICAR 18. As expected, the resulting 18 showed potent anti-DENV activity, which was comparable to that of 1; however, its cytotoxicity was also increased relative to 2. Our findings suggest that prodrugs of 4'-thioribonucleoside derivatives such as EICAR (1) represent an effective approach to developing potent biologically active compounds; however, the balance between antiviral activity and cytotoxicity remains to be addressed. We previously showed that 5-ethynyl-(1-β-D-ribofuranosyl)imidazole-4-carboxamide (1; EICAR) is a potent anti-dengue virus (DENV) compound but is cytotoxic to some cell lines, while its 4-thio derivative, 5-ethynyl-(4-thio-1-β-D-ribofuranosyl)imidazole-4-carboxamide (2; 4'-thioEICAR), has less cytotoxicity but also less anti-DENV activity. Based on the hypothesis that the lower anti-DENV activity of 2 is due to reduced susceptibility to phosphorylation by cellular kinase(s), we investigated whether a monophosphate prodrug of 2 can improve its activity. Here, we first prepared two types of prodrug of 1, which revealed that the S-acyl-2-thioethyl (SATE) prodrug had stronger anti-DENV activity than the aryloxyphosphoramidate (so-called ProTide) prodrug. Based on these findings, we next prepared the SATE prodrug of 4'-thioEICAR 18. As expected, the resulting 18 showed potent anti-DENV activity, which was comparable to that of 1; however, its cytotoxicity was also increased relative to 2. Our findings suggest that prodrugs of 4'-thioribonucleoside derivatives such as EICAR (1) represent an effective approach to developing potent biologically active compounds; however, the balance between antiviral activity and cytotoxicity remains to be addressed.We previously showed that 5-ethynyl-(1-β-D-ribofuranosyl)imidazole-4-carboxamide (1; EICAR) is a potent anti-dengue virus (DENV) compound but is cytotoxic to some cell lines, while its 4-thio derivative, 5-ethynyl-(4-thio-1-β-D-ribofuranosyl)imidazole-4-carboxamide (2; 4'-thioEICAR), has less cytotoxicity but also less anti-DENV activity. Based on the hypothesis that the lower anti-DENV activity of 2 is due to reduced susceptibility to phosphorylation by cellular kinase(s), we investigated whether a monophosphate prodrug of 2 can improve its activity. Here, we first prepared two types of prodrug of 1, which revealed that the S-acyl-2-thioethyl (SATE) prodrug had stronger anti-DENV activity than the aryloxyphosphoramidate (so-called ProTide) prodrug. Based on these findings, we next prepared the SATE prodrug of 4'-thioEICAR 18. As expected, the resulting 18 showed potent anti-DENV activity, which was comparable to that of 1; however, its cytotoxicity was also increased relative to 2. Our findings suggest that prodrugs of 4'-thioribonucleoside derivatives such as EICAR (1) represent an effective approach to developing potent biologically active compounds; however, the balance between antiviral activity and cytotoxicity remains to be addressed.
ArticleNumber	c21-01038
Author	Nakamura, Motoki Saito-Tarashima, Noriko Sato, Akihiko Minakawa, Noriaki Orba, Yasuko Uemura, Kentaro Sawa, Hirofumi Maenaka, Katsumi Matsuda, Akira
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Cites_doi	10.1002/cmdc.200700040 10.1021/jm100863x 10.1002/(SICI)1099-1344(199609)38:9<809::AID-JLCR899>3.0.CO;2-0 10.1021/acscentsci.0c00489 10.1007/978-1-4615-5381-6_139 10.1021/jo201492m 10.1016/0166-3542(92)90026-2 10.1021/jm00297a018 10.1016/j.antiviral.2018.05.003 10.1021/jm950701k 10.1016/j.bmc.2019.04.015 10.1021/jm9007856 10.1002/cmdc.200900289 10.1016/0166-3542(93)90093-X 10.1021/jo9700540 10.1248/cpb.36.2730 10.1021/cr5002035 10.1021/jm00113a016 10.1128/AAC.35.4.679 10.1021/acs.jmedchem.6b01594 10.1038/s41564-019-0476-8 10.1021/acsinfecdis.0c00829 10.1016/j.coviro.2020.07.009 10.1128/AAC.00397-19 10.1021/bi951499q 10.1039/B204993G 10.1021/acs.joc.1c01706 10.1039/C5CC00448A 10.1021/jm00106a045
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Snippet	We previously showed that 5-ethynyl-(1-β-D-ribofuranosyl)imidazole-4-carboxamide (1; EICAR) is a potent anti-dengue virus (DENV) compound but is cytotoxic to...
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StartPage	220
SubjectTerms	4′-thio-modification Antifungal agents Antiviral activity Antiviral Agents - pharmacology Antiviral drugs Bioactive compounds Biological activity Cell Line Cell lines Cytotoxicity Dengue fever dengue virus Dengue Virus - drug effects Drugs Imidazole imidazole nucleoside Imidazoles - pharmacology Kinases Nucleotides Nucleotides - pharmacology Phosphorylation prodrug Prodrugs Prodrugs - pharmacology Toxicity Virus Replication Viruses
Title	Synthesis and Anti-dengue Virus Activity of 5-Ethynylimidazole-4-carboxamide (EICA) Nucleotide Prodrugs
URI	https://www.jstage.jst.go.jp/article/cpb/70/3/70_c21-01038/_article/-char/en https://www.ncbi.nlm.nih.gov/pubmed/34955490 https://www.proquest.com/docview/2634994546 https://www.proquest.com/docview/2614756669
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ispartofPNX	Chemical and Pharmaceutical Bulletin, 2022/03/01, Vol.70(3), pp.220-225
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