Synthesis of Cyclopentenyl Carbocyclic Nucleosides as Potential Antiviral Agents Against Orthopoxviruses and SARS

Cho, Jong Hyun; Bernard, Dale L; Sidwell, Robert W.; Kern, Earl R.; Chu, Chung K.

doi:10.1021/jm0509750

Cited by 133 publications

(64 citation statements)

References 42 publications

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“…None of the compounds was shown to display cytotoxicity against HEL, E 6 SM, HeLa, and Vero cells. Previously, Chu and coworkers [62] has reported the synthesis of cyclopentenyl triazole nucleosides and their antiviral activity (Scheme 21.32). The cyclopentenol 204 [17,54,55] was condensed with methyl-1H-1,2,4-triazole-3-carboxylate and methyl imidazole-4-carboxylate under the Mitsunobu conditions to give the products 205 and 206, respectively.…”

Section: Base Modificationmentioning

confidence: 99%

“…Compounds 213 and 215 displayed moderate antiviral activity against Punta Toro virus (EC 50 ¼ 2.5 mM and 65 mM, respectively), without any cytotoxicity. Compound 214 was slightly active against West Nile virus (EC 50 ¼ 11 mM), while 215 showed marginal activity against SARS CoV (EC 50 ¼ 49 mM).Scheme 21.32 Synthesis of cyclopentenyl-imidazole and triazole nucleosides[62].…”

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confidence: 99%

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Syntheses and Biological Activity of Neplanocin and Analogues

Tosh

Kim

Pal

et al. 2008

Modified Nucleosides

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IntroductionNeplanocin A (1) [1] is a carbocyclic nucleoside which is isolated from Ampullariella regularis and possesses excellent chemical and metabolic stability of the glycosidic bond ( Figure 21.1). Neplanocin A also exhibits potent biological activity such as antiviral and antitumor activities, which result from the inhibition of S-adenosyl-SAH hydrolase catalyzes the interconversion of SAH into adenosine and L-homocysteine [4], and inhibition of this enzyme leads to an accumulation of SAH and a negative inhibition of cellular S-adenosyl-L-methionine (SAM)-dependent methyltransferase ( Figure 21.2). As SAM-dependent methyltransferase is responsible for formation of the 5 0 -terminal methylated N 7 -methylguanosine cap of the mRNA in most animal-infecting viruses, SAH hydrolase is essential for viral replication [4, 5]. Thus, the inhibition of SAH hydrolase can exhibit a broad spectrum of antiviral activity [6].Neplanocin A is one of the most potent inhibitors of SAH hydrolase, and shows a strong antiviral activity against various RNA and DNA viruses. Neplanocin A inhibits SAH hydrolase by virtue of a cofactor-depleting mechanism [5,7,8], and is oxidized to its 3 0 -keto form by the enzyme-bound cofactor NAD þ , which is tightly bound to the reduced cofactor NADH, resulting in the depletion of NAD þ . However, despite its potent enzyme inhibitory activity, neplanocin A could not be developed as a clinically useful antiviral agent because it proved to be too toxic to the host cells. This toxicity was derived from the triphosphorylation of the 5 0 -hydroxyl group of neplanocin A by cellular kinases (including adenosine kinase [9, 10]), with the resultant triphosphate being incorporated into RNA and causing the inhibition of RNA synthesis [10].Aristeromycin (2) [11] is another natural product isolated from Streptomyces citricolor, and has a similar carbocyclic skeleton as neplanocin A, but is devoid of the C4 0 ¼C6 0 double bond. Like neplanocin A, aristeromycin also shows potent inhibitory activity against SAH hydrolase, but again also proved to be cytotoxic and could not be developed as an antiviral agent. The cellular toxicity of aristeromycin was Modified Nucleosides: in Biochemistry, Biotechnology and Medicine. Edited by Piet Herdewijn

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Section: Base Modificationmentioning

confidence: 99%

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confidence: 99%

Syntheses and Biological Activity of Neplanocin and Analogues

Tosh

Kim

Pal

et al. 2008

Modified Nucleosides

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“…Related approaches to carbapentofuranose derivatives have been described before. [27][28][29][30][31][32][33][34][35] …”

Section: Introductionmentioning

confidence: 99%

Carbasugar analogues of galactofuranosides: β-O-linked derivatives and towards β-S-linked derivatives

Frigell¹,

Eriksson²,

Cumpstey³

2011

Carbohydrate Research

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“…which are considered strong antiviral agents. The 1,2,3-triazole analogue of the well-known carbanucleoside Neplanocin A (5) exhibits antiviral activity [3]. In recent years, a number of carbocyclic 1,2,3-triazolo ribavirin analogues and other 1,2,3-triazolemodified derivatives have been described as important bioactive compounds [1d, 5].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Regio- and Stereoisomers of Highly Functionalized 1,2,3- Triazole-substituted Cyclopentanes

Kiss

Forró

Fülöp

2011

LOC

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Highly functionalized regio-and stereoisomers of 1,2,3-triazole-substituted cyclopentanes were prepared in six steps from either bicyclic -lactam 7 or -lactam 23 by 1,3-dipolar cycloaddition of the azido cyclopentanol intermediates with acetylenes. The reactions of azido aminocyclopentanols with non-symmetric acetylenes resulted regioselectively in the corresponding 1,4-disubstitued triazole derivatives under both thermal and Cu(I)-catalysed conditions. These compounds can be regarded as highly functionalized 1,2,3-triazole-modified carbocyclic nucleoside analogues.

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Synthesis of Cyclopentenyl Carbocyclic Nucleosides as Potential Antiviral Agents Against Orthopoxviruses and SARS

Cited by 133 publications

References 42 publications

Syntheses and Biological Activity of Neplanocin and Analogues

Syntheses and Biological Activity of Neplanocin and Analogues

Carbasugar analogues of galactofuranosides: β-O-linked derivatives and towards β-S-linked derivatives

Synthesis of Regio- and Stereoisomers of Highly Functionalized 1,2,3- Triazole-substituted Cyclopentanes

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