Synthesis and antiviral evaluation of enantiomeric 2′,3′-dideoxy- and 2′,3′-didehydro-2′,3′-dideoxy-4′-thionucleosides

Young, Robert J.; Shaw‐Ponter, S.; Thomson, John F.; Miller, Joseph A.; Cumming, John G.; Pugh, Ashley W.; Rider, Peter

doi:10.1016/0960-894x(95)00472-6

Cited by 49 publications

(33 citation statements)

References 26 publications

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“…Examples of medicinally important fluorinated nucleosides include Gemcitabine [23], a newly approved anticancer agent; F-ddA [24], a drug currently in clinical trials against drug-resistant HIV isolates; L-FMAU[13], an anti-HBV agent with an excellent safety margin, and anti-Epstein-Barr virus (EBV) L-nucleoside with a favorable toxicity profile. In addition, carbo-Fd4C and thio-nucleoside L-S-Fd4C were reported by Schinazi and Young et al, respectively [25,26]. Since no glycosidic bond exists in carbocyclic nucleosides, these novel nucleosides should exhibit great acid stability.…”

Section: Table 2 Comparison Of L-fd4c With Other L-nucleosidesmentioning

confidence: 86%

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Comparative Evaluation of L-Fd4C and Related Nucleoside Analogs as Promising Antiviral Agents

Chen

2002

CMC

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As documented in the recent literature, there are more than 50 million people infected with HIV worldwide to date since the emergence of HIV and AIDS in the Western world in 1981. More importantly, about 7000 people die of AIDS daily with 2.5 and 2.6 millions total deaths in 1998 and 1999, respectively. On the other hand, human hepatitis B virus (HBV) is the leading cause of chronic hepatitis in the world. According to WHO executive summary, over 350 millions (approximately 5% of the world s population) people are chronically infected with HBV. There are about 1 million chronic HBV carriers in the United States. Although safe and effective vaccination for HBV is available for developing countries, there is still no effective treatment for the millions of chronically infected individuals. Consequently, long term infection with chronic HBV could lead to cirrhosis, and hepatocellular carcinoma. In light of these facts, it is evident that the discovery and development of novel antiviral agents for the treatment of HIV and HBV is an extremely important undertaking.The interest in L-nucleosides was spurred in recent years by the findings that L-nucleosides are generally endowed with lower host toxicity while maintaining good antiviral activity in comparison to their respective D-nucleosides. The recent FDA approval of Lamivudine [L-BCH 189 (3TC)] for the treatment of HIV and HBV further supports these notions. Since the discovery of Lamivudine, a large number of 2 ,3 -dideoxy (dd)- and 2 ,3 -didehydro-2 ,3 -dideoxy (D4)-L-nucleoside analogs have been synthesized and evaluated in hopes of identifying even better antiviral agents. As a result, 2 ,3 -Dideoxy-2 ,3 -didehydro-beta-L-fluorocytidine (beta-L-Fd4C) was found to be a promising new lead. The first synthesis and antiviral activity assessment of L-Fd4C were reported by Lin and Cheng et al. in 1996. Recent disclosures from several laboratories clearly demonstrated that L-Fd4C was the most potent anti-HBV agent reported to date (vs. 3TC, L-FddC, L-FMAU, etc.). In fact, L-Fd4C proved to be at least 10 times more potent than Lamivudine on HBV DNA synthesis in the hepatoma cell line HepG2 2.2.15. Compared with L-Fd4C, D-Fd4C showed similar anti-HIV activity yet reduced anti-HBV activity. 2 F-L-Fd4C exhibited excellent acid stability but reduced antiviral activity and cytotoxicity. Although L-Fd4C is converted intracellularly by cytoplasmic deoxycytidine kinase to its mono-, di- and triphosphate metabolites,43 the newly prepared bis(SATE)-L-Fd4CMP proved to be more potent against HBV yet less cytotoxic than L-Fd4C itself. The chemically synthesized L-Fd4CTP was found to be a poor substrate for human polymerase gamma. A recent report from Zhu and Cheng et al. indicated that L-Fd4C had no inhibitory effect on mitochondrial DNA synthesis at concentrations up to 10 microM. An in vivo study involving HBV-infected ducks showed that longer administration of L-Fd4C induced a sustained suppression of viremia (>95%) and of viral DNA synthesis in the liver. The same study also demo...

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Section: Table 2 Comparison Of L-fd4c With Other L-nucleosidesmentioning

confidence: 86%

“…Young et al published the synthesis and antiviral activity of this target molecule in 1995 [26]. The key intermediate, O-silylated thialactone 24, was prepared from the commercially available (R)-glycidol in three steps (Scheme 5).…”

Section: Part C: L-fd4c 5'-monophosphate and Its Neutral Prodrugsmentioning

confidence: 99%

Comparative Evaluation of L-Fd4C and Related Nucleoside Analogs as Promising Antiviral Agents

Chen

2002

CMC

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“…20 The 2 0 ,3 0 -dideoxynucleosides (ddNs) have thus far proved to be the most effective therapeutic agents against the human immunodeficiency virus (HIV) 21 and hepatitis B virus (HBV). 22,23 3 0 -Azido-2 0 ,3 0 -dideoxythymidine (AZT), 24 2 0 ,3 0 -dideoxyinosine (ddI) 25 and 2 0 ,3 0 -dideoxycytidine (ddC) 26 have also been approved for the treatment of acquired immune deficiency syndrome (AIDS).…”

Section: Introductionmentioning

confidence: 99%

Recent advances in the synthesis of fluorinated nucleosides

Qiu¹,

Xu²,

Qing³

2010

Tetrahedron

144

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“…Similarly,i ts 4'-thio analogue 1c (X = S, B = cytosine) also exhibited potent anti-HIV-1a ctivity. [6] These nucleosides are intracellularly convertedi nto their triphosphates,w hich are incorporated into the proviral DNA chain, resulting in viral DNA chain termination and/or competitive inhibition of reverse transcriptase (RT), thereby hindering normals ubstrates, nucleoside-5'-triphosphates (NTPs) from being incorporated into the proviral DNA chain. [7] Oxygen, sulfur,a nd methylene have ac hemical isosteric or bioisosteric relationship with selenium.B ased on this concept, we have recently reported various 4'-selenonucleosides with diverseb iological activities.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Anti‐HIV Activity of 5′‐Homo‐2′,3′‐dideoxy‐2′,3′‐didehydro‐4′‐selenonucleosides (5′‐Homo‐4′‐Se‐d4 Ns)

Kim

et al. 2016

Asian J Org Chem

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On the hypothesis that one carbon homologation of 4'-selenonucleosides might relieve the steric repulsion between cellular kinases and bulky selenium, 5'-homo-4'-Se-d4Ns, 3a-e,a sa nti-HIV agents were designed and synthesized stereoselectively from d-gulonic g-lactone, with the conversion of 2',3'-diol into the olefin as the key step. The anti-HIV activity of all synthesized compounds, 5'-homo-4'-Se-d4Ns, was toxicity-dependent, unlike normal4 '-Se-d4Ns, which were inactive against HIV-1. This result indicates that 5'-homo-4'-Se-d4Ns might be phosphorylated by cellulark inasesa sp er the hypothesis.

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Synthesis and antiviral evaluation of enantiomeric 2′,3′-dideoxy- and 2′,3′-didehydro-2′,3′-dideoxy-4′-thionucleosides

Cited by 49 publications

References 26 publications

Comparative Evaluation of L-Fd4C and Related Nucleoside Analogs as Promising Antiviral Agents

Comparative Evaluation of L-Fd4C and Related Nucleoside Analogs as Promising Antiviral Agents

Recent advances in the synthesis of fluorinated nucleosides

Synthesis and Anti‐HIV Activity of 5′‐Homo‐2′,3′‐dideoxy‐2′,3′‐didehydro‐4′‐selenonucleosides (5′‐Homo‐4′‐Se‐d4 Ns)

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