Efficient Syntheses of (E)-5-(2-Bromovinyl)-2'-deoxy-4-thiouridine; A Nucleoside Analogue with Potent Biological Activity

Bašnák, I.; Otter, G. P.; Duncombe, R. J.; Westwood, Nigel; Pietrarelli, M.; Hardy, G.; Mills, G.; Rahim, S. G.; Walker, Richard

doi:10.1080/07328319808005155

Cited by 9 publications

(3 citation statements)

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“…Basnak et al [24] described the optimum method (Scheme 3-4) for the conversion of the dibenzyl-protected thioglycoside 3-21 into the desired glycosyl donor 3-3. The removal of O -benzyl groups using BBr 3 or BCl 3 a n d subsequent reprotection by p-toluoylation has been reported.…”

Section: ' or 3'-deoxy-4'-thionucleosidesmentioning

confidence: 99%

Recent Advances in 4-Thionucleosides as Potential Antiviral and Antitumor Agents

Gunaga¹,

Moon²,

Choi³

et al. 2004

CMC

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The classical 4'-oxonucleoside analogs exhibit interesting biological activities such as antibiotic, antiviral and antitumor, which are believed to be the result of inhibition of the viral or cellular DNA or RNA polymerase after being converted to their corresponding 5'-triphosphates. However, the activity of 4'-oxonucleosides were limited by their susceptibility to degradation by nucleoside phosphorylases or acid hydrolysis. This aspect called for the chemical modification of the carbohydrate portion. This compulsion led to two kinds of strategies; (1) replacement of the 4'-oxygen by the methylene group - carbocyclic nucleosides; (2) replacement of the 4' oxygen by sulphur-4'-thionucleosides. This group has also conferred the resistance to the nucleoside cleavage. Although, there were some pioneering work on 4'-thionucleosides in 1960s and 1970s, the interest in this group of compounds was rekindled by the antiviral activities of 2'-deoxy-4'-thionucleosides reported independently by Secrist et al. and Walker et al. Subsequent contributions by the other authors, enhanced its standing as an important class of antiviral agents. Following is a reasonably exhaustive account of this class of compounds reported after 1990.

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Section: ' or 3'-deoxy-4'-thionucleosidesmentioning

confidence: 99%

Recent Advances in 4-Thionucleosides as Potential Antiviral and Antitumor Agents

Gunaga¹,

Moon²,

Choi³

et al. 2004

CMC

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“…100 The L-dioxolane derivative of (E)-5-(2-bromovinyl)uracil (L-BVODDU) inhibits VZV at an EC 50 value of approximately 0.07 mg/mL. 101 S-BVDU, or (E)-5-(2-bromovinyl)-2 0 -deoxy-4 0 -thio-uridine, 102 is equipotent with BVDU (EC 50 $ 1 ng/mL against VZV). 92 The 2-deoxy-2-C-methylene derivative thereof (S-BVMDU) was found tobe active against VZVat anEC 50 of0.013 mg/mL.…”

Section: T H E ( E ) -2 -B R O M O V I N Y L C O N N E C T I O Nmentioning

confidence: 99%

(E)-5-(2-bromovinyl)-2?-deoxyuridine (BVDU)

Clercq

2005

Med. Res. Rev.

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(E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU, Brivudin, Zostex, Zerpex, Zonavir), now more than 20 years after its discovery, still stands out as a highly potent and selective inhibitor of herpes simplex virus type 1 (HSV-1) and varicella-zoster virus (VZV) infections. It has been used in the topical treatment of herpetic keratitis and recurrent herpes labialis and the systemic (oral) treatment of herpes zoster (zona, shingles). The high selectivity of BVDU towards HSV-1 and VZV depends primarily on a specific phosphorylation of BVDU to its 5'-diphosphate (DP) by the virus-encoded thymidine kinase (TK). After further phosphorylation (by cellular enzymes), to the 5'-triphosphate (TP), the compound interferes as a competitive inhibitor/alternate substrate with the viral DNA polymerase. The specific phosphorylation by the HSV- and VZV-induced TK also explains the marked cytostatic activity of BVDU against tumor cells that have been transduced by the viral TK genes. This finding offers considerable potential in a combined gene therapy/chemotherapy approach for cancer. To the extent that BVDU or its analogues (i.e., BVaraU) are degraded (by thymidine phosphorylase) to (E)-5-(2-bromovinyl)uracil (BVU), they may potentiate the anticancer potency, as well as toxicity, of 5-fluorouracil. This ensues from the direct inactivating effect of BVU on dihydropyrimidine dehydrogenase, the enzyme that initiates the degradative pathway of 5-fluorouracil. The prime determinant in the unique behavior of BVDU is its (E)-5-(2-bromovinyl) substituent. Numerous BVDU analogues have been described that, when equipped with this particular pharmacophore, demonstrate an activity spectrum characteristic of BVDU, including selective anti-VZV activity.

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“…An efficient synthesis has been reported [39]. BVDU exerts its cytotoxic effect not only by incorporation into replicating DNA, but also through inhibition of thymidylate synthase.…”

Section: Prodrugs For Thymidine Kinase (Tk)mentioning

confidence: 99%

Prodrugs for Gene‐Directed Enzyme‐Prodrug Therapy (Suicide Gene Therapy)

Denny

2003

BioMed Research International

105

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This review focuses on the prodrugs used in suicide gene therapy. These prodrugs need to satisfy a number of criteria. They must be efficient and selective substrates for the activating enzyme, and be metabolized to potent cytotoxins preferably able to kill cells at all stages of the cell cycle. Both prodrugs and their activated species should have good distributive properties, so that the resulting bystander effects can maximize the effectiveness of the therapy, since gene transduction efficiencies are generally low. A total of 42 prodrugs explored for use in suicide gene therapy with 12 different enzymes are discussed, particularly in terms of their physiocochemical properties. An important parameter in determining bystander effects generated by passive diffusion is the lipophilicity of the activated form, a property conveniently compared by diffusion coefficients (log P for nonionizable compounds and log D7 for compounds containing an ionizable centre). Many of the early antimetabolite-based prodrugs provide very polar activated forms that have limited abilities to diffuse across cell membranes, and rely on gap junctions between cells for their bystander effects. Several later studies have shown that more lipophilic, neutral compounds have superior diffusion-based bystander effects. Prodrugs of DNA alkylating agents, that are less cell cycle-specific than antimetabolites and more effective against noncycling tumor cells, appear in general to be more active prodrugs, requiring less prolonged dosing schedules to be effective. It is expected that continued studies to optimize the bystander effects and other properties of prodrugs and the activated species they generate will contribute to improvements in the effectiveness of suicide gene therapy.

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Efficient Syntheses of (E)-5-(2-Bromovinyl)-2'-deoxy-4-thiouridine; A Nucleoside Analogue with Potent Biological Activity

Cited by 9 publications

References 0 publications

Recent Advances in 4-Thionucleosides as Potential Antiviral and Antitumor Agents

Recent Advances in 4-Thionucleosides as Potential Antiviral and Antitumor Agents

(E)-5-(2-bromovinyl)-2?-deoxyuridine (BVDU)

Prodrugs for Gene‐Directed Enzyme‐Prodrug Therapy (Suicide Gene Therapy)

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