Mechanism of Antiviral Activity of 5-Ethyl-2′-Deoxyuridine

Abstract

5-Ethyl-2′-deoxyurldine (EDU) is phosphorylated to a much greater extent by herpes simplex virus (HSV)-infected Vero cells than by mock-infected cells. Within the infected cells, EDU is preferentially incorporated into viral DNA and more inhibitory to viral than cellular DNA synthesis     

Synthesis and Antiviral Activity Assay of Novel (E)-3′,5′-Diamino-5-(2-bromovinyl)-2′,3′,5′-trideoxyuridine

Abstract

(E)-3′,5′-diamino-5-(2-bromovinyl)-2′,3′,5′-trideoxyuridine (5), the diamino analogue of BVDU (1), was synthesized from BVDU. In contrast with BVDU, compound 5 did not show activity against herpes simplex virus or varicella-zoster virus.     

Microbiological synthesis of 5-ethyl- and (E)-5-(2-bromovinyl)-2′-deoxyuridine

Summary The title compounds were prepared by an enzymatic transdeoxyribosylation from 2 dGuo or 2 dThd to the respective heterocyclic bases, 5-ethyluracil and (E)-5-(2-bromovinyl)uracil, using the whole bacterial cells ofEscherichia coli as a biocatalyst.     

Synthesis and Antiviral Activity of New 5-Substituted 2′-Deoxyuridine Derivatives

New 5-azole- and 5-oxime-substituted analogues of 2′-deoxyuridine are synthesized. The analogues with azole ring manifest low toxicities and antiherpetic activities on Vero cell culture, the imidazole derivative being the most active. The inhibitory effects of oximes of 5-formyl-deoxyuridine are comparable with those of the azole-containing nucleoside analogues, although their cytotoxicities are found to be higher; oxime of 5-formyldeoxyuridine is particularly toxic. The nucleoside analogues synthesized exhibit no marked activity on cell cultures infected with various variants of poxvirus.     

Relationship Between Conformation and Antiviral Activity -IV. 5-Ethyl-2′-Deoxyurldine and 5-Ethyl-2′-Deoxycytidine +

Abstract

5-Ethyl-2′-deoxyuridine(EtdUrd), though a potent inhibitor of herpes simplex virus (HSV) replication, is rapidly catabolized to produce an inactive pyrimidine base by thymidine and/or uridine phosphorylases. 5-Ethyl-2′-deoxycytidine (EtdCyd) was synthesized to confer metabolic stability and thus improve efficacy against systemic HSV infections. EtdCyd was inactive against HSV in the presence or absence of deaminase inhibitors in VERO cells up to 2 mM. The relationship between molecular conformation and antiherpes activity for EtdUrd and EtdCyd is discussed.

     

The Synthesis and Antiviral Activity of (E)-5-(2-Nitrovinyl)uridine and (E)-5-(2-Nitrovinyl)-2′-deoxyuridine

Abstract

The protection of the sugar moiety of a 5-formyluracil nucleoside with acid-labile protecting groups allows for the deprotection of the sugar of a subsequently formed nucleoside possessing a 5-nitrovinyl side-chain. The synthesis and antiviral activity of (E) -5-(2-nitrovinyl)-uridine and (E)-5-(2-nitrovinyl)-2′-deoxyuridine are reported.     

Chemical and Enzymatic Synthesis of 2′-Deoxy-iso-inosine and Its Incorporation into DNA

Abstract

Two procedures for the preparation of 2′-deoxy-iso-inosine (1) are presented. Synthesis of 3′-phosphoramidite (7) and 3′-phosphonate (8) derivatives are described, as well as an oligodeoxynucleotide containing iso-I.     

Incorporation of shikimate and 4-(2′-carboxyphenyl)-4-oxobutyrate into phylloquinone

The patterns of incorporation of d-[G-¹⁴C]shikimate and variously labelled ¹⁴C-4-(2′-carboxy-phenyl)-4-oxobutyrate into the naphthoquinone nucleus of phylloquinone by maize shoots have been investigated. The results show that (a) the alicyclic ring and C-7 of shikimate give rise to Ring A and either C-1 or C-4, and (b) the phenyl ring, 2′-carboxy and C-4, and C-2 and -3 of 4-(2′-carboxyphenyl)-4-oxobutyrate give rise to Ring A, C-1 and -4 and C-2 and -3. Radioactivity from α-[1-¹⁴C]naphthol, 1,4-[1,4-¹⁴C]naphthoquinone and [Me-¹⁴C]menadione is not incorporated into phylloquinone to any significant extent.     

Synthesis and Antiviral Activities of Some New 5-Heteroaromatic Substituted Derivatives of 2′-Deoxyuridine

Abstract

Eight new 5-heteroaromatic substituted analogues of 2′-deoxyuridine have been synthesized and evaluated for their inhibitory properties against a panel of different viruses. Several analogues containing a substituted thiophene moiety proved to be highly selective against herpes simplex virus type 1 (HSV-1).     

Synthesis and Incorporation of 2′-O-Methyl-Pseudouridine into Oligonucleotides

Abstract

A short multigram synthesis of 2′-O-methylpseudouridine and its phosphoramidite derivative is described which avoids the use of protecting groups on the nitrogens. A binding study of oligonucleotides containing this modification suggest an increased binding affinity to RNA when compared to oligonucleotides incorporating 2′-O-methyluridine.     

Synthesis of 3′-Amino and 5′-Amino Hydantoin 2′-Deoxynucleosides

Abstract

3′-Amino and 5′-amino derivatives of hydantoin 2′-deoxynucleosides have been prepared from the corresponding 3′-phthalimido and 5′-azido nucleosides, respectively, which in turn were prepared by condensation of appropriate sugars with 5-benzylidenehydantoin. The amino nucleosides were tested for their potential activity against HIV and HSV.     

Synthesis of the Fully Protected Phosphoramidite of the Benzene-DNA Adduct,N 2-(4-Hydroxyphenyl)-2′-Deoxyguanosine and Incorporation of the Later into DNA Oligomers

N²- (4-Hydroxyphenyl)-2 ′-deoxyguanosine-5 ′-O-DMT-3 ′-phosphoramidite has been synthesized and used to incorporate the N²-(4-hydroxyphenyl)-2 ′-dG (N²-4-HOPh-dG) into DNA, using solid-state synthesis technology. The key step to obtaining the xenonucleoside is a palladium (Xantphos-chelated) catalyzed N²-arylation (Buchwald-Hartwig reaction) of a fully protected 2 ′-deoxyguanosine derivative by 4-isobutyryloxybromobenzene. The reaction proceeded in good yield and the adduct was converted to the required 5 ′-O-DMT-3 ′-O-phosphoramidite by standard methods. The latter was used to synthesize oligodeoxynucleotides in which the N²-4-HOPh-dG adduct was incorporated site-specifically. The oligomers were purified by reverse-phase HPLC. Enzymatic hydrolysis and HPLC analysis confirmed the presence of this adduct in the oligomers.     

Adducts of Mannose 6-Phosphate with 5-Iodo-2′-Deoxyuridine and 2-5A as Potential Antiviral Agents

Abstract

To examine the possibility that the mannose 6-phosphate receptor system might be capitalized upon to facilitate uptake of nucleotides or nucleotides into cell, adducts of mannose 6-phosphate with 5-iodo-2′-deoxyuridine 5′-monophosphate and with adenosine 5′-monophosphate, p5′A2′p5′A and p5′A2′p5′A2′p5′A were prepared and evaluated for their antiviral activities. The adducts with 2′,5′-oligoadenylates possessed no significant antiviral activity. The adduct with 5-iodo-2′-deoxyuridine 5′-monophosphate showed activity that could be fully explained by extracellular cleavage to free 5-iodo-2′-deoxyuridine.     

Effect of Acridine with Various Linker Arms Attached to C5 Position of 2′-Deoxyuridine on the Stability of DNA/DNA and DNA/RNA Duplexes

Abstract

Acridine-modified oligodeoxyribonucleotides (ODNs) at the C5-position of a 2′-deoxyuridine via different lengths of linker arms were synthesized. Reaction of 5-(N-aminoalkyl)carbamoylmethyl-2′-deoxyuridines with 9-phenoxyacridine gave the acridine-modified 2′-deoxyuridines which were incorporated into ODNs. The duplexes containing the acridine-modified strands and their complementary DNA or RNA were thermally more stable than that containing the unmodified strand. Thermal stability of the duplexes of the modified ODNs varied depending on the length of the linker arms.

     

Synthesis of (E)-5-(2-cIOdovinyl)-3′-0-(1-Methyl-1,4-Dihydropyridyl-3 -Carbonyl)-2′-Fluoro-2′-Deoxyuridine (Ivfru-Cds) for Brain Targetted Delivery of Ivfru,an Antiviral Nucleoside

Abstract

(E)-5-(2-lodovinyl)-2′-fluoro-3′-0-(1-methyl-1,4-dihydropyridyl-3-carbonyl)-2′-deoxyuridine (11) was synthesized for future evaluation as a lipophilic, brain-selective, pyrimidine phosphorylase-resistant, antiviral agent for the treatment of Herpes simplex encephalitis (HSE). Treatment of (E)-5-(2-iodovinyl)-2′-fluoro-2′-deoxyuridine (6) with TBDMSCI in the presence of imidazole in DMF yielded the protected 5′-O-t-butyldimethylsilyl derivative (7). Subsequent reaction with nicotinoyl chloride hydrochloride in pyridine afforded (E)-5-(-2-iodovinyl)-2′-fluoro-3′-O-(3-pyridylcarbonyl)-5′-O-t-butyldimethylsily-2′-deoxyuridine (8). Deprotection of the silyl ether moiety of 8 with n-Bu₄N⁺F^? and quaternization of the resulting 3′-O-(3-pyridylcarbonyl) derivative 9 using iodomethane afforded the corresponding 1-methylpyridinium salt 10. The latter was reduced with sodium dithionite to yield (E)-5-(2-iodovinyl)-2′-fluoro-3′-O-(1-methyl-1,4-dihydropyridyl-3-carbonyl)-2′-deoxyuridine (11).     

Conformation and Antiherpes Activity of 3′- and 5′-Azido and Amino Analogs of 5-Methoxymethyl-2′-Deoxyuridine

Abstract

The molecular conformations of 3′- and 5′-azido and amino derivatives of 5-methoxymethyl-2′-deoxyuridine, 1, were investigated by nmr. The glycosidic conformation of 5-methoxymethyl-5′-amino-2′,5′-dideoxy-uridine, 5 had a considerable population of the syn form. The 5′-derivatives show a preference for the S conformation of the furanose ring as in 1. In contrast, the 3′-derivatives show preference for the N conformation. For 5-methoxymethyl-3′-amino-2′,3′-dideoxyuridine, 3, the shift towards the N state is pH dependent. The preferred conformation for the exocyclic (C4′,C5′) side chain is g⁺ for all compounds except 5 which has a strong preference for the t rotamer (79%). Compounds 1, 3 and 5 inhibited growth of HSV-1 by 50% at 2, 18 and 70 μg/ml respectively, whereas 2 and 4 were not active up to 256 μg/ml (highest concentration tested). The compounds were not cytotoxic up to 3,000 μM.     

Synthesis and Biological Activity of BIS(Pivaloyloxymethyl) Ester of 2′-Azido-2′-Deoxyuridine 5′-Monophosphate

Abstract

Bis(pivaloyloxymethyl) ester of 2′-azido-2′-deoxyuridine 5′-monophosphate was prepared as a prodrug to generate 2′-azido-2′-deoxyuridine 5′-diphosphate inside the cell. A synthetic route utilizing stannyl phosphate was adopted in the preparation. The prodrug was evaluated for cell growth inhibition against a variety of tumor cell lines along with 2′-azido-2′-deoxyuridine and 2′-azido-2′-deoxycytidine.     

New Synthesis of 5-Carboxy-2′-deoxyuridine and Its Incorporation into Synthetic Oligonucleotides

Abstract

5-Carboxy-2′-deoxyuridine is a methyl oxidation product of thymidine. It can be formed by the menadione-mediated photosensitization of thymidine in aerated aqueous solution. Here in we present a new four-step synthesis of the 5-carboxy-2′-deoxyuridine phosphoramidite building block based on the alkaline hydrolysis of 5-trifluoromethyl-2′-deoxyuridine. The phosphoramidite derivative has been incorporated at defined sites into oligonucleotides using the solid phase synthesis approach.