Antiviral iodinated pyrimidine deoxyribonucleosides: 5-iodo-2′-deoxyuridine; 5′-iodo-2′-deoxycytidine; 5-iodo-5′-amino-2′,5′-didoxyuridine

Prusoff, William H.; Chen, Ming S.; Fischer, Paul; Lin, Tsung‐I; Shiau, George T.; Schinazi, Raymond F.; Walker, Jamieson

doi:10.1016/0163-7258(79)90023-8

Cited by 38 publications

(12 citation statements)

References 193 publications

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“…These protocols would minimize the number of samples needed to determine cell-cycle parameters, thereby facilitating clinical studies on tumor proliferation. In many biological systems, BrdUrd-or IdUrd-DNA has higher affinity for chromatin proteins, including histones and regulatory proteins, than does normal DNA (20,24). It is possible that many of the effects of BrdUrd on cellular differentiation, gene expression, and sister chromatid exchanges may be mediated by this increased DNA-protein affinity.…”

Section: Discussionmentioning

confidence: 99%

Improved high‐affinity monoclonal antibody to lododeoxyuridine

et al. 1986

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Three monoclonal antibodies (Mabs), IU-1, IU-4, and B-44 were evaluated in enzyme immunoassays (ELISA) and by flow cytometry for their abilities to recognize bromodeoxyuridine (BrdUrd)-and iododeoxyuridine (1dUrd)-substituted DNA's, nucleotides, and nucleosides. IU-4 is a new Mab, derived from mice immunized with 5-iodo-2'-deoxyuridine-5'-monophosphate (IdUMP) conjugated through the phosphate group to albumin. This immunogen was selected to resemble IdUMP in DNA. In competition ELISA assays, IU-4 prefers IdUrd to BrdUrd and prefers halogenated nucleotides over the corresponding nucleosides. In both ELISA and flow analysis, IU-4 recognizes IdUrd in DNA at substitution frequencies at least as low as one IdUrd one per 1,000 normal bases. The high affinity of IU-4 for IdUrd-DNA contrasts with IU-1 and B-44, which show a strong binding dependency on the frequency of base substitution and require DNA that is essentially fully substituted with BrdUrd for binding in bath flow and ELISA assays. The high affinity of IU-4 for IdUrd in DNA and its independence of IdUrd residue spacing make it a superior reagent for the quantitative labeling of halogenated thymidine analogues in whole cells.Key terms: Fj-Rromo-Z'-deoxyuridine, flow cytometry, 5-iodo-2'-deoxyuridine, ELISA, DNA immunoassay, cell kineticsImmunoassays for DNA substituted with the halogenated nucleosides bromodeoxyuridine (BrdUrd) and iododeoxyuridine (IdUrd) are widely used in applications such as the quantification of cell cycle kinetics, the detection of unscheduled DNA synthesis, and the isolation of nascent DNA (7,15). Several monoclonal antibodies (Mabs) suitable for these assays have been reported, and all share some common developmental histories and properties (13,14,25,28,29). In all cases, the immunogen was a halogenated ribouracil conjugated to a carrier protein using the periodatehorohydride method developed by Erlanger and Beiser (11). This conjugation method changes the ribose to a six-membered ring containing nitrogen. The epitope in common with DNA is limited to the halogenated uracil. The choice of bromine or iodine in the base appears not to influence antibody specificity, since, where reported, the resulting antibodies react equally with both IdUrd and BrdUrd. The antibodies are of generally low affinity (Ka's of approximately lo6 M-for BrdUrd in solution) and only recognize the altered base in single-stranded DNA (ss-DNA), not in native DNA. For many applications, these characteristics have not been limiting, and the antibodies have found wide use.For a number of experiments, however, the antibodies are unsuitable. For example, we report here that one disadvantge of Mabs IU-1(30) and B-44 (14) is that both require a high local linear density of BrdUrd substitution in the DNA strand in order to bind. The magnitude of binding depends both on the total amount of incorporated BrdUrd as well as the spacing between BrdUrd residues. High linear density is readily obtained for assays on cell lines grown in vitro but is harder to achieve when tissues...

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Section: Discussionmentioning

confidence: 99%

Improved high‐affinity monoclonal antibody to lododeoxyuridine

et al. 1986

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“…The organic phase was washed with brine and dried (Na2SO4). The filtrate was concentrated under reduced pressure, and the residue was purified on column chromatography over silica gel (14% AcOEt in hexane) to give 9 (5.54 g, 63%, syrup): 1 …”

Section: 4-anhydro-235-tri-o-benzyl-4-thio-d-arabitol (9)mentioning

confidence: 99%

A Facile, Alternative Synthesis of 4‘-Thioarabinonucleosides and Their Biological Activities

et al. 1997

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4'-Thioarabinonucleosides, which are potential antiviral agents, were synthesized from D-glucose. 1,4-Anhydro-4-thioarabitol (8), which can be derived from diacetone glucose in nine steps, was subjected to Pummerer rearrangement after protection of the hydroxyl groups to give 1-O-acetyl-4-thioarabinose (11), which was condensed with nucleobases to give 4'-thioarabinonucleosides. The 5-substituted-4'-thioaraU (6a-e) derivatives showed anti-HSV-1 activity (ED50 = 0.43-3.50 micrograms/mL). 4'-ThioaraG (6h) and 2,6-diaminopurine 4'-thioarabinonucleoside (4'-thioaraDAP, 6g) showed antiviral activity against several herpes viruses and were particularly potent against human cytomegalovirus (0.010 and 0.022 microgram/mL, respectively).

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“…IOU is phosphorylated in virus-infected and uninfected host cells by deoxythymidine kinases and successfully competes with deoxythymidine triphosphate in the DNA synthetic pathway. It is thus incorporated into the DNA of both virus-infected and normal host cells (Prusoff et al 1979). The toxicity observed following intravenous use of this drug (mainly bone marrow depression and hepatotoxicity) is probably due to its incorporation into host DNA (Prusoff and Ward 1976).…”

Section: Idoxuridinementioning

confidence: 99%

Herpes Simplex Virus

Mindel¹

1989

The Bloomsbury Series in Clinical Science

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Antiviral iodinated pyrimidine deoxyribonucleosides: 5-iodo-2′-deoxyuridine; 5′-iodo-2′-deoxycytidine; 5-iodo-5′-amino-2′,5′-didoxyuridine

Cited by 38 publications

References 193 publications

Improved high‐affinity monoclonal antibody to lododeoxyuridine

Improved high‐affinity monoclonal antibody to lododeoxyuridine

A Facile, Alternative Synthesis of 4‘-Thioarabinonucleosides and Their Biological Activities

Herpes Simplex Virus

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