Synthesis and Structural Elucidation of 2′-Deoxy-4′-thio-L-threo-pentofuranosylpyrimidine and -purine Nucleosides

Wirsching, Jörn; Voß, Jürgen; Adiwidjaja, Ḡunadi; Giesler, Anja; Kopf, Jürgen

doi:10.1002/1099-0690(200103)2001:6<1077::aid-ejoc1077>3.0.co;2-0

Cited by 22 publications

(11 citation statements)

References 57 publications

(48 reference statements)

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“…No-carrier-added sodium 131 I-iodide was obtained from Amersham Biosciences, and no-carrier-added sodium 123 Iiodide was purchased from Zyklotron AG. The 5-trimethylstannyl precursor of ITdU and the standard compound ITdU were synthesized according to previously reported methods (8,(13)(14)(15).…”

Section: Chemicalsmentioning

confidence: 99%

123I-ITdU-Mediated Nanoirradiation of DNA Efficiently Induces Cell Kill in HL60 Leukemia Cells and in Doxorubicin-, -, or -Radiation-Resistant Cell Lines

Reske

Deisenhofer²,

Glatting³

et al. 2007

Journal of Nuclear Medicine

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Resistance to radiotherapy or chemotherapy is a common cause of treatment failure in high-risk leukemias. We evaluated whether selective nanoirradiation of DNA with Auger electrons emitted by 5-123 I-iodo-49-thio-29-deoxyuridine ( 123 I-ITdU) can induce cell kill and break resistance to doxorubicin, b-, and g-irradiation in leukemia cells. Methods: 49-thio-29-deoxyuridine was radiolabeled with 123/131 I and purified by high-performance liquid chromatography. Cellular uptake, metabolic stability, DNA incorporation of 123 I-ITdU, and the effect of the thymidylate synthase (TS) inhibitor 5-fluoro-29-deoxyuridine (FdUrd) were determined in HL60 leukemia cells. DNA damage was assessed with the comet assay and quantified by the olive tail moment. Apoptosis induction and irradiation-induced apoptosis inhibition by benzoylcarbonylVal-Ala-Asp-fluoromethyl ketone (z-VAD.fmk) were analyzed in leukemia cells using flow cytometry analysis. Results: The radiochemical purity of ITdU was 95%. Specific activities were 900 GBq/mmol for 123 I-ITdU and 200 GBq/mmol for 131 I-ITdU. An in vitro cell metabolism study of 123 I-ITdU with wild-type HL60 cells demonstrated an uptake of 1.5% of the initial activity/10 6 cells of 123 I-ITdU. Ninety percent of absorbed activity from 123 I-ITdU in HL60 cells was specifically incorporated into DNA. 123 I-ITdU caused extensive DNA damage (olive tail moment . 12) and induced more than 90% apoptosis in wild-type HL60 cells. The broad-spectrum inhibitor of caspases zVAD-fmk reduced 123 IITdU-induced apoptosis from more than 90% to less than 10%, demonstrating that caspases were central for 123 I-ITdU-induced cell death. Inhibition of TS with FdUrd increased DNA uptake of 123 I-ITdU 18-fold and the efficiency of cell kill about 20-fold. In addition, 123 I-ITdU induced comparable apoptotic cell death (.90%) in sensitive parental leukemia cells and in leukemia cells resistant to b-irradiation, g-irradiation, or doxorubicin at activities of 1.2, 4.1, 12.4, and 41.3 MBq/mL after 72 h. This finding indicates that 123 I-ITdU breaks resistance to b-irradiation, g-irradiation, and doxorubicin in leukemia cells. Conclusion: 123 I-ITdU-mediated nanoirradiation of DNA efficiently induced apoptosis in sensitive and resistant leukemia cells against doxorubicin, b-irradiation, and g-irradiation and may provide a novel treatment strategy for overcoming resistance to conventional radiotherapy or chemotherapy in leukemia. Cellular uptake and cell kill are highly amplified by inhibiting TS with FdUrd.

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Section: Chemicalsmentioning

confidence: 99%

123I-ITdU-Mediated Nanoirradiation of DNA Efficiently Induces Cell Kill in HL60 Leukemia Cells and in Doxorubicin-, -, or -Radiation-Resistant Cell Lines

Reske

Deisenhofer²,

Glatting³

et al. 2007

Journal of Nuclear Medicine

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“…However, α-4'-thiothymidine (3-9α α α α) showed anti-HSV-1 activity with 0. 8 µM of IC 50 in Vero cells and β-4'-thiothymidine (3-9β β β β) showed anti-HCMV activity comparable to ganciclovir.…”

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

confidence: 97%

“…001-4 µM of EC 50 and anti-HCMV activity in a range of 0. 06-10 µM of EC 50 . In particular, 2-amino-6-(cyclopropylamino)purine derivative 3-86h was the most potent and selective agent against HCMV and HBV replication in vitro.…”

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

confidence: 99%

“…Wirsching et al [50] in an effort to synthesize the L-2'-deoxy-4'-thionucleosides. 3-52 was synthesized starting from 2-deoxy-D-ribose via dithioacetal 3-19 (Scheme 3-28).…”

Section: Following Is a Brief Account Of Synthesis (Scheme 3-22)mentioning

confidence: 99%

“…Once incorporated into viral DNA, they are better inhibitor of viral DNA synthesis than their corresponding 4'-oxo counterparts, either because they are not recognized, and thus not removed, by viral uracil-DNA glycosylase, or because they preferentially interfere with viral DNA polymerase. Most of 2'-deoxy-4'-thiouridines were active against HSV-1 (IC50 = 0. 013-16 µM), HSV-2 (IC 50 of the best one 3-9: 0.…”

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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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L‐Nucleosides

Perrone

Capobianco

2013

Chemical Synthesis of Nucleoside Analogues

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Synthesis and Structural Elucidation of 2′-Deoxy-4′-thio-L-threo-pentofuranosylpyrimidine and -purine Nucleosides

Cited by 22 publications

References 57 publications

123I-ITdU-Mediated Nanoirradiation of DNA Efficiently Induces Cell Kill in HL60 Leukemia Cells and in Doxorubicin-, -, or -Radiation-Resistant Cell Lines

123I-ITdU-Mediated Nanoirradiation of DNA Efficiently Induces Cell Kill in HL60 Leukemia Cells and in Doxorubicin-, -, or -Radiation-Resistant Cell Lines

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

L‐Nucleosides

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