2,6-disubstituted pyran-4-one and thiopyran-4-one inhibitors of DNA-Dependent protein kinase (DNA-PK).

  title={2,6-disubstituted pyran-4-one and thiopyran-4-one inhibitors of DNA-Dependent protein kinase (DNA-PK).},
  author={Jonathan James Hollick and Bernard T Golding and Ian R Hardcastle and Niall M. B. Martin and Caroline J. Richardson and Laurent Jean Martin Rigoreau and Graeme C M Smith and Roger John Griffin},
  journal={Bioorganic \& medicinal chemistry letters},
  volume={13 18},
6-aryl-2-morpholin-4-yl-4H-pyran-4-ones and 6-aryl-2-morpholin-4-yl-4H-thiopyran-4-ones were synthesised and evaluated as potential inhibitors of the DNA repair enzyme DNA-dependent protein kinase (DNA-PK). Several compounds in each series exhibited superior activity to the chromenone LY294002, and were of comparable potency to the benzochromenone NU7026 (IC(50)=0.23 microM). Importantly, members of both structural classes were found to be selective inhibitors of DNA-PK over related… Expand
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ABSTRACT One-pot reaction between 3,4-dihydro-3-((benzylamino)methylene)-4-thioxochromen-2-ones and alkyl-2-cyanoacetates in the presence of an excess amount of triethylamine and a catalytic amountExpand
Synthesis of sulfonamide-based kinase inhibitors from sulfonates by exploiting the abrogated SN2 reactivity of 2,2,2-trifluoroethoxysulfonates.
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Chemistry of Pent-4-yne-1,3-diones (Acetylenic β-diketones) as Precursors for Heterocyclic Compounds
Abstract The pent-4-yne-1,3-diones (acetylenic β-diketones) have different reactive functionalities which let them attractive, particularly as precursors for heterocyclic compounds. This chapterExpand
Identification of a highly potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor (NU7441) by screening of chromenone libraries.
A solution-phase multiple-parallel synthesis approach was employed for the preparation of 6-, 7- and 8-aryl-substituted chromenone libraries, which were screened as inhibitors of the DNA repairExpand
Antiproliferative activity of novel thiopyran analogs on MCF-7 breast and HCT-15 colon cancer cells: synthesis, cytotoxicity, cell cycle analysis, and DNA-binding.
These compounds were synthesized and evaluated for their cytotoxic effect against HCT-15 colon and MCF-7 breast cancer cell lines using Sulforhodamine B (SRB) assay and showed that these compounds could exhibit a good cytotoxicity to both cell lines. Expand
Antiproliferative activity of novel derivative of thiopyran on breast and colon cancer lines and DNA binding.
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Mapping the ATP-binding domain of DNA-dependent protein kinase (DNA-PK) with coumarin- and isocoumarin-derived inhibitors.
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One such compound, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one, LY294002, completely and specifically abolished PtdIns 3-kinase activity, which may be beneficial in the treatment of proliferative diseases as well as in elucidating the biological role of the kinase in cellular proliferation and growth factor response. Expand
Synthesis of 2-Amino-6-phenyl-4H-pyran-4-ones
The treatment of a series of phenylacetylenic β-keto amides with methanesulfonic acid produces a high yielding intramolecular cyclization to the corresponding 2-amino-6-phenyl-4H-pyran-4-ones
Radiosensitization of human tumor cells by the phosphatidylinositol3-kinase inhibitors wortmannin and LY294002 correlates with inhibition of DNA-dependent protein kinase and prolonged G2-M delay.
Inhibition of cellular DNA-PK activity occurred at the same concentrations of wortmannin that caused radiosensitization, and this correlation was found in a range of tumor cell lines, suggesting a new class of radiosensitizers that inhibit the repair of DNA damage. Expand
DNA-PK inhibitor wortmannin enhances DNA damage induced by bleomycin in V79 Chinese hamster cells.
Evaluated concentrations of WM show that WM clearly enhances the efficacy of BLM in terms of DNA damage inflicted and therefore reinforces its use as a chemosensitizer. Expand
The DNA-dependent protein kinase.
Studies on DNA-PK should provide a better understanding of degenerative diseases and cancer, and may lead to improved therapies for these conditions, as well as related proteins involved in DNA damage detection. Expand
DNA-dependent protein kinase.
  • S. Jackson
  • Biology, Medicine
  • The international journal of biochemistry & cell biology
  • 1997
Studies on DNA-PK should provide a better understanding of degenerative disease and cancer, and may lead to improved therapies for these conditions, as well as related proteins involved in DNA damage detection. Expand
Mechanisms of enhancement of cytotoxicity in etoposide and ionising radiation-treated cells by the protein kinase inhibitor wortmannin.
Investigation of the effects of the protein kinase inhibitor wortmannin on the cytotoxic mechanisms of etoposide and ionising radiation in the Chinese hamster ovary K1 cell line suggests that WM inhibits in intact cells both DNA-PK and either or both the AT-related gene products ATM and ATR. Expand
A Targeted Inhibition of DNA-Dependent Protein Kinase Sensitizes Breast Cancer Cells Following Ionizing Radiation
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Therapeutic potential of phosphoinositide 3-kinase inhibitors.
There are now several patent specifications published that describe newPI3K inhibitors, including some that are more selective for the delta isoform of PI3K, which has immense potential use for the treatment of patients with inflammatory and autoimmune disorders as well as cancer and cardiovascular diseases. Expand
Sensing and repairing DNA double-strand breaks.
An increased knowledge of DSB repair and of other DNA DSB responses may provide opportunities for developing more effective treatments for cancer, with particular emphasis on non-homologous end-joining and homologous recombination. Expand