Bernard T. Golding

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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 repair enzyme DNA-dependent protein kinase (DNA-PK). These studies resulted in the identification of 8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one (NU7441) as a(More)
In this study we investigated the in vitro time dependence of radiosensitisation, pharmacokinetics and metabolism of NU7026, a novel inhibitor of the DNA repair enzyme DNA-dependent protein kinase (DNA-PK). At a dose of 10 μM, which is nontoxic to cells per se, a minimum NU7026 exposure of 4 h in combination with 3 Gy radiation is required for a significant(More)
This review describes enzymes that contain radicals and/or catalyze reactions with radical intermediates. Because radicals irreversibly react with dioxygen, most of these enzymes occur in anaerobic bacteria and archaea. Exceptions are the families of coenzyme B(12)- and S-adenosylmethionine (SAM)-dependent radical enzymes, of which some members also occur(More)
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(More)
Cyclin-dependent kinases (CDK) play a crucial role in the control of the cell cycle. Aberrations in the control of cell cycle progression occur in the majority of human malignancies; hence, CDKs are promising targets for anticancer therapy. Here, we define the cellular effects of the novel CDK inhibitor NU6140, alone or in association with paclitaxel, with(More)
Aberrant control of cyclin-dependent kinases (CDKs) is a central feature of the molecular pathology of cancer. Iterative structure-based design was used to optimize the ATP- competitive inhibition of CDK1 and CDK2 by O6-cyclohexylmethylguanines, resulting in O6-cyclohexylmethyl-2-(4′- sulfamoylanilino)purine. The new inhibitor is 1,000-fold more potent than(More)
Human alpha-1-proteinase inhibitor is a well-characterized protease inhibitor with a wide spectrum of anti-protease activity. Its major physiological role is inhibition of neutrophil elastase in the lungs, and its deficiency is associated with progressive ultimately fatal emphysema. Currently in the US, only plasma-derived human alpha-1-proteinase inhibitor(More)
Modified tetrapyrroles such as chlorophyll, heme, siroheme, vitamin B(12), coenzyme F(430), and heme d(1) underpin a wide range of essential biological functions in all domains of life, and it is therefore surprising that the syntheses of many of these life pigments remain poorly understood. It is known that the construction of the central molecular(More)
Substituted guanines and pyrimidines were tested as inhibitors of cyclin B1/CDK1 and cyclin A3/CDK2 and soaked into crystals of monomeric CDK2. O6-Cyclohexylmethylguanine (NU2058) was a competitive inhibitor of CDK1 and CDK2 with respect to ATP (Ki values: CDK1, 5 +/- 1 microM; CDK2, 12 +/- 3 microM) and formed a triplet of hydrogen bonds (i.e., NH-9 to Glu(More)
Poly(ADP-ribose) polymerase (PARP) plays an important role in a number of cellular processes including DNA repair. Since poly(ADP-ribosyl)ation occurs in response to radiation- or drug-induced DNA damage, inhibitors of the enzyme may enhance the antitumour activity of radiotherapy or cytotoxic drug treatment. In this review the development of PARP(More)