The Experts below are selected from a list of 48 Experts worldwide ranked by ideXlab platform
Robert G Croy - One of the best experts on this subject based on the ideXlab platform.
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convergent synthesis of a steroidal antiestrogen mitomycin c hybrid using click chemistry
Organic and Biomolecular Chemistry, 2012Co-Authors: Robert N Hanson, Edward Hua, David Labaree, Richard B Hochberg, Kyle Proffitt, John M Essigmann, Robert G CroyAbstract:A convergent synthesis of a novel estrogen receptor-targeted drug hybrid was developed based on structures of the potent anti-proliferative mitomycin C and the steroidal anti-estrogen RU 39411. The steroidal antiestrogen was prepared with an azido-triethylene glycoloxy linker while the mitomycin C derivative (porfirimycin) incorporated a complementary 7-N-terminal alkyne. The two components were ligated using the Huisgen [3 + 2] cycloaddition (“click”) reaction. Preliminary biological assays demonstrated that the final hybrid compound retained both potent anti-estrogenic and anti-proliferative activities.
Joshua W Hamilton - One of the best experts on this subject based on the ideXlab platform.
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preferential effects of the chemotherapeutic dna crosslinking agent mitomycin c on inducible gene expression in vivo
Environmental and Molecular Mutagenesis, 1995Co-Authors: Rosemary M Caron, Joshua W HamiltonAbstract:The immediate effects of a single dose of the chemotherapeutic DNA crosslinking agent, mitomycin C (MMC), on the expression of several constitutive and drug-inducible genes were examined in a simple in vivo system, the 14 day chick embryo. We observed no effect of MMC on the steady-state mRNA expression of the constitutively expressed beta-actin, transferrin, or albumin genes. In contrast, MMC treatment significantly altered both the basal and drug-inducible mRNA expression of two glutethimide-inducible genes, 5-aminolevulinic acid (ALA) synthase and cytochrome P450 CYP2H1. The basal expression of these genes was transiently but significantly increased over a 24 hr period following a single dose of MMC. Conversely, MMC significantly suppressed the glutethimide-inducible expression of these genes when administered 1 to 24 hr prior to the inducing drug. The effects of MMC on both basal and drug-inducible ALA synthase and CYP2H1 mRNA expression were principally a result of changes in the transcription rates of these genes. In contrast, MMC treatment had little or no effect on glutethimide-induced expression of ALA synthase or CYP2H1 when administered 1 hr after the inducing drug, suggesting that a very early event in the induction process represents the target for these MMC effects. Covalent binding studies demonstrated that the effects of MMC on gene expression were closely correlated temporally with formation of [3H]-Porfiromycin-DNA adducts. These results support the hypothesis that genotoxic chemicals specifically target their effects to inducible genes in vivo.
Alan C Sartorelli - One of the best experts on this subject based on the ideXlab platform.
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the intracellular location of nadh cytochrome b5 reductase modulates the cytotoxicity of the mitomycins to chinese hamster ovary cells
Journal of Biological Chemistry, 1998Co-Authors: Michael F Belcourt, Sara Rockwell, William F Hodnick, Alan C SartorelliAbstract:Abstract NADH:cytochrome b 5reductase activates the mitomycins to alkylating intermediates in vitro. To investigate the intracellular role of this enzyme in mitomycin bioactivation, Chinese hamster ovary cell transfectants overexpressing rat NADH:cytochrome b 5 reductase were generated. An NADH:cytochrome b 5reductase-transfected clone expressed 9-fold more enzyme than did parental cells; the levels of other mitomycin-activating oxidoreductases were unchanged. Although this enzyme activates the mitomycins in vitro, its overexpression in living cells caused decreases in sensitivity to mitomycin C in air and decreases in sensitivity to Porfiromycin under both air and hypoxia. Mitomycin C cytotoxicity under hypoxia was similar to parental cells. Because NADH:cytochrome b 5 reductase resides predominantly in the mitochondria of these cells, this enzyme may sequester these drugs in this compartment, thereby decreasing nuclear DNA alkylations and reducing cytotoxicity. A cytosolic form of NADH:cytochrome b 5 reductase was generated. Transfectants expressing the cytosolic enzyme were restored to parental line sensitivity to both mitomycin C and Porfiromycin in air with marked increases in drug sensitivity under hypoxia. The results implicate NADH:cytochrome b 5 reductase in the differential bioactivation of the mitomycins and indicate that the subcellular site of drug activation can have complex effects on drug cytotoxicity.
Robert N Hanson - One of the best experts on this subject based on the ideXlab platform.
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convergent synthesis of a steroidal antiestrogen mitomycin c hybrid using click chemistry
Organic and Biomolecular Chemistry, 2012Co-Authors: Robert N Hanson, Edward Hua, David Labaree, Richard B Hochberg, Kyle Proffitt, John M Essigmann, Robert G CroyAbstract:A convergent synthesis of a novel estrogen receptor-targeted drug hybrid was developed based on structures of the potent anti-proliferative mitomycin C and the steroidal anti-estrogen RU 39411. The steroidal antiestrogen was prepared with an azido-triethylene glycoloxy linker while the mitomycin C derivative (porfirimycin) incorporated a complementary 7-N-terminal alkyne. The two components were ligated using the Huisgen [3 + 2] cycloaddition (“click”) reaction. Preliminary biological assays demonstrated that the final hybrid compound retained both potent anti-estrogenic and anti-proliferative activities.
Rosemary M Caron - One of the best experts on this subject based on the ideXlab platform.
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preferential effects of the chemotherapeutic dna crosslinking agent mitomycin c on inducible gene expression in vivo
Environmental and Molecular Mutagenesis, 1995Co-Authors: Rosemary M Caron, Joshua W HamiltonAbstract:The immediate effects of a single dose of the chemotherapeutic DNA crosslinking agent, mitomycin C (MMC), on the expression of several constitutive and drug-inducible genes were examined in a simple in vivo system, the 14 day chick embryo. We observed no effect of MMC on the steady-state mRNA expression of the constitutively expressed beta-actin, transferrin, or albumin genes. In contrast, MMC treatment significantly altered both the basal and drug-inducible mRNA expression of two glutethimide-inducible genes, 5-aminolevulinic acid (ALA) synthase and cytochrome P450 CYP2H1. The basal expression of these genes was transiently but significantly increased over a 24 hr period following a single dose of MMC. Conversely, MMC significantly suppressed the glutethimide-inducible expression of these genes when administered 1 to 24 hr prior to the inducing drug. The effects of MMC on both basal and drug-inducible ALA synthase and CYP2H1 mRNA expression were principally a result of changes in the transcription rates of these genes. In contrast, MMC treatment had little or no effect on glutethimide-induced expression of ALA synthase or CYP2H1 when administered 1 hr after the inducing drug, suggesting that a very early event in the induction process represents the target for these MMC effects. Covalent binding studies demonstrated that the effects of MMC on gene expression were closely correlated temporally with formation of [3H]-Porfiromycin-DNA adducts. These results support the hypothesis that genotoxic chemicals specifically target their effects to inducible genes in vivo.