19 research outputs found
Inhibition of vascular endothelial growth factor with a sequence-specific hypoxia response element antagonist
Vascular endothelial growth factor (VEGF) and its receptors have been implicated as key factors in tumor angiogenesis that are up-regulated by hypoxia. We evaluated the effects of DNA-binding small molecules on hypoxia-inducible transcription of VEGF. A synthetic pyrrole-imidazole polyamide designed to bind the hypoxia response element (HRE) was found to disrupt hypoxia-inducible factor (HIF) binding to HIRE. In cultured HeLa cells, this resulted in a reduction of VEGF mRNA and secreted protein levels. The observed effects were polyamide-specific and dose-dependent. Analysis of genome-wide effects of the HIRE-specific polyamide revealed that a number of hypoxia-inducible genes were down-regulated. Pathway-based regulation of hypoxia-inducible gene expression with DNA-binding small molecules may represent a new approach for targeting angiogenesis
Completion of a Programmable DNA-Binding Small Molecule Library
Hairpin pyrrole-imidazole (Py-Im) polyamides are programmable oligomers that bind the DNA minor groove in a sequence-specific manner with affinities comparable to those of natural DNA-binding proteins. These cell-permeable small molecules have been shown to enter the nuclei of live cells and downregulate endogenous gene expression. We complete here a library of 27 hairpin Py-Im polyamides, which bind seven-base-pair sequences of the general form 5′-WWGNNNW-3′ (where W=A or T, N=W, G, or C). Their equilibrium association constants (K_a) range from K_a=1×10^8 to 4×10^(10) M^(−1) with good sequence specificity. A table of binding affinities and sequence contexts for this completed 27-member library has been assembled for the benefit of the chemical biology community interested in molecular control of transcription
Quantification and pharmacokinetic study of tumor-targeting agent MHI148-clorgyline amide in mouse plasma using liquid chromatography-electrospray ionization tandem mass spectrometry
A high-performance liquid chromatography-electrospray ionization tandem mass spectrometric (HPLC-ESI-MS/MS) method was developed for the quantification of MHI148-clorgyline amide (NMI-amide), a novel tumor-targeting monoamine oxidase A inhibitor, in mouse plasma. The method was validated in terms of sensitivity, precision, accuracy, recovery and stability and then applied to a pharmacokinetic study of NMI-amide in mice following intravenous administration. NMI-amide together with the internal standard (IS), MHI-148, was extracted by protein precipitation using acetonitrile. Multiple reaction monitoring was used for quantification of NMI-amide by detecting m/z transition of 491.2–361.9, and 685.3–258.2 for NMI-amide and the IS, respectively. The lower limit of quantification (LLOQ) of the HPLC–MS/MS method for NMI-amide was 0.005 μg/mL and the linear calibration curve was acquired with R2 > 0.99 in the concentration range of 0.005–2 μg/mL. The intra- and inter-day precisions of the assay were assessed by percentage of the coefficient of variations, which was within 9.8% at LLOQ and 14.0% for other quality control samples, whereas the mean accuracy ranged from 86.8% to 113.2%. The samples were stable under storage and experimental conditions. This method was successfully applied to a pharmacokinetic study in mice following intravenous administration of 5 mg/kg NMI-amide. Keywords: MHI148-clorgyline, HPLC, Mass spectrometry, Pharmacokinetic
A Selective Mitochondrial-Targeted Chlorambucil with Remarkable Cytotoxicity in Breast and Pancreatic Cancers
Nitrogen
mustards, widely used as chemotherapeutics, have limited
safety and efficacy. Mitochondria lack a functional nucleotide excision
repair mechanism to repair DNA adducts and are sensitive to alkylating
agents. Importantly, cancer cells have higher intrinsic mitochondrial
membrane potential (Δψ<sub>mt</sub>) than normal cells.
Therefore, selectively targeting nitrogen mustards to cancer cell
mitochondria based on Δψ<sub>mt</sub> could overcome those
limitations. Herein, we describe the design, synthesis, and evaluation
of Mito-Chlor, a triphenylphosphonium derivative of the nitrogen mustard
chlorambucil. We show that Mito-Chlor localizes to cancer cell mitochondria
where it acts on mtDNA to arrest cell cycle and induce cell death,
resulting in a 80-fold enhancement of cell kill in a panel of breast
and pancreatic cancer cell lines that are insensitive to the parent
drug. Significantly, Mito-Chlor delayed tumor progression in a mouse
xenograft model of human pancreatic cancer. This is a first example
of repurposing chlorambucil, a drug not used in breast and pancreatic
cancer treatment, as a novel drug candidate for these diseases
In vivo anticancer activity of rhomboidal Pt(II) metallacycles
Photograph used for a newspaper owned by the Oklahoma Publishing Company. Caption: "(Photo of an airport's control tower cab being lifted to the tower's top, a worker at the top of the tower, two cranes, and more.)
Correction to Inhibition of Hypoxia Inducible Factor 1–Transcription Coactivator Interaction by a Hydrogen Bond Surrogate α-Helix
Completion of a Programmable DNABinding Small Molecule Library
Hairpin pyrrole-imidazole (Py-Im) polyamides are programmable oligomers that bind the DNA minor groove in a sequence-specific manner with affinities comparable to those of natural DNA-binding proteins. These cell-permeable small molecules have been shown to enter the nuclei of live cells and downregulate endogenous gene expression. We complete here a library of 27 hairpin Py-Im polyamides, which bind seven-base-pair sequences of the general form 5′-WWGNNNW-3′ (where W=A or T, N=W, G, or C). Their equilibrium association constants (Ka) range from Ka=1×108 to 4×1010 M−1 with good sequence specificity. A table of binding affinities and sequence contexts for this completed 27-member library has been assembled for the benefit of the chemical biology community interested in molecular control of transcription