10 research outputs found

    Synthesis of a 2-aryl-3-aroyl indole salt (OXi8007) resembling combretastatin A-4 with application as a vascular disrupting agent

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    The natural products colchicine and combretastatin A-4 are potent inhibitors of tubulin assembly, and they have inspired the design and synthesis of a large number of small-molecule, potential anticancer agents. The indole-based molecular scaffold is prominent among these SAR modifications, leading to a rapidly increasing number of agents. The water-soluble phosphate prodrug 33 (OXi8007) of 2-aryl-3-aroylindole-based phenol 8 (OXi8006) was prepared by chemical synthesis and found to be strongly cytotoxic against selected human cancer cell lines (GI50 = 36 nM against DU-145 cells, for example). The free phenol, 8 (OXi8006), was a strong inhibitor (IC 50 = 1.1 μM) of tubulin assembly. The corresponding phosphate prodrug 33 (OXi8007) also demonstrated pronounced interference with tumor vasculature in a preliminary in vivo study utilizing a SCID mouse model bearing an orthotopic PC-3 (prostate) tumor as imaged by color Doppler ultrasound. The combination of these results provides evidence that the indole-based phosphate prodrug 33 (OXi8007) functions as a vascular disrupting agent that may prove useful for the treatment of cancer. © 2013 The American Chemical Society and American Society of Pharmacognosy

    Combretastatin dinitrogen-substituted stilbene analogues as tubulin-binding and vascular-disrupting agents

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    Several stilbenoid compounds having structural similarity to the combretastatin group of natural products and characterized by the incorporation of two nitrogen-bearing groups (amine, nitro, serinamide) have been prepared by chemical synthesis and evaluated in terms of biochemical and biological activity. The 2′,3′-diamino B-ring analogue 17 demonstrated remarkable cytotoxicity against selected human cancer cell lines in vitro (average GI50 = 13.9 nM) and also showed good activity in regard to inhibition of tubulin assembly (IC50 = 2.8 μM). In addition, a single dose (10 mg/kg) of compound 17 caused a 40% tumor-selective blood flow shutdown in tumor-bearing SCID mice at 24 h, thus suggesting the potential value of this compound and its corresponding salt formulations as new vascular-disrupting agents. © 2008 American Chemical Society and American Society of Pharmacognosy

    Design, synthesis, and biological evaluation of combretastatin nitrogen-containing derivatives as inhibitors of tubulin assembly and vascular disrupting agents

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    A series of analogs with nitro or serinamide substituents at the C-2′-, C-5′-, or C-6′-position of the combretastatin A-4 (CA4) B-ring was synthesized and evaluated for cytotoxic effects against heart endothelioma cells, blood flow reduction to tumors in SCID mice, and as inhibitors of tubulin polymerization. The synthesis of these analogs typically featured a Wittig reaction between a suitably functionalized arylaldehyde and an arylphosphonium salt followed by separation of the resultant E- and Z-isomers. Several of these nitrogen-modified CA4 derivatives (both amino and nitro) demonstrate significant inhibition of tubulin assembly as well as cytotoxicity and in vivo blood flow reduction. 2′-Aminostilbenoid 7 and 2′-amino-3′-hydroxystilbenoid 29 proved to be the most active in this series. Both compounds, 7 and 29, have the potential for further pro-drug modification and development as vascular disrupting agents for treatment of solid tumor cancers and certain ophthalmological diseases. © 2006 Elsevier Ltd. All rights reserved

    2-(3-tert-butyldimethylsiloxy-4-methoxyphenyl)-6-methoxy-3-(3,4, 5-trimethoxybenzoyl)indole

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    In the crystal structure of the title compound, C32H39NO7Si, all geometric parameters fall within experimental error of expected values. The analysis of molecular-packing plots reveals an infinite two-dimensional linear array running parallel to the b axis, formed by one N-H⋯O intermolecular hydrogen-bonding interaction. Several potential C-H⋯O interactions are also present

    Combretastatin dinitrogen-substituted stilbene analogues as tubulin-binding and vascular-disrupting agents

    No full text
    Several stilbenoid compounds having structural similarity to the combretastatin group of natural products and characterized by the incorporation of two nitrogen-bearing groups (amine, nitro, serinamide) have been prepared by chemical synthesis and evaluated in terms of biochemical and biological activity. The 2',3'-diamino B-ring analogue 17 demonstrated remarkable cytotoxicity against selected human cancer cell lines in vitro (average GI(50) = 13.9 nM) and also showed good activity in regard to inhibition of tubulin assembly (IC50 = 2.8 mu M). In addition, a single dose (10 mg/kg) of compound 17 caused a 40% tumor-selective blood flow shutdown in tumor-bearing SCID mice at 24 h, thus suggesting the potential value of this compound and its corresponding salt formulations as new vascular-disrupting agents

    Guaifenesin Derivatives Promote Neurite Outgrowth and Protect Diabetic Mice from Neuropathy

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    In diabetic patients, an early index of peripheral neuropathy is the slowing of conduction velocity in large myelinated neurons and a lack of understanding of the basic pathogenic mechanisms hindered therapeutics development. Racemic (<i>R</i>/<i>S</i>)-guaifenesin (<b>1</b>) was identified as a potent enhancer of neurite outgrowth using an in vitro screen. Its <i>R</i>-enantiomer (<i>R</i>)-<b>1</b> carried the most biological activity, whereas the <i>S</i>-enantiomer (<i>S</i>)-<b>1</b> was inactive. Focused structural variations to (<i>R</i>/<i>S</i>)-<b>1</b> was conducted to identify potentially essential groups for the neurite outgrowth activity. In vivo therapeutic studies indicated that both (<i>R</i>/<i>S</i>)-<b>1</b> and (<i>R</i>)-<b>1</b> partially prevented motor nerve conduction velocity slowing in a mouse model of type 1 diabetes. In vitro microsomal assays suggested that compounds (<i>R</i>)-<b>1</b> and (<i>S</i>)-<b>1</b> are not metabolized rapidly, and PAMPA assay indicated moderate permeability through the membrane. Findings revealed here could lead to the development of novel drugs for diabetic neuropathy
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