- Synthesis and Pharmacological Evaluation of σ2 Receptor Ligands Based on a 3-Alkoxyisoxazole Scaffold: Potential Antitumor Effects against Osteosarcoma
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Since its initial discovery as the basis for nicotinic acetylcholine receptor ligands, the 3-alkoxyisoxazole scaffold has been shown to be a versatile platform for the development of potent σ1 and σ2 receptor ligands. Herein we report a further SAR exploration of the 3-alkoxyisoxazole scaffold with the aim of obtaining potent σ2 receptor ligands. Various substitutions on the benzene ring and at the basic amino regions resulted in a total of 21 compounds that were tested for their binding affinities for the σ2 receptor. In particular, compound 51 [(2S)-1-(4-ammoniobutyl)-2-(((5-((3,4-dichlorophenoxy)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-ium chloride] was identified as one of the most potent σ2 ligands within the series, with a Ki value of 7.9 nM. It demonstrated potent antiproliferative effects on both osteosarcoma cell lines 143B and MOS?J (IC50 values of 0.89 and 0.71 μM, respectively), relative to siramesine (IC50 values of 1.81 and 2.01 μM). Moreover, compound 51 inhibited clonal formation of osteosarcoma 143B cells at 1 μM, corresponding to half the dose required of siramesine for similar effects. The general cytotoxicity profile of compound 51 was assessed in a number of normal cell lines, including HaCaT, HAF, and LO2 cells. Furthermore, FACS analysis showed that compound 51 likely inhibits osteosarcoma cell growth by disruption of the cell cycle and promotion of apoptosis.
- Shi, Jun-Jie,Jia, Kun-Hang,Sun, Hao,Gunosewoyo, Hendra,Yang, Fan,Tang, Jie,Luo, Jian,Yu, Li-Fang
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- TARGET PROTEIN EED DEGRADATION-INDUCING DEGRADUCER, PREPARATION METHOD THEREOF, AND PHARMACEUTICAL COMPOSITION FOR PREVENTING OR TREATING DISEASES RELATED TO EED, EZH2, OR PRC2, COMPRISING SAME AS ACTIVE INGREDIENT
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The present invention relates to a target protein degradation-inducing Degraducer, a preparation method thereof, and a pharmaceutical composition for preventing or treating diseases related to EED, EZH2, or PRC2 comprising same as an active ingredient. A novel compound represented by formula 1, according to the present invention is a Degraducer compound that induces degradation of a target protein, i.e., embryonic ectoderm development (EED) or polycomb repressive complex 2 (PRC2), utilizing cereblon E3 ubiquitin ligase, von Hippel-Lindau tumor suppressor (VHL) E3 ubiquitin ligase, mouse double minute 2 homolog (MDM2) E3 ubiquitin ligase, and cellular inhibitor of apoptosis protein 1 (cIAP) E3 ubiquitin ligase, wherein the compound has an aspect of remarkably achieving target protein degradation-inducing activity through a ubiquitin proteasome system (UPS), and therefore there is a useful effect in that it is possible to provide a pharmaceutical composition for preventing or treating diseases or conditions related to a target protein, and a functional health food composition for preventing or improving same, comprising said compound as an active ingredient.
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- Agent for Preventing or Ameliorating Hearing Impairment
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It is to provide an agent for preventing or improving hearing loss, which comprises a low molecular compound which can be produced relatively easily and inexpensively as an active ingredient. One or more compounds selected from the group consisting of compounds represented by the following formulas (I0), (II), and (III) and a pharmaceutically acceptable salt of the compounds when R3 is OH are used as an agent for preventing or improving hearing loss.
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- Erythropoietin Expression Promoter
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The present invention provides an erythropoietin expression-enhancing agent that can cancel the suppression of erythropoietin production or promote erythropoietin production, and a therapeutic or preventive drug for anemia, a liver function-improving agent, an ischemic injury-improving agent, a renal protective agent, and an insulin secretagogue comprising the erythropoietin expression-enhancing agent. The erythropoietin expression-enhancing agent of the present invention comprises one or more compounds selected from the group consisting of compounds represented by the following general formulas (I), (II), and (III) and pharmaceutically acceptable salts thereof when R3 is OH.
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- Synthesis and biological characterization of new aminophosphonates for mitochondrial pH determination by 31P NMR spectroscopy
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A series of mitochondria targeted α-aminophosphonates combining a diethoxyphosphoryl group and an alkyl chain-connected triphenylphosphonium bromide tail were designed and synthesized, and their pH-sensitive 31P NMR properties and biological activities in vitro and in vivo were evaluated. The results showed a number of these mito-aminophosphonates exhibiting pKa values fitting the mitochondrial pH range, short relaxation, and chemical shift parameters compatible with sensitive 31P NMR detection, and low cytotoxicity on green algae and murine fibroblasts cell cultures. Of these, two selected compounds demonstrated to distribute at NMR detectable levels within the cytosolic and mitochondrial sites following their perfusion to isolated rat livers, with no detrimental effects on cell energetics and aerobic respiration. This study provided a new molecular scaffold for further development of in situ spectroscopic real-time monitoring of mitochondrion/cytosol pH gradients.
- Culcasi, Marcel,Casano, Gilles,Lucchesi, Céline,Mercier, Anne,Clément, Jean-Louis,Pique, Valérie,Michelet, Laure,Krieger-Liszkay, Anja,Robin, Maxime,Pietri, Sylvia
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p. 2487 - 2499
(2013/05/22)
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- ALKYLOXY SUBSTITUTED THIAZOLOQUINOLINES AND THIAZOLONAPHTHYRIDINES
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Thiazoloquinolines and thiazolonaphthyridines with an alkoxy substituent at the 6, 7, 8, or 9-position, pharmaceutical compositions containing the compounds, intermediates, methods of making and methods of use of these compounds as immunomodulators, for inducing cytokine biosynthesis in animals and in the treatment of diseases including viral and neoplastic diseases are disclosed.
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Page/Page column 95
(2008/06/13)
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- ALKOXY SUBSTITUTED IMIDAZOQUINOLINES
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Imidazoquinoline compounds with an alkoxy substituent at the 6, 7, 8, or 9-position, pharmaceutical compositions containing the compounds, intermediates, methods of making, and methods of use of these compounds as immunomodulators, for inducing or inhibit
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Page/Page column 138
(2008/06/13)
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- An immunotherapeutic program for the treatment of nicotine addiction: Hapten design and synthesis
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People continue to smoke and use tobacco products despite well-established hazardous consequences. The most contributing factor is the addictive nature of nicotine. There is no highly effective treatment for the problem of nicotine dependence. Immunotherapy offers an alternative to conventional approaches. The chemistry necessary for a comprehensive immunopharmacological program is presented. Haptens for the generation of antibodies specific for naturally occurring (S)-nicotine, (S)- and (R)-nornicotine, and the metabolite (S)-cotinine were prepared with high optical purity. Preliminary data for antinicotine antibodies are reported.
- Isomura,Wirsching,Janda
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p. 4115 - 4121
(2007/10/03)
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- Synthesis of 17H-tetrabenzofluorene derivatives as chiral selectors for enantiomeric separation by HPLC on porous graphitised carbon
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The synthesis of the amides 2 which are designed to be selectors containing the chiral N-(3,5-dinitrobenzoyl)-α-phenylglycine covalently linked to tetrabenzofluorene is described.These amides are strongly adsorbed onto porous graphitised carbon, which affords chiral stationary phases that are able to resolve both racemic aromatic alcohols 3 and the methyl esters of Fmoc amino acids 4 on microgram quantities using high-pressure liquid chromatography.Two methods of preparation of these chiral phases from 2 and porous graphitised carbon are described and the stability of these phases to the chromatographic conditions and to water have also been investigated.
- Dutton, Jonathan K.,Knox, John H.,Radisson, Xavier,Ritchie, Harold J.,Ramage, Robert
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p. 2581 - 2588
(2007/10/02)
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