- H-bonding directed one-step synthesis of novel macrocyclic peptides from ε-aminoquinolinecarboxylic acid
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Two macrocyclic peptides 1a and 1b were synthesized directly from ε-aminoquinolinecarboxylic acid 2a and 2b, respectively. The preorganization of the uncyclized intermediates mediated by hydrogen bonding assisted the cyclization. The structures of 1a and 1b were characterized by 1H and 13C NMR spectroscopy and MALDI-TOF MS analysis. Solid state structure of 1a was investigated by single crystal X-ray studies. Their aggregation behaviors in solution were studied by both variable concentration and temperature 1H NMR experiments.
- Li, Fei,Gan, Quan,Xue, Lin,Wang, Zhong-ming,Jiang, Hua
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- Compound used as CDK7 kinase inhibitor and application thereof
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The invention relates to a compound used as a CDK7 kinase inhibitor and application thereof. Specifically, the compound disclosed by the invention has a structure shown as a formula I, and the definitions of all groups and substituents are as described in the specification. The compounds of the present invention are useful as inhibitors of cyclin-dependent kinase 7 (CDK7) for the treatment or prevention of proliferative diseases such as cancer, especially for modulating and treating diseases associated with abnormal activity of cyclin-dependent kinase 7 (CDK7).
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- Drug Design Targeting T-Cell Factor-Driven Epithelial-Mesenchymal Transition as a Therapeutic Strategy for Colorectal Cancer
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Metastasis is the cause of 90% of mortality in cancer patients. For metastatic colorectal cancer (mCRC), the standard-of-care drug therapies only palliate the symptoms but are ineffective, evidenced by a low survival rate of ～11%. T-cell factor (TCF) transcription is a major driving force in CRC, and we have characterized it to be a master regulator of epithelial-mesenchymal transition (EMT). EMT transforms relatively benign epithelial tumor cells into quasi-mesenchymal or mesenchymal cells that possess cancer stem cell properties, promoting multidrug resistance and metastasis. We have identified topoisomerase IIα (TOP2A) as a DNA-binding factor required for TCF-transcription. Herein, we describe the design, synthesis, biological evaluation, and in vitro and in vivo pharmacokinetic analysis of TOP2A ATP-competitive inhibitors that prevent TCF-transcription and modulate or reverse EMT in mCRC. Unlike TOP2A poisons, ATP-competitive inhibitors do not damage DNA, potentially limiting adverse effects. This work demonstrates a new therapeutic strategy targeting TOP2A for the treatment of mCRC and potentially other types of cancers.
- Abraham, Adedoyin D.,Esquer, Hector,Zhou, Qiong,Tomlinson, Nicholas,Hamill, Brayden D.,Abbott, Joshua M.,Li, Linfeng,Pike, Laura A.,Rinaldetti, Sébastien,Ramirez, Dominique A.,Lunghofer, Paul J.,Gomez, Jose D.,Schaack, Jerome,Nemkov, Travis,D'Alessandro, Angelo,Hansen, Kirk C.,Gustafson, Daniel L.,Messersmith, Wells A.,Labarbera, Daniel V.
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p. 10182 - 10203
(2019/11/29)
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- Melanin-concentrating hormone receptor 1 antagonists. Synthesis and structure-activity relationships of novel 3-(aminomethyl)quinolines
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It was found that 3-(aminomethyl)quinoline derivatives showed high binding affinities for melanin-concentrating hormone receptor 1 (MCHR1) with reduced affinity for serotonin receptor 2c (5-HT2c) when the dihydronaphthalene nucleus of compound 1 (human MCHR1, IC50 = 1.9 nM; human 5-HT2c receptor, IC50 = 0.53 nM) was replaced by other bicyclic core scaffolds. Among the synthesized compounds, 8-methylquinoline derivative 5v especially showed high binding affinity (IC50 = 0.54 nM), potent in vitro antagonistic activity (IC50 = 2.8 nM) for MCHR1, and negligible affinity for 5-HT2c receptor (IC50 > 1000 nM). Oral administration of 5v significantly and dose-dependently suppressed nocturnal food intake in diet-induced obese rats and did not affect food intake in MCHR1-deficient mice. These results and rat pharmacokinetic study findings suggested that compound 5v is a highly potent, orally bioavailable, and centrally acting nonpeptide MCHR1 antagonist.
- Kamata, Makoto,Yamashita, Toshiro,Imaeda, Toshihiro,Tanaka, Toshio,Masada, Shinichi,Kamaura, Masahiro,Kasai, Shizuo,Hara, Ryoma,Sasaki, Shigekazu,Takekawa, Shiro,Asami, Asano,Kaisho, Tomoko,Suzuki, Nobuhiro,Ashina, Shuntaro,Ogino, Hitomi,Nakano, Yoshihide,Nagisa, Yasutaka,Kato, Koki,Kato, Kaneyoshi,Ishihara, Yuji
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p. 2353 - 2366
(2012/05/05)
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