- Discovery of Novel Aryl Carboxamide Derivatives as Hypoxia-Inducible Factor 1α Signaling Inhibitors with Potent Activities of Anticancer Metastasis
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In order to discover novel hypoxia-inducible factor 1 (HIF-1) inhibitors for the cancer metastasis treatment, 68 new aryl carboxamide compounds were synthesized and evaluated for their inhibitory effect by dual luciferase-reporter assay. Based on five rounds of investigation on structure-activity relationships step by step, compound 30m was discovered as the most active inhibitor (IC50 = 0.32 μM) with no obvious cytotoxicity (CC50 > 50 μM). It effectively attenuated hypoxia-induced HIF-1α protein accumulation and reduced transcription of vascular epidermal growth factor in a dose-dependent manner, which was further demonstrated by its inhibitory potency on capillary-like tube formation, angiogenesis of zebrafish as well as cellular migration and invasion. Importantly, compound 30m exhibited antimetastatic potency in breast cancer lung metastasis in the mice model, indicating its promising therapeutic potential for prevention and treatment of tumor metastasis. These results definitely merit attention for further rational design of more efficient HIF-1 inhibitors in the future.
- Liu, Mingming,Liang, Yuru,Zhu, Zhongzhen,Wang, Jin,Cheng, Xingxing,Cheng, Jiayi,Xu, Binpeng,Li, Rong,Liu, Xinhua,Wang, Yang
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p. 9299 - 9314
(2019/10/16)
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- P2X3 AND/OR P2X2/3 COMPOUNDS AND METHODS
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The present disclosure provides novel compounds and methods for preparing and using these compounds. In one embodiment, the compounds are of the structure of formula (I), wherein R1-R7 are defined herein. In a further embodiment, these compounds are useful in method for regulating one or both of the P2X3 or P2X2/3 receptors. In another embodiment, these compounds are useful for treating pain in patients by administering one or more of the compounds to a patient. In another embodiment, these compounds are useful for treating respiratory dysfunction in patients by administering one or more of the compounds to a patient.
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Paragraph 0307-0308
(2018/04/17)
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- Practical and efficient synthesis of the (R)-atropisomer of a 4-phenyl 1,2,4-triazole derivative as a selective GlyT1 inhibitor
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Herein we describe a novel and efficient method for synthesizing the (R)-atropisomer of 3-[3-ethyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2- methylbenzonitrile 1, a novel GlyT1 inhibitor. The diastereomeric salt formation of 3-[3-ethyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2-methylbenzoic acid 7 with (1R,2S)-(-)-2-amino-1,2-diphenylethanol afforded the desired (R)-atropisomer. We also report the determination of the absolute configuration of (R)-7 by powder X-ray diffraction.
- Sugane, Takashi,Hamada, Noritaka,Tobe, Takahiko,Hamaguchi, Wataru,Shimada, Itsuro,Maeno, Kyoichi,Miyata, Junji,Suzuki, Takeshi,Kimizuka, Tetsuya,Sakamoto, Shuichi,Tsukamoto, Shin-Ichi
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p. 1528 - 1533
(2013/02/23)
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