1136-45-4Relevant articles and documents
Stem cells are the most sensitive screening tool to identify toxicity of GATA4-targeted novel small-molecule compounds
Karhu, S. Tuuli,V?lim?ki, Mika J.,Jumppanen, Mikael,Kinnunen, Sini M.,Pohjolainen, Lotta,Leigh, Robert S.,Auno, Samuli,F?ldes, Gábor,Boije af Genn?s, Gustav,Yli-Kauhaluoma, Jari,Ruskoaho, Heikki,Talman, Virpi
, p. 2897 - 2911 (2018)
Safety assessment of drug candidates in numerous in vitro and experimental animal models is expensive, time consuming and animal intensive. More thorough toxicity profiling already in the early drug discovery projects using human cell models, which more closely resemble the physiological cell types, would help to decrease drug development costs. In this study we aimed to compare different cardiac and stem cell models for in vitro toxicity testing and to elucidate structure–toxicity relationships of novel compounds targeting the cardiac transcription factor GATA4. By screening the effects of eight compounds at concentrations ranging from 10?nM up to 30?μM on the viability of eight different cell types, we identified significant cell type- and structure-dependent toxicity profiles. We further characterized two compounds in more detail using high-content analysis. The results highlight the importance of cell type selection for toxicity screening and indicate that stem cells represent the most sensitive screening model, which can detect toxicity that may otherwise remain unnoticed. Furthermore, our structure–toxicity analysis reveals a characteristic dihedral angle in the GATA4-targeted compounds that causes stem cell toxicity and thus helps to direct further drug development efforts towards non-toxic derivatives.
Design, synthesis and in vitro biological evaluation of isoxazol-4-carboxa piperidyl derivatives as new anti-influenza A agents targeting virus nucleoprotein
Pei, Shuchen,Xia, Shihao,Yang, Fating,Chen, Junlin,Wang, Mengdie,Sun, Wanlin,Li, Ziqiang,Yuan, Kangyao,Chen, Jun
, p. 4446 - 4454 (2020/02/13)
Influenza infection is a major cause of morbidity and mortality during seasonal epidemics and sporadic pandemics. It is important and urgent to develop new anti-influenza agents with a new mechanism of action. Nucleozin has been reported as a potent antagonist of nucleoprotein accumulation in the nucleus. In this study, a new series of isoxazol-4-carboxa piperidyl derivatives 1a-j were synthesized and their chemical structures were confirmed by 1H, 13C NMR and mass spectral data. Furthermore, all the synthesized compounds were evaluated for in vitro anti-influenza virus activity against influenza virus (A/PR/8/34 H1N1). Among all the compounds, 1a, 1b, 1c, 1f and 1g exhibited more potent activity than the standard drug, and compound 1b has showed most promising anti-influenza virus activity. These results are also consistent with the docking study results in terms of the design of compounds targeting influenza A via viral nucleoprotein.
Oxime-mediated facile access to 5-methylisoxazoles and applications in the synthesis of valdecoxib and oxacillin
Dong, Kui-Yong,Qin, Hai-Tao,Bao, Xing-Xing,Liu, Feng,Zhu, Chen
, p. 5266 - 5268 (2015/01/09)
A palladium-catalyzed efficient synthesis of 5-methylisoxazoles via oxime-mediated functionalization of unactivated olefins is described. The reaction affords a variety of 5-methylisoxazoles in moderate to good yields. To further demonstrate the utility of the method, the rapid synthesis of valdecoxib and oxacillin is reported. (Chemical Equation Presented).
