- Enhanced selectivities for the hydroxyl-directed methanolysis of esters using the 2-acyl-4-aminopyridine class of acyl transfer catalysts: Ketones as binding sites
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In this paper we describe the preparation of a series of 2-acyl-4- aminopyridines, and their use as catalysts for the hydroxyl-directed methanolysis of α-hydroxy esters in preference to α-methoxy esters. Hydroxyl-direction with these catalysts, which contain ketones at the 2- position of the pyridine, is achieved by reversible addition of the alcohol of the hydroxy ester to the ketone to provide the corresponding hemiketal. Their activity is compared to that of the previously described catalyst 2- formyl-4-pyrrolidinopyridine (FPP), which contains an aldehyde at the 2- position of the pyridine. The catalysts which contain ketones at the 2- position range in reactivity from 10 times slower to slightly faster than FPP, and certain of these are much more selective for the methanolysis of hydroxy esters than FPP. This increase in selectivity is ascribed to a decrease in the rate of the nondirected methanolysis reaction with the ketone-derived catalysts. The evidence suggests that the nondirected reaction does not proceed by an intermolecular general base mechanism, but rather via a nucleophilic catalysis mechanism in which the hydroxyl group of the hemiacetal formed upon addition of methanol to the aldehyde of FPP acts as the nucleophile. Since the hydroxyl group derived from a hemiketal is more hindered and less nucleophilic than that derived from a hemiacetal, the nondirected reaction is much slower for the catalysts containing ketones as binding sites.
- Sammakia, Tarek,Hurley, T. Brian
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- Synthesis and evaluation of new thiourea derivatives as antitumor and antiangiogenic agents
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A series of novel thiourea derivatives were synthesized and evaluated by biological activities. Among them, compound 10e containing 3,5-bis(trifluoromethyl)phenyl moiety (R1) at the terminal thiourea and phenylamino (R2) at the terminal acyl position showed the best cytotoxic activities against seven cancer cell lines (NCI-H460, Colo-205, HCT116, MDA-MB-231, MCF-7, HepG2, PLC/PRF/5) and HUVECs. Moreover, compound 10e moderately inhibited various RTKs such as VEGFR2, VEGFR3, and PDGFRβ. Notably, 10e exhibited much better inhibitory effect of tumor formation and antiangiogenic activities than Sorafenib and Regorafenib at the same concentration. Further docking studies suggested that 10e could serve as potential candidate for cancer therapy.
- Bai, Wenjing,Huang, Qiang,Ji, Jianxin,Wei, Wei
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- Discovery of novel picolinamide-based derivatives as novel VEGFR-2 kinase inhibitors: Synthesis,: in vitro biological evaluation and molecular docking
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Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a crucial role in tumor angiogenesis, and inhibition of the VEGFR-2 signaling pathway has emerged as an attractive target for cancer therapy. In our effort, a novel series of picolinamide-based derivatives were designed and synthesized as potent and effective VEGFR-2 inhibitors. All the newly prepared compounds were evaluated in vitro for their antiproliferative activity against A549 and HepG2 cell lines. Among the new compounds, 8j and 8l exhibited better activity against both A549 and HepG2 cell lines. Molecular docking was performed to investigate the binding capacity and binding mode with VEGFR-2 (PDB code: 4ASD).
- Sun, Wuji,Fang, Shubiao,Yan, Hong
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p. 1054 - 1058
(2018/06/27)
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- Design, synthesis and biological activities of sorafenib derivatives as antitumor agents
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A series of novel sorafenib derivatives, 9a-w, was designed and synthesized in high yields using various substituted anilines, and their antiproliferative activities against HCT116, PC-3 and MDA-MB-231 cell lines were also evaluated and described. All compounds exhibited potent antiproliferative activity against HCT116 and PC-3 cells with IC50 = 2.8-52.0 and 2.2-45.6 μM; compounds 9p and 9q demonstrated competitive antiproliferative activities to sorafenib against all three cancer cell lines, the cytotoxicity of compound 9r is more potent than that of sorafenib. Compounds (9g, 9p, 9q and 9r) were chosen for further evaluation of the anti-angiogenesis activity, and showed the inhibition of sprout formation from aortic ring ex vivo. The structures of all the newly synthesized compounds were determined by 1H NMR, 13C NMR and HRMS.
- Yao, Jianwen,He, Zuopeng,Chen, Jing,Sun, Wei,Fang, Hao,Xu, Wenfang
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p. 6549 - 6553,5
(2012/12/12)
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- Design, synthesis and antiproliferative activities of diaryl thiourea derivatives as anticancer agents
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Two new series of diaryl thiourea containing sorafenib derivatives 9a-9t were designed and synthesized, and their antiproliferative activities against PC-3, HCT116 and MDA-MB-231 cell lines were evaluated. All compounds generally showed antiproliferative activity to PC-3 cells, most of the analogs exhibited potent antiproliferative activity to HCT116 cells, and compounds 9e, 9f, 9o and 9p demonstrated inhibitory activities against all three cell lines. The structures of all the newly synthesized compounds were determined by 1H NMR, 13C NMR and HRMS. Two series of diaryl thiourea derivatives have been designed, prepared, and tested for cytotoxicity against human tumor cells PC-3, HCT116 and MDA-MB-231. The results showed that all compounds generally had antiproliferative activity against PC-3 cells, and some compounds demonstrated competitive antiproliferative activities to sorafenib. Copyright
- Yao, Jianwen,He, Zuopeng,Chen, Jing,Chen, Daquan,Sun, Wei,Xu, Wenfang
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p. 2423 - 2430,8
(2020/09/16)
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- DIARYL UREA DERIVATIVES USEFUL FOR THE TREATMENT OF PROTEIN KINASE DEPENDENT DISEASES
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The invention relates to the use of diaryl urea derivatives in the treatment of protein kinase dependent diseases or for the manufacture of pharmaceutical compositions for use in the treatment of said diseases, methods of use of diaryl urea derivatives in the treatment of said diseases, pharmaceutical preparations comprising diaryl urea derivatives for the treatment of said diseases, diaryl urea derivatives for use in the treatment of said diseases, novel diaryl urea derivatives, pharmaceutical preparations comprising these novel diaryl urea derivatives, processes for the manufacture of the novel diaryl urea derivatives, the use or methods of use of the novel diaryl urea derivatives as mentioned above, and/or these novel diaryl urea derivatives for use in the treatment of the animal or human body.
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Page 107, 108
(2008/06/13)
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