295330-64-2Relevant articles and documents
Design, synthesis and biological evaluation of sulfamoylphenyl-quinazoline derivatives as potential EGFR/CAIX dual inhibitors
Zhang, Bin,Liu, Zhikun,Xia, Shengjin,Liu, Qingqing,Gou, Shaohua
, (2021/03/01)
Multi-target, especially dual-target, drug design has become a popular research field for cancer treatment. Development of small molecule dual-target inhibitors through hybridization strategy can provide highly potent and selective anticancer agents. In this study, three series of quinazoline derivatives bearing a benzene-sulfonamide moiety were designed and synthesized as dual EGFR/CAIX inhibitors. All the synthesized compounds were evaluated against epidermoid carcinoma (A431) and non-small cell lung cancer (A549 and H1975) cell lines, which displayed weak to potent anticancer activity. In particular, compound 8v emerged as the most potent derivative against mutant-type H1975 cells, which exhibited comparable activity to osimertinib. Importantly, 8v exhibited stronger anti-proliferative activity than osimertinib against H1975 cells under hypoxic condition. Kinase inhibition studies indicated that 8v showed excellent inhibitory effect on EGFRT790M enzyme, which was 41 times more effective than gefitinib and almost equal to osimertinib. Mechanism studies revealed that 8v exhibited remarkable CAIX inhibitory effect comparable to acetazolamide and significantly inhibited the expression of p-EGFR as well as its downstream p-AKT and p-ERK in H1975 cells. Notably, 8v was found to inhibit the expression of CAIX and its upstream HIF-1α in H1975 cells under hypoxic condition. Molecular docking was also performed to gain insights into the ligand-binding interactions of 8v inside EGFRWT, EGFRT790M and CAIX binding sites.
Facile Synthesis of Novel Perfluorocarbon-Modulated 4-Anilinoquinazoline Analogues
Shi, Huiping,Lai, Bonan,Chen, Shizhen,Zhou, Xin,Nie, Jing,Ma, Jun-An
, p. 1693 - 1700 (2017/09/06)
4-Anilinoquinazoline analogues stand out among many kinds of small molecules that inhibit the tyrosine kinase activities of epidermal growth factor receptor (EGFR), thus serving as significant molecular targets for anticancer drug design. Herein, a series of novel perfluorocarbon (PFC) modulated 4-anilinoquinazolines were designed and prepared straightforwardly by nucleophilic substitution reaction of various anilinoquinazolines and PFC-derived methanesulfonate. In the presence of base, the reaction proceeded smoothly to afford a wide range of 4-anilinoquinazolines with different substituents on aniline moiety in good to high yields. Furthermore, the PFC-modified analogues of gefitinib and erlotinib were also obtained in 93% and 90% respectively, which may have potential for developing new inhibitors of the epidermal growth factor receptor (EGFR) tyrosine kinase and fluorinated contrast agents (CA) for 19F MRI.
Model 18 F mark 4-amino-quinazoline derivatives and its preparation method and tumor PET imaging applications
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Paragraph 0104-0106, (2016/11/28)
The invention provides novel F marked 4-aminoquinazoline compounds. The novel F marked 4-aminoquinazoline compounds are characterized in that one end of each of the novel F marked 4-aminoquinazoline compounds has a F substituted alkyloxy structure; the other end of each of the compounds has a 6,7-substituted quinazoline structure, and a substituent R1 is positioned in the 3 position of a 4-aminobenzene ring which is the quinazoline maternal, and is H, F, Cl, Br, I, a trifluoromethyl group or an acetenyl group; a substituent R2 is positioned in the 4 position of the 4-aminobenzene ring which is the quinazoline maternal, and is H, F, Cl, Br, a methyl group, a methoxy group, a 3-fluorophenoxyl group, or a 2-pyridyloxy group; and n is 1-5. The structural formula of the compounds is shown as A in the specification. Results of experiments show that the precursor of the marker of the compounds is easy to synthesize, marks through using a two-step method and has a high marking rate. The compounds have a good bioactivity, for example, the compounds have high absorption and slow removal in tumor tissues and low intake and fast removal in normal tissues and blood, so the compounds have a high tumor/background ratio, and especially have a high tumor/blood ratio, a high tumor/flesh ratio and a high tumor/brain ration, are in favor of the PET tumor development, and perform a huge potential as a brain tumor developer.
