162012-69-3Relevant articles and documents
Design, synthesis, antiproliferative activity and docking studies of quinazoline derivatives bearing oxazole or imidazole as potential EGFR inhibitors
OuYang, Yiqiang,Wang, Caolin,Zhao, Bingbing,Xiong, Hehua,Xiao, Zhen,Zhang, Bingliang,Zheng, Pengwu,Hu, Jiayi,Gao, Yanli,Zhang, Manli,Zhu, Wufu,Xu, Shan
, p. 17203 - 17215 (2018)
Six series of quinazoline derivatives bearing oxazole or imidazole (8a-f, 9a-f, 10a-d, 11a-f, 12a-d and 13a-i) were designed, synthesized and their IC50 values evaluated against three cancer cell lines (A549, MCF-7 and PC-3). Most of the thirty-five target compounds showed excellent antiproliferative activity against one or several cancer cell lines. Compound 12a showed the best activity against A549, MCF-7 and PC-3 cancer cell lines, with IC50 values of 1.90 ± 0.13 μM, 2.23 ± 0.28 μM and 2.03 ± 0.14 μM, respectively. Four selected compounds (8a, 9d, 10a and 12a) were further evaluated for the inhibitory activity against EGFR kinase. AnnexinV-FITC, propidium iodide (PI) double staining and acridine orange single staining results indicated that compound 12a could induce apoptosis of human lung cancer A549 cells.
Structure-based virtual screening of Src kinase inhibitors
Lee, Kyungik,Kim, Jongwoo,Jeong, Ki-Woong,Lee, Ki Won,Lee, Yeonjoo,Song, Ji Yeon,Kim, Maeng Sup,Lee, Gwan Sun,Kim, Yangmee
, p. 3152 - 3161 (2009)
Src is an important target in multiple processes associated with tumor growth and development, including proliferation, neovascularization, and metastasis. In this study, hit identification was performed by virtual screening of commercial and in-house compound libraries. Docking studies for the hits were performed, and scoring functions were used to evaluate the docking results and to rank ligand-binding affinities. Subsequently, hit optimization for potent and selective candidate Src inhibitors was performed through focused library design and docking analyses. Consequently, we report that a novel compound '43' with an IC50 value of 89 nM, representing (S)-N-(4-(5-chlorobenzo[d][1,3]dioxol-4-ylamino)-7-(2-methoxyethoxy)quin azolin-6-yl)pyrrolidine-2-carboxamide, is highly selective for Src in comparison to EGFR (IC50 ratio > 80-fold) and VEGFR-2 (IC50 ratio > 110-fold). Compound 43 exerted anti-proliferative effects on Src-expressing PC3 human prostate cancer and A431 human epidermoid carcinoma cells, with calculated IC50 values of 1.52 and 0.78 μM, respectively. Moreover, compound 43 (0.1 μM) suppressed the phosphorylation of extracellular signal-regulated kinases and p90 ribosomal S6 kinase, downstream molecules of Src, in a time-dependent manner, in both PC3 and A431 cell lines. The docking structure of compound 43 with Src disclosed that the chlorobenzodioxole moiety and pyrrolidine ring of C-6 quinazoline appeared to fit tightly into the hydrophobic pocket of Src. Additionally, the pyrrolidine NH forms a hydrogen bond with the carboxyl group of Asp348. These results confirm the successful application of virtual screening studies in the lead discovery process, and suggest that our novel compound 43 can be an effective Src inhibitor candidate for further lead optimization.
Afatinib refined product synthetic method
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, (2019/06/12)
The invention discloses an afatinib refined product synthetic method, and belongs to the technical field of organic synthesis. The method particularly comprises the following steps that 4-fluoro-2-aminobenzoic acid and formamidine acetate are subjected to a ring-closure reaction to synthesize a compound of the formula I; the compound of the formula I is subjected to a nitration reaction to synthesize a compound of the formul II; the compound of the formula II and 3-chloro-4-fluoroaniline are subjected to dehydration to synthesize a compound of the formula III, the compound of the formula III and 3-hydroxy-tetrahydrofuran synthesize a compound of a formula IV through a nucleophilic substitution reaction; the compound of the formula IV is reduced to generate a compound of the formula V underthe Pd/C catalysis; the compound of the formula V and crotonic acid synthesizes a compound of the formula VI through a dehydration condensation reaction; the compound of the formula VI and dimethylamine finally synthesize the compound of the formula VII, that is to say, an afatinib refined product is obtained. According to the afatinib refined product synthetic method, the reaction process condition is mild, the corrosion risk to reaction equipment is lowered, the reaction process is simplified, operation is easy, the purity of the product is high, and the yield is increased conveniently.
STEFs: Activated Vinylogous Protein-Reactive Electrophiles
Hansen, Bente K.,Loveridge, Christopher J.,Thyssen, Stine,W?rmer, Gustav J.,Nielsen, Andreas D.,Palmfeldt, Johan,Johannsen, Mogens,Poulsen, Thomas B.
supporting information, p. 3533 - 3537 (2019/02/14)
Reported here is the synthesis of a class of semi-oxamide vinylogous thioesters, designated STEFs, and the use of these agents as new electrophilic warheads. This work includes preparation of simple probes that contain this reactive motif as well as its installation on a more complex kinase inhibitor scaffold. A key aspect of STEFs is their reactivity towards both thiol and amine groups. Shown here is that amine conjugations in peptidic and proteinogenic samples can be facilitated by initial, fast conjugation to proximal thiol residues. Evidence that both the selectivity and the reactivity can be tuned by the structure of STEFs is provided, and given the unique ability of this functionality to conjugate by an addition-elimination mechanism, STEFs are electrophilic warheads that could find broad use in chemical biology.
