- Design, synthesis and biological evaluation of cinnamamide-quinazoline derivatives as potential EGFR inhibitors to reverse T790M mutation
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Gatekeeper T790M mutation in EGFR is the most common factor for acquired resistance. Acrylamide-bearing 4-anilinoquinazoline scaffold are powerful irreversible inhibitors for overcoming resistance. In this work, three series of EGFR inhibitors derived from incorporation of cinnamamide into the quinazoline scaffold were designed and synthesized to reverse resistance resulting from insurgence of T790M mutation. SAR studies revealed that methoxy and acetoxy substitutions on the cinnamic phenyl ring were found to elevate the activity. In particular, compound 7g emerged as the most potent derivative against mutant-type H1975 cells, which exhibited comparable activity to osimertinib (0.95 μM) towards H1975 cells with an IC50 value of 1.22 μM. Kinase inhibition studies indicated that 7g showed excellent inhibitory effect on EGFRT790M enzyme, which was 11 times more effective than gefitinib. Besides, selectivity index of 7g toward the EGFRT790M mutant over the EGFRWT is 2.72, hinting its effect of reducing off-target. Mechanism study indicated that 7g induced apoptosis of H1975 cells and arrest the cell cycle at G2/M phase in a dose-dependent manner. Moreover, 7g could significantly inhibit the expression of p-EGFR and its downstream p-AKT and p-ERK in H1975 cells. Molecular docking was also performed to gain insights into the ligand-binding interactions of 7g inside EGFRWT and EGFRT790M binding sites.
- Zhang, Bin,Xu, Zichen,Liu, Qingqing,Xia, Shengjin,Liu, Zhikun,Liao, Zhixin,Gou, Shaohua
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- HER2 Kinase-Targeted Breast Cancer Therapy: Design, Synthesis, and in Vitro and in Vivo Evaluation of Novel Lapatinib Congeners as Selective and Potent HER2 Inhibitors with Favorable Metabolic Stability
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HER2 kinase as a well-established target for breast cancer (BC) therapy is associated with aggressive clinical outcomes; thus, herein we present structural optimization for HER2-selective targeting. HER2 profiling of the developed derivatives demonstrated
- Elwaie, Tamer A.,Abbas, Safinaz E.,Aly, Enayat I.,George, Riham F.,Ali, Hamdy,Kraiouchkine, Nikolai,Abdelwahed, Khaldoun S.,Fandy, Tamer E.,El Sayed, Khalid A.,Abd Elmageed, Zakaria Y.,Ali, Hamed I.
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p. 15906 - 15945
(2021/01/09)
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- Method for synthesizing lapatinib or intermediate thereof
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The invention relates to a method for synthesizing lapatinib or an intermediate thereof. The method for synthesizing the intermediate comprises the steps as follows: under the condition that a catalytic quantity of a catalyst exists in a solvent, 4-amino-5-(4-(3-chloro-4-(3-fluorobenzyloxy) phenylamino)-quinazoline reacts with furfural for preparation of 5-(4-(3-chloro-4-(3-fluorobenzyloxy) phenylamino)-quinazoline-6-yl)furyl-2-carboxaldehyde hydrochloride, and the intermediate is prepared. The invention further relates to a method for synthesizing lapatinib and/or salt of lapatinib, the intermediate of lapatinib and/or pharmaceutically acceptable salt of the intermediate, and the method is performed with the intermediate which is synthesized by the previous method. The method has the advantages that steps are simplified, a reagent is cheap, available and high in use ratio, pollution from heavy metal is avoided, and requirements for reaction conditions/operation are relatively low and/or the yield is high.
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- Design, synthesis and biological evaluation of quinazoline–phosphoramidate mustard conjugates as anticancer drugs
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A series of novel compounds with phosphoramide mustard functionality incorporated into the quinazoline scaffold of EGFR/HER2 inhibitors were designed and synthesized as multi-target-directed ligands against tumor cells. In?vitro assays showed that tumor cell lines with high HER2 level were more sensitive to the compounds than tumor cells with low HER2 level. Compound 10d (EMB-3) was one of the most potent inhibitors with IC50of 7.4?nM and 82?nM against EGFR and HER2, respectively. The mechanism studies were also supported by the effect of 10d-induced DNA damage in MDA-MB-468?cells. In?vivo efficacy study showed that 10d could significantly inhibit H522 tumor xenograft model with a TGI of 68% at dose of 100?mg/kg (QDx28, p.o.) and no significant body weight loss was observed. MTD study indicated that compound 10d had no acute toxicity to mice at doses up to 900?mg/kg (single dose).
- Lin, Songwen,Li, Yingbo,Zheng, Yufen,Luo, Laichun,Sun, Qi,Ge, Zemei,Cheng, Tieming,Li, Runtao
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p. 442 - 458
(2017/01/18)
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- Toward discovery of mutant EGFR inhibitors; Design, synthesis and in vitro biological evaluation of potent 4-arylamino-6-ureido and thioureido-quinazoline derivatives
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A new series of 4-anilinoquinazolines with C-6 ureido and thioureido side chains and various substituents at the C-4 anilino moiety was designed, synthesized and evaluated as wild type (WT) and mutant EGFR inhibitors. Most of the compounds inhibited EGFR kinase wild type (EGFR WT) with IC50values in the low nanomolar range (50?=?1.76–2.38?μM) in these mutant lines and significant Her2 enzyme inhibition (IC50?=?19.2–40.6?nM) compared to lapatinib (60.1?nM). The Binding mode of compounds 6d, 6f, 7a, 7b and 8b were demonstrated. Furthermore, growth inhibition against gefitinib insensitive cell lines PC9-GR4 (Del19/T790M) were tested, compounds 6f and 7e showed about eight and three folds respectively greater potency than gefitinib. Our structure–activity relationships (SAR) studies suggested that presence of ethyl piperidino urea/thiourea at 6-position and bulky group of (3-chloro-4-(3-fluorobenzyloxy)phenyl)amino at 4-position of quinazoline may serve as promising scaffold for developing inhibitors against wild type and mutant EGFR.
- Mowafy, Samar,Galanis,Doctor, Zainab M.,Paranal, Raymond M.,Lasheen, Deena S.,Farag, Nahla A.,J?nne, Pasi A.,Abouzid, Khaled A.M.
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p. 3501 - 3512
(2016/07/20)
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- Microwave-assisted synthesis of new 6-ureido-4-anilinoquinazoline derivatives
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An efficient rapid method for the synthesis of new 6-ureido-4-anilinoquinazoline derivatives derived from 2-amino-5-nitrobenzoic acid under microwave irradiation has been developed. All of the new compounds were identified by 1H NMR, 13C NMR, IR, MS and elemental analyses.
- Zheng, Youguang,Gao, Caiyun,Huang, Rongrong,Liu, Yi,Xue, Yunsheng,An, Lin
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- Targeting EGFR/HER2 tyrosine kinases with a new potent series of 6-substituted 4-anilinoquinazoline hybrids: Design, synthesis, kinase assay, cell-based assay, and molecular docking
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Coexpression of EGFR and HER2 has been found in many tumors such as breast, ovarian, colon and prostate cancers, with poor prognosis of the patients. Herein, our team has designed and synthesized new eighteen compounds with 6-substituted 4-anilinoquinazol
- Elkamhawy, Ahmed,Farag, Ahmed Karam,Viswanath, Ambily Nath Indu,Bedair, Tarek M.,Leem, Dong Gyu,Lee, Kyung-Tae,Pae, Ae Nim,Roh, Eun Joo
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p. 5147 - 5154
(2015/11/09)
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- Metabolism and pharmacokinetics of allitinib in cancer patients: The roles of cytochrome p450s and epoxide hydrolase in its biotransformations
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Allitinib, a novel irreversible selective inhibitor of the epidermal growth factor receptor (EGFR) 1 and human epidermal receptor 2 (ErbB2), is currently in clinical trials in China for the treatment of solid tumors. It is a structural analog of lapatinib but has an acrylamide side chain. Sixteen metabolites of allitinib were detected by ultra-high-performance liquid chromatography/quadrupole time-offlight mass spectrometry. The pharmacologically active a,b-unsaturated carbonyl group was the major metabolic site. The metabolic pathways included O-dealkylation, amide hydrolysis, dihydrodiol formation, hydroxylation, and secondary phase 2 conjugation. The metabolite of amide hydrolysis (M6) and 27,28-dihydrodiol allitinib (M10) were the major pharmacologically active metabolites in the circulation. The steady-state exposures to M6 and M10 were 11% and 70% of that of allitinib, respectively. The biotransformation of allitinib was determined using microsomes and recombinant metabolic enzymes. In vitro phenotyping studies demonstrated that multiple cytochrome P450 (P450) isoforms, mainly CYP3A4/5 and CYP1A2, were involved in the metabolism of allitinib. Thiol conjugates (M14 and M16) and dihydrodiol metabolites (M5 and M10) were detected in humans, implying the formation of reactive intermediates. The formation of a glutathione conjugate of allitinib was independent of NADPH and P450 isoforms, but was catalyzed by glutathione-Stransferase. P450 enzymes and epoxide hydrolase were involved in M10 formation. Overall, our study showed that allitinib was metabolized by the O-dealkylation pathway similar to lapatinib, but that amide hydrolysis and the formation of dihydrodiol were the dominant metabolic pathways. The absorbed allitinib was extensively metabolized by multiple enzymes.
- Lin, Lishan,Xie, Cen,Gao, Zhiwei,Chen, Xiaoyan,Zhong, Dafang
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p. 872 - 884
(2014/05/06)
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- AMINOQUINAZOLINE DERIVATIVES AND THEIR SALTS AND METHODS OF USE THEREOF
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Provided herein are aminoquinazoline compounds, salts and uses thereof. The compounds have Formula (I), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug ther
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- Combinatorial synthesis of labelled drugs and PET tracers: Synthesis of a focused library of 11C-carbonyl-labelled acrylamides as potential biomarkers of EGFR expression
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Combinatorial synthesis is extensively used in drug development and lead optimisation. However, this approach has rarely been used for positron emission tomography because of limitations in available technologies. [ 11C]Carbon monoxide is amenable to combinatorial synthesis in transition-metal-catalysed reactions because it can react with a wide variety of electrophiles and nucleophiles, which opens up the possibilities for combinatorial radiochemistry. Herein, we exemplify the combinatorial approach by 11C-labelling a library of epidermal growth factor receptor inhibitors. The selection of candidates was guided by molecular docking. Epidermal growth factor receptor is overexpressed in a variety of tumours, and it has become an important drug target. The 11C-labelling reactions were performed using four substituted vinyl iodides and three different 4-anilino-6-aminoquinazolines using a palladium-mediated reaction with [ 11C]carbon monoxide using a single set of reaction conditions. In total, 12 labelled acrylamide derivatives were radiolabelled and obtained in 24-61% decay-corrected radiochemical yield (from [11C]carbon monoxide). Starting from 5.6 GBq [11C]carbon monoxide, 0.85 GBq of formulated N-[4-(3-bromo-phenylamino)-quinazolin-6-yl]-acryl[ 11C]amide [11C]12da was obtained within 47 min from end of bombardment (specific activity of 60 GBq μmol-1). This strategy is an example of how [11C]carbon monoxide can be utilised in the labelling of libraries of drug candidates and positron emission tomography tracers for in vitro and in vivo testing. Copyright
- ?berg, Ola,L?ngstr?ma, Bengt
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p. 477 - 483
(2013/03/28)
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- The polymorph forms of 4-anilinoquinazoline derivatives, the preparation methods and uses thereof
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The present invention relates to polymorphic forms of N-{4-[3-chloro-4-(3-fluoro-benzyloxy)phenylamino]-quinazolin-6-yl}-acrylamide p-toluenesulfonate with the characteristic X-ray powder diffraction data as stated in the description, preparation methods
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- Compositions Comprising Quinazoline Derivatives, Preparation Methods and Uses Thereof
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The present invention provides a pharmaceutical composition, useful for the treatment of diseases characterized by abnormal PTKs activity of erbB family in a mammal, comprising pharmaceutically acceptable salts of N-{4-[3-chloro-4-(3-fluoro-benzyloxy)phen
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- COMPOSITIONS COMPRISING QUINAZOLINE DERIVATIVES, PREPARATION METHODS AND USES THEREOF
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The present invention provides a pharmaceutical composition, useful for the treatment of diseases characterized by abnormal PTKs activity of erbB family in a mammal, comprising pharmaceutically acceptable salts of N-{4-[3-chloro-4-(3-fluoro-benzyloxy) phe
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- THE POLYMORPHS OF 4-ANILINOQUINAZOLINE DERIVATIVES, THE PREPARATION METHODS AND USES THEREOF
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The present invention relates to polymorphic forms of N-{4-[3-chloro-4-(3-fluoro-benzyloxy)phenylamino]-quinazolin-6-yl}-acrylamide p-toluenesulfonate with the characteristic X-ray powder diffraction data as stated in the description, preparation methods
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- SALTS OF 4-ANILINE QUINAZOLINE DERIVATIVE
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The present invention relates to salt forms of N-{4-[3-chloro-4-(3-fluoro-benzyloxy)phenylamino]-quinazolin-6-yl}-acrylamide, methods for preparation thereof, pharmaceutical compositions comprising the same and their use thereof. The salt forms of the pre
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Page/Page column 4
(2010/07/08)
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- THE SALTS OF 4-ANILINE QUINAZOLINE DERIVATIVE
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The present invention relates to salt forms of N-{4-[3-chloro-4-(3-fluoro-benzyloxy)phenylamino]-quinazolin-6-yl}-acrylamide, methods for preparation thereof, pharmaceutical compositions comprising the same and their use thereof. The salt forms of the pre
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Page/Page column 6
(2009/12/05)
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- QUINAZOLINE DERIVATIVES,PREPARATION METHODS AND USES THEREOF
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The present invention has disclosed a compound of formula I and a pharmaceutically acceptable salt or a solvate thereof, wherein the substituents are as defined in the description. The invention has also disclosed a method for preparing the compound of formula I, the pharmaceutical compositions comprising the same and their uses in the preparation of an anti- tumor medicament.
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Page/Page column 9
(2008/12/08)
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- Quinazoline Derivatives, Preparation Methods and Uses Thereof
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The present invention has disclosed a compound of formula I and a pharmaceutically acceptable salt or a solvate thereof, wherein the substituents are as defined in the description. The invention has also disclosed a method for preparing the compound of formula I, the pharmaceutical compositions comprising the same and their uses in the preparation of an anti-tumor medicament.
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Page/Page column 5-6
(2009/01/20)
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- QUINAZOLINE DERIVATIVES FOR INHIBITING CANCER CELL GROWTH AND METHOD FOR THE PREPARATION THEREOF
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The present invention relates to a novel quinazoline derivative and a pharmaceutically acceptable salt thereof for inhibiting the growth of cancer cells, a method for the preparation thereof and a pharmaceutical composition comprising same as an active ingredient.
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Page/Page column 35-36
(2008/06/13)
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