- Discovery of Potent EGFR Inhibitors With 6-Arylureido-4-anilinoquinazoline Derivatives
-
According to the classical pharmacophore fusion strategy, a series of 6-arylureido-4-anilinoquinazoline derivatives (Compounds 7a–t) were designed, synthesized, and biologically evaluated by the standard CCK-8 method and enzyme inhibition assay. Among the title compounds, Compounds 7a, 7c, 7d, 7f, 7i, 7o, 7p, and 7q exhibited promising anti-proliferative bioactivities, especially Compound 7i, which had excellent antitumor activity against the A549, HT-29, and MCF-7 cell lines (IC50 = 2.25, 1.72, and 2.81?μM, respectively) compared with gefitinib, erlotinib, and sorafenib. In addition, the enzyme activity inhibition assay indicated that the synthesized compounds had sub-micromolar inhibitory levels (IC50, 11.66–867.1?nM), which was consistent with the results of the tumor cell line growth inhibition tests. By comparing the binding mechanisms of Compound 7i (17.32?nM), gefitinib (25.42?nM), and erlotinib (33.25?nM) to the EGFR, it was found that Compound 7i could extend into the effective region with a similar action conformation to that of gefitinib and interact with residues L85, D86, and R127, increasing the binding affinity of Compound 7i to the EGFR. Based on the molecular hybridization strategy, 14 compounds with EGFR inhibitory activity were designed and synthesized, and the action mechanism was explored through computational approaches, providing valuable clues for the research of antitumor agents based on EGFR inhibitors.
- Li, Meng,Xue, Na,Liu, Xingang,Wang, Qiaoyun,Yan, Hongyi,Liu, Yifan,Wang, Lei,Shi, Xiaowei,Cao, Deying,Zhang, Kai,Zhang, Yang
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- Discovery of quinazolinyl-containing benzamides derivatives as novel HDAC1 inhibitors with in vitro and in vivo antitumor activities
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A series of quinazolinyl-containing benzamide derivatives were designed, synthesized and evaluated for their in vitro histone deacetylase 1 (HDAC1) inhibitory activities. Compounds 11a surpassed the known class I selective HDAC inhibitor MS-275 in both HDAC1 enzymatic inhibitory activity and cellular anti-proliferative activity against a selected set of cancer cell types (Hut78, K562, Hep3B and HCT116 cells) with no observed effects on human normal cells. In particular, compound 11a inhibited HDAC1 over the other tested HDACs isoforms (HDAC2, HDAC6 and HDAC8) with acceptable safety profiles. Moreover, compound 11a displayed favorable oral pharmacokinetic properties and showed significant antitumor activity in the A549 tumor xenograft model in vivo.
- Zhang, Zixue,Zhang, Qingwei,Zhang, Hao,Jiao, Minru,Guo, Zheng,Peng, Xinyan,Fu, Lei,Li, Jianqi
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-
- Preparation method of medicine for treating bile duct cancer
-
The invention belongs to the field of medical industry, and discloses a preparation method of a medicine for treating bile duct cancer. The preparation method of the drug Varlitinib for treating bileduct cancer comprises the following steps: with 2-amino-5-nitrobenzoic acid as a starting material, carrying out cyclization and chlorination on 2-amino-5-nitrobenzoic acid and methylimidazole acetateso as to synthesize an intermediate I; with 2-chloro-5-nitrophenol as a starting material, carrying out 2-chloromethylthiazole substitution and nitro reduction to synthesize an intermediate II; with1-amino-2-propanol as a starting material, carrying out a cyclization reaction of BTC, and carrying out chlorination to synthesize an intermediate III; and carrying out C-N coupling and nitro reduction on the intermediate I and the intermediate II, and finally carrying out a C-N coupling reaction on the intermediate I and the intermediate II and an intermediate III to synthesize Varlitinib. The method is simple and convenient to synthesize, short in route, economical in raw materials, high in yield, friendly to environment and suitable for industrial production.
- -
-
Paragraph 0016; 0028; 0033-0034
(2020/08/23)
-
- Design, synthesis and biological evaluation of 4-aniline quinazoline derivatives conjugated with hydrogen sulfide (H2S) donors as potent EGFR inhibitors against L858R resistance mutation
-
In this study, a series of 4-aniline quinazoline derivatives bearing hydrogen sulfide (H2S) donors were designed, synthesized and evaluated for biological activities. The synthesized compounds were screened for the enzymatic activities against EGFR and EGFR mutants by kinase target-based cell screening method. The results demonstrate that most compounds exhibit selectively inhibitory activities against TEL-EGFR-L858R–BaF3, especially compound 9h with GI50 = 0.008 μM (TEL-EGFR-L858R–BaF3), 0.0069 μM (TEL-EGFR-C797S–BaF3), >10 μM (BaF3), >10 μM (TEL-EGFR-BaF3) and 6.03 μM (TEL-EGFR-T790M-L858R–BaF3). The results from anti-proliferative assays in two NSCLC cell lines indicate that synthetic derivatives (9g, 9h, 15e and 15f) with H2S donor ACS81 display greater anti-proliferative potency against NSCLC cell line H3255 bearing EGFR mutant (L858R) with GI50 values ranging from 0.3486 to 1.348 μM. In addition, compound 9h exhibits weak anti-proliferative effects on other tumor cells (HepG2, MCF-7, HT-29 and A431) and has lower toxic effect on HUVEC cells than AZD9291 (positive control). Meanwhile, compound 9h inhibits the phosphorylation of EGFR in H3255 cells in a dose-dependent manner. Cell cycle analysis reveals that compound 9h suppresses the proliferation of cells by inducing cell cycle arrest in G0-G1 phase. The result of H2S release evaluation suggests that the H2S release of compound 9h is significantly more and faster than other compounds.
- An, Lin,Gao, Cai-Yun,Li, Cheng-Lin,Liu, Yi,Meng, Long,Wu, Xiao-Qing,Xu, Liang,Zhang, Ling,Zhang, Wu-Qi,Zheng, You-Guang
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-
- Design of Turn-On Near-Infrared Fluorescent Probes for Highly Sensitive and Selective Monitoring of Biopolymers
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Simple, sensitive, and selective detection of specific biopolymers is critical in a broad range of biomedical and technological areas. We present a design of turn-on near-infrared (NIR) fluorescent probes with intrinsically high signal-to-background ratio
- Ducharme, Gerard T.,LaCasse, Zane,Nesterov, Evgueni E.,Nesterova, Irina V.,Sheth, Tanya
-
supporting information
p. 8440 - 8444
(2020/03/24)
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- Intramolecular Ring-Opening of Oxetanes: Access to Functionalised Hydroxymethyl 2,3-Dihydroimidazo[1,2- c ]quinazolines
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An intramolecular oxetane ring-opening was developed, affording novel 2-(hydroxymethyl)-2,3-dihydroimidazo[1,2- c ]quinazolines from N -(3-methyloxetan-3-yl)quinazolin-4-amines under mild conditions. The resulting medicinally relevant tricyclic scaffolds were synthesised in good yields with diverse substituents. Moreover, reaction optimisation led to the development of a one-pot procedure.
- Bagal, Sharan K.,Bodnarchuk, Michael S.,King, Thomas A.,Luo, Xuehong,McKerrecher, Darren,Steward, Oliver R.,Wang, Peng
-
supporting information
p. 502 - 506
(2020/03/13)
-
- Hetero-aromatic compound and its use in medicine
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The invention provides a hetero-aromatic compound or a stereisomer, geometric isomer, tautomer, despinner, nitrogen oxide, hydrate, solvate, metabolite, metabolism precursor and pharmaceutically acceptable salt or prodrug thereof, which is used for treating proliferative diseases. The invention also discloses a pharmaceutical composition containing the compound and an application of the compound or pharmaceutical composition thereof in preparation of a medicine for treating proliferative diseases.
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-
- Method for preparing lapatinib key intermediates
-
The invention discloses a method for preparing lapatinib key intermediates. The method includes steps of (1), carrying out chlorination on formamidine or salt of the formamidine and N-chlorosuccinimide to prepare compounds 2 or salt of the compounds 2; (2), carrying out reaction on the compounds 2 or the salt of the compounds 2 and compounds 3 to obtain compounds 5; (3), carrying out reaction on the compounds 5 and thionyl chloride to obtain compounds 6 which are the lapatinib key intermediates. The method has the advantages of inexpensive and easily available starting materials, simplified steps, high atom utilization rate, mild reaction conditions, high yield, suitability for industrial production and the like.
- -
-
Paragraph 0010; 0024; 0036-0041; 0050-0053
(2018/09/12)
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- Design, synthesis, and biological evaluation of novel 4-anilinoquinazoline derivatives bearing amino acid moiety as potential EGFR kinase inhibitors
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In this study, a series of 4-anilinoquinazoline derivatives bearing amino acid moiety were designed, synthesized and evaluated for biological activities. The synthesized compounds were screened for anticancer activity against human hepatocellular carcinoma cell HepG2 using SRB assay. In?vitro cell growth inhibition assays indicated that compound 6m exhibited moderate inhibitory activities only against human hepatocellular carcinoma cells HepG2 with IC50 of 8.3?μM. Synthetic derivatives showed excellent selectivity, such as compound 6m demonstrated a strong inhibition of EGFR (IC50?=?0.0032?μM), with selectivity of over 2000-fold over other kinases. Apoptosis analysis revealed that compound 6m caused obvious induction of cell apoptosis. 6m significantly down-regulated the expression of Bcl-2 and up-regulated the expression of Bax, decreased mitochondrial membrane potential (ΔΨm), promoted the mitochondrial cytochrome c release into the cytoplasm, activated caspase-3, and finally induced apoptosis of HepG2 cells. Molecular docking indicated that compound 6m could bind well with EGFR. Therefore, compound 6m may be a potential agent for cancer therapy deserving further research.
- Zheng, You-Guang,Su, Jun,Gao, Cai-Yun,Jiang, Ping,An, Lin,Xue, Yun-Sheng,Gao, Jian,Liu, Yi
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p. 393 - 405
(2017/03/10)
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- Design, synthesis and biological evaluation of novel histone deacetylase inhibitors incorporating 4-aminoquinazolinyl systems as capping groups
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A series of hydroxamic acid-based HDACIs with 4-aminoquinazolinyl moieties as capping groups was profiled. Most compounds showed more potent HDACs inhibition activity than clinically used drug SAHA. Among them, compounds 5f and 5h selectively inhibited HDAC 1,2 over HDAC8, and showed strong activity in several cellular assays, not possessing significant toxicity to primary human cells and hERG inhibition. Strikingly, 5f possessed acceptable pharmacokinetic characteristics and exhibited significant antitumor activity in an A549 xenograft model study at well tolerated doses.
- Zhang, Qingwei,Li, Yang,Zhang, Baoyin,Lu, Bingliu,Li, Jianqi
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supporting information
p. 4885 - 4888
(2017/09/27)
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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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- 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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- 6-AMINO QUINAZOLINE OR 3-CYANO QUINOLINE DERIVATIVES, PREPARATION PROCESS AND PHARMACEUTICAL USE THEREOF
-
The present disclosure relates to 6-amino quinazoline or 3-cyano quinoline derivatives, preparation processes and pharmaceutical compositions containing them. Specifically, the present disclosure relates to novel 6-amino quinazoline or 3-cyano quinoline derivatives presented by formula (I), or its tautomer, enantiomer, diastereomer, racemate or pharmaceutically acceptable salts thereof, or metabolite, metabolic precursor or prodrug thereof, and the uses for treatment especially for protein kinase inhibitors, in which each substitute group of general formula (I) is as defined in the specification.
- -
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Page/Page column 41
(2016/10/08)
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- Phenyl [...] compound and its preparation method, pharmaceutical composition, drug use (by machine translation)
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The invention provides a phenylurea coupling quinazoline compound or a pharmaceutically acceptable salt thereof represented by formula (I), wherein R1 represents H, represents Br, Cl or F, represents -CH3, -CH2-CH3, -CH2(CH3)2 or -CF3, represents -O-CH3, -O-CH2-CH3 or -O-CH2(CH3)2, or represents -C[triple bond]CH or -C[triple bond]N; n1 is 1, 2, 3, 4 or 5; one of R2 and R3 is a group represented by formula (II); R4 represents H, represents Br, Cl or F, represents -CH3, -CH2-CH3, -CH2(CH3)2 or -CF3, represents -O-CH3, -O-CH2-CH3 or -O-CH2(CH3)2, represents -NH2, or represents -NO2; n2 is 1, 2, 3, 4 or 5; and the other one of R2 and R3 represents H, -O-CH3, -O-CH2-CH3, -O-CH2(CH3)2, or the following groups.
- -
-
Paragraph 0329; 0331; 0334; 0335
(2016/10/27)
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- H2S donor compound based on quinazoline structure and application thereof
-
The invention discloses an H2S donor compound based on a quinazoline structure and an application thereof. The H2S donor compound is a compound shown as a formula (I) or a pharmaceutically-acceptable salt thereof, wherein Ar is substituted or unsubstituted phenyl, and a substituent thereof is selected from one or more of halogen, nitro, C1-C4 alkyl, halogenated C1-C4 alkyl, alkoxy with 1-4 carbon atoms and halogenated alkoxy with 1-4 carbon atoms; X is alkoxy with 1-4 carbon atoms, a B-NH or A-CH2CO-NH- group; Y is a H, B-CnH2nO- or A-CnH2nO- group; A or B is a H2S donor group; n is an integer being 1-5; Y is not H when X is alkoxy with 1-3 carbon atoms. A series of H2S donor compounds based on a 4-anilino quinazoline structure are designed and synthesized, and the antineoplastic activity of a medicament is increased under the synergistic action of H2S and 4-anilino quinazoline derivatives. The formula of the H2S donor compound is shown in the description.
- -
-
Paragraph 0181-0190
(2017/07/20)
-
- TARGETED COVALENT PROBES AND INHIBITORS OF PROTEINS CONTAINING REDOX-SENSITIVE CYSTEINES
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Covalent, irreversible small-molecule inhibitors that modify the sulfenyl form (i.e., sulfenic acid, RSOH and sulfenamide, RSNR'2) of therapeutically important proteins (particularly kinases and phosphatases) are disclosed, where the compositions include a compound having a substituted aryl or heterocyclic core structure that promotes binding interactions with a specific protein, and a nucleophilic reaction center (carbon, nitrogen, sulfur, or phosphorous) that is capable of forming a covalent bond with a sulfenic acid- or sulfenamide-modified cysteine residue in the protein. Methods for synthesizing these compounds are also disclosed, as well as methods of using them for determining the bioactivity of a chemical composition comprising an active compound toward a specific protein and for determining the potency of an inhibitor against a specific protein.
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-
- Design, synthesis and bioactivities evaluation of novel quinazoline analogs containing oxazole units
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A novel type of quinazoline derivatives, which were designed by the combination of quinazoline as the backbone and oxazole scaffold as the substituent, have been synthesized and their biological activities were evaluated for anti-proliferative activities and EGFR inhibitory potency. Compound 12b demonstrated the most potent inhibitory activity (IC 50=0.95 μmol/L for EGFR), which could be optimized as a potential EGFR inhibitor in the further study. The structures of the synthesized quinazoline analogs and all intermediates were comfirmed by 1H and 13C NMR, 2D NMR spectra, IR spectra and MS spectra. Copyright
- Hou, Xuehui,Zhang, Jingyu,Zhao, Xuan,Chang, Liming,Hu, Ping,Liu, Hongmin
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p. 538 - 544
(2014/07/08)
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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
- -
-
Paragraph 00255-00256
(2014/11/13)
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- Synthesis, biological evaluation and QSAR study of a series of substituted quinazolines as antimicrobial agents
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A novel series of 1-N-substituted-3-(4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2- ylthio)quinazolin-6-yl)urea/thiourea derivatives (6a-6r) and 1-N-substituted-3-(7-(4-methylpiperazin-1-yl)-4-(5-(pyridin-3-yl)-1,3, 4-oxadiazol-2-ylthio)quinazolin-6-yl)urea/thiourea derivatives (14a-14s) were synthesized and screened for antimicrobial activity against Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa, and Escherichia coli. Biological results indicated that the synthesized compounds showed a broad-spectrum activity against tested microorganisms at MIC values between 6.25 and 100 μg/mL. Compound 6r showed a broad spectrum of activity and was found to be active against all tested species. A quantitative structure-activity relationship study has been carried out on the synthesized compounds to get better insights into pharmacophoric features responsible for the antibacterial activity. Genetic function approximation technique was used to identify descriptors that influence biological activity. Hydrophobic (AlogP98), electronic (atomic polarizability), and topological (radius of gyration) descriptors were found to affect the activity significantly. Generated model was found to be statistically significant (r 2 = 0.86, predictive index = 0.96) and predictive as indicated by very low residuals in internal and external cross-validation.
- Buha, Vipul M.,Rana, Dharmaraj N.,Chhabria, Mahesh T.,Chikhalia, Kishor H.,Mahajan, Bhushan M.,Brahmkshatriya, Pathik S.,Shah, Nisha K.
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p. 4096 - 4109
(2013/09/02)
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- Targeting gain of function and resistance mutations in Abl and KIT by hybrid compound design
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Mutations in the catalytic domain at the gatekeeper position represent the most prominent drug-resistant variants of kinases and significantly impair the efficacy of targeted cancer therapies. Understanding the mechanisms of drug resistance at the molecular and atomic levels will aid in the design and development of inhibitors that have the potential to overcome these resistance mutations. Herein, by introducing adaptive elements into the inhibitor core structure, we undertake the structure-based development of type II hybrid inhibitors to overcome gatekeeper drug-resistant mutations in cSrc-T338M, as well as clinically relevant tyrosine kinase KIT-T670I and Abl-T315I variants, as essential targets in gastrointestinal stromal tumors (GISTs) and chronic myelogenous leukemia (CML). Using protein X-ray crystallography, we confirm the anticipated binding mode in cSrc, which proved to be essential for overcoming the respective resistances. More importantly, the novel compounds effectively inhibit clinically relevant gatekeeper mutants of KIT and Abl in biochemical and cellular studies.
- Richters, Andre,Ketzer, Julia,Getlik, Matth?us,Grütter, Christian,Schneider, Ralf,Heuckmann, Johannes M.,Heynck, Stefanie,Sos, Martin L.,Gupta, Anu,Unger, Anke,Schultz-Fademrecht, Carsten,Thomas, Roman K.,Bauer, Sebastian,Rauh, Daniel
-
p. 5757 - 5772
(2013/08/23)
-
- 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
-
p. 477 - 483
(2013/03/28)
-
- 6-AMINO QUINAZOLINE OR 3-CYANO QUINOLINE DERIVATIVES, PREPARATION METHODS AND PHARMACEUTICAL USES THEREOF
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6-amino quinazoline or 3-cyano quinoline derivatives, preparation methods and pharmaceutical uses thereof are disclosed. Specifically, the present disclosure discloses novel 6-amino quinazoline or 3-cyano quinoline derivatives presented by general formula (I), or tautomers, enantiomers, diastereomers, racemates or pharmaceutically acceptable salts thereof, or metabolites, metabolic precursors or prodrugs thereof, and their uses as treatment agents especially as protein kinase inhibitors, in which each substitutent group of general formula (I) is as defined in the specification.
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Page/Page column 21-22
(2012/07/13)
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- Cl3CCN/PPh3 and CBr4/PPh3: Two efficient reagent systems for the preparation of N-heteroaromatic halides
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Cl3CCN/PPh3 and CBr4/PPh3 are two highly reactive reagent systems for the conversion of N-heteroaromatic hydroxy compounds into N-heteroaromatic chlorides or bromides in moderate to excellent yields under mild and acid-free conditions.
- Kijrungphaiboon, Woranun,Chantarasriwong, Oraphin,Chavasiri, Wainthorn
-
scheme or table
p. 674 - 677
(2012/02/15)
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- QUINOLINE OR QUINAZOLINE DERIVATIVES WITH APOPTOSIS INDUCING ACTIVITY ON CELLS
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Provided is a pharmaceutical composition comprising, as an active ingredient, a quinoline or quinazoline derivative of formula (I), a pharmaceutically acceptable salt, an isomer, a hydrate, and a solvate thereof, which is effective in the prevention and treatment of a cancer, inflammation, autoimmune diseases or neurodegenerative disorders which are induced by the overexpression of inhibitor of apoptosis proteins (IAPs).
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Page/Page column 57
(2012/03/26)
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- One-pot synthesis of 4-aminoquinazolines by hexamethyldisilazane-mediated reaction of quinazolin-4(3h)-ones with amines
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Hexamethyldisilazane-mediated reaction of quinazolin-4(3H)-ones with primary amines led to facile formation of 4-aminoquinazolines through tandem silylation and substitution in a single pot. Excellent yields of the products (83-97%) and environmental friendliness (avoiding the use of chlorination reagents) are the advantages of this method. Copyright Taylor & Francis Group, LLC.
- Shen, Zhen-Lu,He, Xiao-Fei,Hong, Yi-Ming,Hu, Xin-Quan,Mo, Wei-Min,Hu, Bao-Xiang,Sun, Nan
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experimental part
p. 3644 - 3653
(2011/10/09)
-
- SALTS OF 4-ANILINE QUINAZOLINE DERIVATIVE
-
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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- Novel irreversible epidermal growth factor receptor inhibitors by chemical modulation of the cysteine-trap portion
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Irreversible EGFR inhibitors can circumvent acquired resistance to first-generation reversible, ATPcompetitive inhibitors in the treatment of non-small-cell lung cancer. They contain both a driver group, which assures target recognition, and a warhead, generally an acrylamide or propargylamide fragment that binds covalently to Cys797 within the kinase domain of EGFR. We performed a systematic exploration of the role for the warhead group, introducing different cysteine-trapping fragments at position 6 of a traditional 4-anilinoquinazoline scaffold. We found that different reactive groups, including epoxyamides (compounds 3-6) and phenoxyacetamides (compounds 7-9), were able to irreversibly inhibit EGFR. In particular, at significant lower concentrations than gefitinib (1), (2R,3R)N-(4-(3-bromoanilino)quinazolin-6-yl)- 3 -(piperidin-1 -ylmethyl)oxirane-2-carboxamide (6) inhibited EGFR autophosphorylation and downstream signaling pathways, suppressed proliferation, and induced apoptosis in gefitinib-resistant NSCLC H1975 cells, harboring the T790M mutation in EGFR.
- Carmi, Caterina,Cavazzoni, Andrea,Vezzosi, Stefano,Bordi, Fabrizio,Vacondio, Federica,Silva, Claudia,Rivara, Silvia,Lodola, Alessio,Alfieri, Roberta R.,La Monica, Silvia,Galetti, Maricla,Ardizzoni, Andrea,Petronini, Pier Giorgio,Mor, Marco
-
scheme or table
p. 2038 - 2050
(2010/08/20)
-
- 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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- NOVEL BIFUNCTIONAL COMPOUNDS WHICH INHIBIT PROTEIN KINASES AND HISTONE DEACETYLASES
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The present invention relates to a bifunctional compound of formula I or its pharmaceutically acceptable salts or solvates A-L-B (I) wherein A is a histone deacetylase (HDAC) inhibitory moiety, L is a single bond or a linker group and B is a protein kinase inhibitory moiety. The bifunctional compound according to formula (I) is useful for the treatment of malignant and non-malignant neoplasia and diseases related to abnormal cell growth
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Page/Page column 46; 102
(2009/06/27)
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- Processes and intermediates for the preparation of N4-phenyl-quinazoline-4-amine derivatives
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This invention provides compounds of Formula (I), wherein B, G, A, E, R1, R2, R3, m and n are as defined herein, which are useful as type I receptor tyrosine kinase inhibitors, and methods of use thereof in the treatment of hyperproliferative disorders in mammals.
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Page/Page column 59
(2009/09/05)
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- Synthesis and characterization of rhenium and technetium-99m tricarbonyl complexes bearing the 4-[3-bromophenyl]quinazoline moiety as a biomarker for EGFR-TK imaging
-
Aiming at the development of technetium-99m (99mTc) complexes for early detection and staging of EGFR positive tumors, the tyrosine kinase inhibitor 6-amino-4-[(3-bromophenyl)amino]quinazoline was derivatized with pyridine-2-carboxaldehyde to g
- Bourkoula, Athanasia,Paravatou-Petsotas, Maria,Papadopoulos, Apostolos,Santos, Isabel,Pietzsch, Hans-Jurgen,Livaniou, Evangelia,Pelecanou, Maria,Papadopoulos, Minas,Pirmettis, Ioannis
-
scheme or table
p. 4021 - 4027
(2009/12/04)
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- Hybrid compound design to overcome the gatekeeper T338M mutation in cSrc
-
The emergence of drug resistance remains a fundamental challenge in the development of kinase inhibitors that are effective over long-term treatments. Allosteric inhibitors that bind to sites lying outside the highly conserved ATP pocket are thought to be more selective than ATP-competitive inhibitors and may circumvent some mechanisms of drug resistance. Crystal structures of type I and allosteric type III inhibitors in complex with the tyrosine kinase cSrc allowed us to employ principles of structure-based design to develop these scaffolds into potent type II kinase inhibitors. One of these compounds, 3c (RL46), disrupts FAK-mediated focal adhesions in cancer cells via direct inhibition of cSrc. Details gleaned from crystal structures revealed a key feature of a subset of these compounds, a surprising flexibility in the vicinity of the gatekeeper residue that allows these compounds to overcome a dasatinib-resistant gatekeeper mutation emerging in cSrc.
- Getlik, Matth?us,Grütter, Christian,Simard, Jeffrey R.,Klüter, Sabine,Rabiller, Matthias,Rode, Haridas B.,Robubi, Armin,Rauh, Daniel
-
experimental part
p. 3915 - 3926
(2009/12/28)
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- Development of a fluorescent-tagged kinase assay system for the detection and characterization of allosteric kinase inhibitors
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Kinase disregulation disrupts the intricate network of intracellular signaling pathways and contributes to the onset of diseases such as cancer. Although several kinase inhibitors are on the market, inhibitor selectivity and drug resistance mutations persist as fundamental challenges in the development of effective long-term treatments. Chemical entities binding to less conserved allosteric sites would be expected to offer new opportunities for scaffold development. Because no high-throughput method was previously available, we developed a fluorescence-based kinase binding assay for identifying and characterizing ligands which stabilize the inactive kinase conformation. Here, we present a description of the development and validation of this assay using the serine/threonine kinase p38R. By covalently attaching fluorophores to the activation loop of the kinase, we were able to detect conformational changes and measure the Kd, kon, and koff associated with the binding and dissociation of ligands to the allosteric pocket. We report the SAR of a synthesized focused library of pyrazolourea derivatives, a scaffold known to bind with high affinity to the allosteric pocket of p38R. Additionally, we used protein X-ray crystallography together with our assay to examine the binding and dissociation kinetics to characterize potent quinazoline- and quinoline-based type II inhibitors, which also utilize this binding pocket in p38α. Last, we identified the b-Raf inhibitor sorafenib as a potent low nanomolar inhibitor of p38α and used protein X-ray crystallography to confirm a unique binding mode to the inactive kinase conformation.
- Simard, Jeffrey R.,Getlik, Matthaeus,Gruetter, Christian,Pawar, Vijaykumar,Wulfert, Sabine,Rabiller, Matthias,Rauh, Daniel
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supporting information; experimental part
p. 13286 - 13296
(2010/01/30)
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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 7
(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
(2009/01/20)
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- Radioiodination of new EGFR inhibitors as potential SPECT agents for molecular imaging of breast cancer
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In our search for the development of novel SPECT radioligands for EGFR positive tumours, new potentially irreversible tyrosine kinase (TK) inhibitors are being explored. The radioiodination of N-{4-[(3-chloro-4-fluorophenyl) amino]quinazoline-6-yl}-3-brom
- Fernandes, Celia,Oliveira, Cristina,Gano, Lurdes,Bourkoula, Athanasia,Pirmettis, Ioannis,Santos, Isabel
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p. 3974 - 3980
(2008/03/18)
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- The combi-targeting concept: Synthesis of stable nitrosoureas designed to inhibit the epidermal growth factor receptor (EGFR)
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According to the "combi-targeting" concept, the EGFR tyrosine kinase (TK) inhibitory potency of compounds termed "combi-molecules" is critical for selective growth inhibition of tumor cells with disordered expression of EGFR or its closest family member erbB2. Here we report on the optimization of the EGFR TK inhibitory potency of the combi-molecules of the nitrosourea class by comparison with their aminoquinazoline and ureidoquinazoline precursors. This led to the discovery of a new structural parameter that influences their EGFR TK inhibitory potency, i.e., the torsion angle between the plane of the quinazoline ring and the ureido or the nitrosoureido moiety of the synthesized drugs. Compounds (3′-Cl and Br series) with small angles (0.5-3°) were generally stronger EGFR TK inhibitors than those with large angles (18-21°). This was further corroborated by ligand-receptor van der Waals interaction calculations that showed significant binding hindrance imposed by large torsion angles in the narrow ATP cleft of EGFR. Selective antiproliferative studies in a pair of mouse fibroblast NIH3T3 cells, one of which NIH3T3/neu being transfected with the erbB2 oncogene, showed that IC50 values for inhibition of EGFR TK could be good predictors of their selective potency against the serum-stimulated growth of the erbB2-tranfected cell line (Pearson r = 0.8). On the basis of stability (t1/2), EGFR TK inhibitory potency (IC50), and selective erbB2 targeting, compound 23, a stable nitrosourea, was considered to have the structural requirements for further development.
- Domarkas, Juozas,Dudouit, Fabienne,Williams, Christopher,Qiyu, Qiu,Banerjee, Ranjita,Brahimi, Fouad,Jean-Claude, Bertrand Jacques
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p. 3544 - 3552
(2007/10/03)
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- High-affinity epidermal growth factor receptor (EGFR) irreversible inhibitors with diminished chemical reactivities as positron emission tomography (PET)-imaging agent candidates of EGFR overexpressing tumors
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Previous studies with the anilinoquinazoline epidermal growth factor receptor (EGFR) irreversible inhibitor [11C]-ML03 demonstrated a rapid metabolism of the tracer, which led to its low in vivo accumulation in EGFR overexpressing tumors. To enhance tumor uptake, the chemical structure of the compound was modified, and four new groups of EGFR inhibitors with a wide range of chemical reactivities were synthesized. Chemical reactivity assay of the compounds, performed with reduced glutathione (GSH), revealed that the group C (4-(dimethylamino)-but-2-enoic amide) derivative was the least chemically reactive against the nucleophilic attack of GSH. Nonetheless, it demonstrated a high inhibitory potency and bound irreversibly to the EGFR. Consequently, the blood stability of the group C compound (5a, ML04) labeled with 11C was studied. In a time frame of 60 min, no radioactive metabolites were detected in blood. The stability of [11C]-5a, as indicated both from in vitro blood-stability assays and injection into nude rats, was significantly higher as compared to [11C]-ML03. Since group C presented a greater promise for tumor accumulation, it represents, to date, the most suitable candidate for radiolabeling with long-lived positron emission tomography (PET) radioisotopes.
- Mishani, Eyal,Abourbeh, Galith,Jacobson, Orit,Dissoki, Samar,Ben Daniel, Revital,Rozen, Yulia,Shaul, Mazal,Levitzki, Alexander
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p. 5337 - 5348
(2007/10/03)
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- Synthesis of half-mustard combi-molecules with fluorescence properties: Correlation with EGFR status
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The synthesis of 6-(2-chloroethylamino)-4-anilinoquinazolines ZR2002 and ZR2003 designed to block EGFR tyrosine kinase and to damage genomic DNA is described. These compounds present fluorescence properties that permitted the quantitation of their subcellular uptake by flow cytometry. Fluorescence intensities increased with increasing levels of EGFR in a panel of isogenic and established cell lines.
- Rachid, Zakaria,Brahimi, Fouad,Domarkas, Juozas,Jean-Claude, Bertrand Jacques
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p. 1135 - 1138
(2007/10/03)
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- 4-ANILIDO SUBSTITUTED QUINAZOLINES AND USE THEREOF AS INHIBITORS OF EPIDERMAL GROWTH FACTOR RECEPTOR KINASES
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The present invention provides 4-anilido substituted quinazoline compounds which are potent inhibitors of protein tyrosine (PTK) kinase activity, particularly epidermal growth factor receptor (EGFR) kinase activity, and pharmaceutical compositions comprising these compounds. The present invention further provides methods of inhibiting the activity of a protein tyrosine kinase (PTK), for example an EGFR kinase, comprising the step of contacting the PTK with an effective inhibitory amount of any of the quinazoline compounds defined herein. The present invention further provides a method of inhibiting the activity of a protein tyrosine kinase (PTK) in a subject, for example an EGFR kinase, comprising the step of administering to the subject a therapeutically effective amount of any of the quinazoline compounds defined herein. The present invention further provides a method of treating or preventing a protein tyrosine kinase (PTK) related disorder in a subject, for example an EGFR related disorder, comprising the step of administering to the subject a therapeutically effective amount of any of the quinazoline compounds defined herein. The quinazoline compounds are useful in treating a variety of PTK related disorders such as cell proliferative disorders, fibrotic disorders, metabolic disorders and cancer.
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- Novel iodine-124 labeled EGFR inhibitors as potential PET agents for molecular imaging in cancer
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The in vivo results with our previously reported irreversible labeled inhibitor [11C]-ML03 suggested that more chemically stable inhibitors, labeled with a longer-lived radioisotope, could be better candidates for molecular imaging of epidermal growth factor receptor (EGFR) positive tumors. On the basis of this hypothesis we synthesized three new irreversible tyrosine kinase (TK) inhibitors with various chemical reactivities. The three new inhibitors were successfully labeled on the anilino moiety with [ 124I], starting with the 6-amino-4-[(3-tributylstannylphenyl)amino]- quinazoline (9) precursor. The cell-free results, obtained with these new irreversible inhibitors, indicated that compounds 5 (α-chloro-acetamide derivative) and 6 (4-dimethylamino-but-2-enoic amide derivative) possessed high potencies toward the EGFR with an irreversible inhibition effect. Compound 4 (α-methoxy-acetamide derivative) was found to be less potent, with only a partially irreversible effect. The high potency of compounds 5 and 6 toward the EGFR establishes their potential as PET agents for molecular imaging of EGFR positive tumors. Their prospect as PET biomarkers is further being investigated.
- Shaul, Mazal,Abourbeh, Galith,Jacobson, Orit,Rozen, Yulia,Laky, Desideriu,Levitzki, Alexander,Mishani, Eyal
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p. 3421 - 3429
(2007/10/03)
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- A novel structural class of potent inhibitors of NF-κB activation: Structure-activity relationships and biological effects of 6-aminoquinazoline derivatives
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In this study, we have investigated the roles of substituents on the terminal phenyl ring at the C(4)-position of the quinazoline core to complete the structure-activity relationships (SARs) of our NF-κB activation inhibitors. Among them, compound 12j aff
- Tobe, Masanori,Isobe, Yoshiaki,Tomizawa, Hideyuki,Nagasaki, Takahiro,Takahashi, Hirotada,Hayashi, Hideya
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p. 3869 - 3878
(2007/10/03)
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- Discovery of quinazolines as a novel structural class of potent inhibitors of NF-κB activation
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We disclose here a new structural class of low-molecular-weight inhibitors of NF-κB activation that were designed and synthesized by starting from quinazoline derivative 6a. Structure-activity relationship (SAR) studies based on 6a elucidated the structural requirements essential for the inhibitory activity toward NF-κB transcriptional activation, and led to the identification of the 6-amino-4-phenethylaminoquinazoline skeleton as the basic framework. In this series of compounds, 11q, containing the 4-phenoxyphenethyl moiety at the C(4)-position, showed strong inhibitory effects on both NF-κB transcriptional activation and TNF-α production. Furthermore, 11q exhibited an anti-inflammatory effect on carrageenin-induced paw edema in rats.
- Tobe, Masanori,Isobe, Yoshiaki,Tomizawa, Hideyuki,Nagasaki, Takahiro,Takahashi, Hirotada,Fukazawa, Tominaga,Hayashi, Hideya
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p. 383 - 391
(2007/10/03)
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- The combi-targeting concept: Chemical dissection of the dual targeting properties of a series of "combi-triazenes"
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The combi-targeting concept postulates that a molecule termed a "combi-molecule" designed to interact with an oncoreceptor on its own and allowed to further degrade to another more stable inhibitor of the latter receptor + a DNA-damaging species should be more potent than the individual combination of the same inhibitor with a DNA-damaging agent in cells expressing the targeted receptor. Recently, using the epidermal growth factor receptor (EGFR) as a target, we demonstrated the feasibility of combi-molecules with dual EGFR/DNA-targeting properties and with the ability to degrade to another potent inhibitor of EGFR. However, despite a clear demonstration of their superior potency when compared with classical combinations in EGFR-expressing cells, the true contribution of each fragment of the combi-molecules to their overall antiproliferative activity remained elusive. Here, we report a structure-function approach whereby a series of quinazoline-based "combi-triazenes" were altered to either abrogate the affinity of the EGFR-targeting quinazoline head or to suppress the DNA-damaging property of the triazene tail. The results showed that (a) inactivation of the quinazoline head by appending an N-methylaniline group to its 4-position reduced EGFR tyrosine kinase (TK) inhibitory activity by ca. 200-fold and decreased the ability of the combi-molecule to block serum-induced growth stimulation in c-erbB2 transfected NIH3T3 cells by ca. 10-fold, (b) abrogation of the alkylating activity or the DNA-damaging potential of the triazene tail by forming 3,3-dimethyltriazenes did not suppress EGFR TK inhibitory affinity but decreased the antiproliferative activity in basal growth assays, and (c) the antiproliferative activities of the monoalkyltriazenes that possessed binary EGFR TK inhibitory and alkylating activities were superior to those of their monotargeted counterparts. The results in toto suggest that each component of the dual targeting property of combi-triazenes plays a critical role in their overall antiproliferative activity.
- Rachid, Zakaria,Brahimi, Fouad,Katsoulas, Athanasia,Teoh, Nicole,Jean-Claude, Bertrand J.
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p. 4313 - 4321
(2007/10/03)
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- Irreversible inhibitors of tyrosine kinases
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The present invention provides compounds that are irreversible inhibitors of tyrosine kinases. Also provided is a method of treating cancer, restenosis, atherosclerosis, endometriosis, and psoriasis and a pharmaceutical composition that comprises a compound that is an irreversible inhibitor of tyrosine kinases.
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Page column 48-49
(2008/06/13)
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- Structure-activity relationships of quinazoline derivatives: Dual-acting compounds with inhibitory activities toward both TNF-α production and T cell proliferation
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We synthesized 4-chlorophenethylaminoquinazoline derivatives and evaluated their inhibitory activities toward both TNF-α production and T cell proliferation responses. Compound 2f, containing a piperazine ring at the C(7)-position of the quinazoline ring, exhibited more potent inhibitory activities toward both than the lead compound 1a. A smaller N-substituent in the piperazine ring was required for inhibition of TNF-α production.
- Tobe, Masanori,Isobe, Yoshiaki,Tomizawa, Hideyuki,Matsumoto, Mitsuhiro,Obara, Fumihiro,Nagasaki, Takahiro,Hayashi, Hideya
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p. 545 - 548
(2007/10/03)
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- Tyrosine kinase inhibitors. 17. Irreversible inhibitors of the epidermal growth factor receptor: 4-(phenylamino)quinazoline- and 4- (phenylamino)pyrido[3,2-d]pyrimidine-6-acrylamides bearing additional solubilizing functions
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4-Anilinoquinazoline- and 4-anilinopyrido[3,2-d]pyrimidine-6-acrylamides substituted with solubilizing 7-alkylamine or 7-alkoxyamine side chains were prepared by reaction of the corresponding 6-amines with acrylic acid or acrylic acid anhydrides. In the pyrido[3,2-d]pyrimidine series, the intermediate 6-amino-7-alkylamines were prepared from 7-bromo-6- fluoropyrido[3,2-d]pyrimidine via Stille coupling with the appropriate stannane under palladium-(0) catalysis. This proved a versatile method for the introduction of cationic solubilizing side chains. The compounds were evaluated for their inhibition of phosphorylation of the isolated EGFR enzyme and for inhibition of EGF-stimulated autophosphorylation of EGFR in A431 cells and of heregulin-stimulated autophosphorylation of erbB2 in MDA-MB 453 cells. Quinazoline analogues with 7-alkoxyamine solubilizing groups were potent irreversible inhibitors of the isolated EGFR enzyme, with IC50([app]) values from 2 to 4 nM, and potently inhibited both EGFR and erbB2 autophosphorylation in cells. 7-Alkylamino- and 7- alkoxyaminopyrido[3,2-d]pyrimidines were also irreversible inhibitors with equal or superior potency against the isolated enzyme but were less effective in the cellular autophosphorylation assays. Both quinazoline- and pyrido[3,2- d]pyrimidine-6-acrylamides bound at the ATP site alkylating cysteine 773, as shown by electrospray ionization mass spectrometry, and had similar rates of absorptive and secretory transport in Caco-2 cells. A comparison of two 7- propoxymorpholide analogues showed that the pyrido[3,2-d]pyrimidine-6- acrylamide had greater amide instability and higher acrylamide reactivity, being converted to glutathione adducts in cells more rapidly than the corresponding quinazoline. This difference may contribute to the observed lower cellular potency of the pyrido[3,2-d]pyrimidine-6-acrylamides. Selected compounds showed high in vivo activity against A431 xenografts on oral dosing, with the quinazolines being superior to the pyrido[3,2-d]pyrimidines. Overall, the quinazolines proved superior to previous analogues in terms of aqueous solubility, potency, and in vivo antitumor activity, and one example (CI 1033) has been selected for clinical evaluation.
- Smaill, Jeff B.,Rewcastle, Gordon W.,Loo, Joseph A.,Greis, Kenneth D.,Chan, O. Helen,Reyner, Eric L.,Lipka, Elke,Showalter, H. D. Hollis,Vincent, Patrick W.,Elliott, William L.,Denny, William A.
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p. 1380 - 1397
(2007/10/03)
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