19815-16-8Relevant articles and documents
Discovery of Potent EGFR Inhibitors With 6-Arylureido-4-anilinoquinazoline Derivatives
Li, Meng,Xue, Na,Liu, Xingang,Wang, Qiaoyun,Yan, Hongyi,Liu, Yifan,Wang, Lei,Shi, Xiaowei,Cao, Deying,Zhang, Kai,Zhang, Yang
, (2021/06/14)
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.
Discovery of quinazolinyl-containing benzamides derivatives as novel HDAC1 inhibitors with in vitro and in vivo antitumor activities
Zhang, Zixue,Zhang, Qingwei,Zhang, Hao,Jiao, Minru,Guo, Zheng,Peng, Xinyan,Fu, Lei,Li, Jianqi
, (2021/10/16)
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.
Intramolecular Ring-Opening of Oxetanes: Access to Functionalised Hydroxymethyl 2,3-Dihydroimidazo[1,2- c ]quinazolines
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)
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.
Preparation method of medicine for treating bile duct cancer
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Paragraph 0016; 0028; 0033-0034, (2020/08/23)
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.
Design, synthesis and biological evaluation of 4-aniline quinazoline derivatives conjugated with hydrogen sulfide (H2S) donors as potent EGFR inhibitors against L858R resistance mutation
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
, (2020/07/03)
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.
Design of Turn-On Near-Infrared Fluorescent Probes for Highly Sensitive and Selective Monitoring of Biopolymers
Ducharme, Gerard T.,LaCasse, Zane,Nesterov, Evgueni E.,Nesterova, Irina V.,Sheth, Tanya
supporting information, p. 8440 - 8444 (2020/03/24)
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
Hetero-aromatic compound and its use in medicine
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Paragraph 1684; 1690-1693, (2019/07/04)
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.
Method for preparing lapatinib key intermediates
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Paragraph 0010; 0024; 0036-0041; 0050-0053, (2018/09/12)
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.
Method for synthesizing lapatinib or intermediate thereof
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Paragraph 0043; 0044; 0045, (2017/06/30)
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.
Design, synthesis, and biological evaluation of novel 4-anilinoquinazoline derivatives bearing amino acid moiety as potential EGFR kinase inhibitors
Zheng, You-Guang,Su, Jun,Gao, Cai-Yun,Jiang, Ping,An, Lin,Xue, Yun-Sheng,Gao, Jian,Liu, Yi
, p. 393 - 405 (2017/03/10)
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.
