169205-77-0Relevant academic research and scientific papers
Microwave-assisted synthesis of new 6-ureido-4-anilinoquinazoline derivatives
Zheng, Youguang,Gao, Caiyun,Huang, Rongrong,Liu, Yi,Xue, Yunsheng,An, Lin
, p. 95 - 98 (2016)
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.
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)
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.
4-Anilinoquinazolines with Lavendustin A subunit as inhibitors of epidermal growth factor receptor tyrosine kinase: Syntheses, chemical and pharmacological properties
Albuschat, Rica,L?we, Werner,Weber, Manuela,Luger, Peter,Jendrossek, Verena
, p. 1001 - 1011 (2004)
4-Anilinoquinazoline derivatives are widely investigated due to their potent epidermal growth factor receptor (EGFR) tyrosine kinase inhibitory activity. Two 4-anilinoquinazolines with Lavendustin A subunit (10a,b) were synthesized and examined for their EGFR tyrosine kinase inhibitory activity as well as their antiproliferative properties on variant human cancer cell lines. Both compounds maintained their EGFR tyrosine kinase inhibitory activity at the 10-7:M level and led to significant growth inhibition in certain leukemia, non-small cell lung cancer (NSCLC), ovarian cancer, renal cancer and breast cancer cell lines with GI50 values at the 10-6 M level. There could not be observed any notable difference between 10a and 10b regarding to their antiproliferative activity. Interestingly, we observed the high tendency of 10a and 10b to include certain solvents, e.g. water, DMF, DMSO, which may be due to the remarkable number of hydrogen accepting/donating groups in 10a and b. An X-ray analysis of 10a including water and DMF illustrates a possible hydrogen bond pattern and could serve as information for preferred receptor (e.g. EGFR tyrosine kinase) binding sites. Finally, we aimed for irreversible EGFR tyrosine kinase inhibitors. The p-quinone derivatives 11a and 11b, which contain a Michael acceptor position according to the irreversible inhibitor CI-1033, could be derived from the p-hydroquinone derivatives 10a or 10b, respectively, by oxidation. However, due to their instability 11a and 11b could not be obtained in a pure form.
Structural insights into how irreversible inhibitors can overcome drug resistance in EGFR
Michalczyk, Anja,Klueter, Sabine,Rode, Haridas B.,Simard, Jeffrey R.,Gruetter, Christian,Rabiller, Matthias,Rauh, Daniel
, p. 3482 - 3488 (2008)
Resistance to kinase- targeted cancer drugs has recently been linked to a single point mutation in the ATP binding site of the kinase. In EGFR, the crucial Thr790 gatekeeper residue is mutated to a Met and prevents reversible ATP competitive inhibitors from binding. Irreversible 4-(phenylamino)quinazolines have been shown to overcome this drug resistance and are currently in clinical trials. In order to obtain a detailed structural understanding of how irreversible inhibitors overcome drug resistance, we used Src kinase as a model system for drug resistant EGFR-T790M. We report the first crystal structure of a drug resistant kinase in complex with an irreversible inhibitor. This 4-(phenylamino)quinazoline inhibits wild type and drug resistant EGFR in vitro at low nM concentrations. The co-crystal structure of drug resistant cSrc-T338M kinase domain provides the structural basis of this activity.
Design, synthesis and biological evaluation of cinnamamide-quinazoline derivatives as potential EGFR inhibitors to reverse T790M mutation
Zhang, Bin,Xu, Zichen,Liu, Qingqing,Xia, Shengjin,Liu, Zhikun,Liao, Zhixin,Gou, Shaohua
, (2021/10/16)
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.
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.
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.
A THERANOSTIC PROBE AND ITS USE FOR TARGETING AND/OR LABELING THE EGFR KINASE AND/OR THE CELLS EXPRESSING EGFR OR ITS FAMILY MEMBERS
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Page/Page column 12-13; 16, (2020/09/08)
The present application is directed to a theranostic probe and its use for targeting and/or labeling the EGFR kinase and/or the cells expressing EGFR or its family members.
Novel series of 6-(2-substitutedacetamido)-4-anilinoquinazolines as EGFR-ERK signal transduction inhibitors in MCF-7 breast cancer cells
Ismail, Rania S.M.,Abou-Seri, Sahar M.,Eldehna, Wagdy M.,Ismail, Nasser S.M.,Elgazwi, Sara M.,Ghabbour, Hazem A.,Ahmed, Mahmoud Salama,Halaweish, Fathi T.,Abou El Ella, Dalal A.
supporting information, p. 782 - 796 (2018/06/29)
Epidermal growth factor receptor (EGFR) signaling pathway has been previously investigated for its significant role in the progression of different types of malignant tumors, where development of small molecules targeting EGFR is well known strategy for design of antitumor agents. Herein, we report the design and synthesis of two series of 6-(2-substitutedacetamido)-4-anilinoquinazolines (6a-x and 13a-d) as EGFR inhibitors. All the newly synthesized quinazoline derivatives were in vitro evaluated for their anti-proliferative activity towards MCF-7 (Breast Cancer) and HepG2 (Hepatocellular carcinoma) cell lines. In particular, compound 6n showed significant inhibitory activity against MCF-7 and HepG2 cell lines (IC50 = 3 and 16 μM, respectively), compared to that of Erlotinib (IC50 = 20 and 25 μM, respectively). Western blotting of 6n at MCF-7 cell line revealed the dual inhibitory activity of 6n towards diminishing the phosphorylated levels for EGFR and ERK. Also, ELISA assay confirmed the anti-EGFR activity of compound 6n (IC50 = 0.037 μM). Finally, a molecular docking study showed the potential binding mode of 6n within the ATP catalytic binding site of EGFR, exhibiting similar binding mode to EGFR inhibitor Erlotinib.
Design, synthesis and biological evaluation of quinazoline–phosphoramidate mustard conjugates as anticancer drugs
Lin, Songwen,Li, Yingbo,Zheng, Yufen,Luo, Laichun,Sun, Qi,Ge, Zemei,Cheng, Tieming,Li, Runtao
, p. 442 - 458 (2017/01/18)
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).
