183322-18-1Relevant academic research and scientific papers
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.
Discovery of New 4-Indolyl Quinazoline Derivatives as Highly Potent and Orally Bioavailable P-Glycoprotein Inhibitors
Chen, Zhe-Sheng,Dai, Qing-Qing,Li, Guo-Bo,Liu, Hong-Min,Liu, Hui,Wang, Bo,Wang, Shaomeng,Yu, Bin,Yuan, Shuo,Zhang, Jing-Ya,Zhang, Xiao-Nan,Zuo, Jia-Hui
, p. 14895 - 14911 (2021/10/12)
The major drawbacks of P-glycoprotein (P-gp) inhibitors at the clinical stage make the development of new P-gp inhibitors challenging and desirable. In this study, we reported our structure-activity relationship studies of 4-indolyl quinazoline, which led to the discovery of a highly effective and orally active P-gp inhibitor, YS-370. YS-370 effectively reversed multidrug resistance (MDR) to paclitaxel and colchicine in SW620/AD300 and HEK293T-ABCB1 cells. YS-370 bound directly to P-gp, did not alter expression or subcellular localization of P-gp in SW620/AD300 cells, but increased the intracellular accumulation of paclitaxel. Furthermore, YS-370 stimulated the P-gp ATPase activity and had moderate inhibition against CYP3A4. Significantly, oral administration of YS-370 in combination with paclitaxel achieved much stronger antitumor activity in a xenograft model bearing SW620/Ad300 cells than either drug alone. Taken together, our data demonstrate that YS-370 is a promising P-gp inhibitor capable of overcoming MDR and represents a unique scaffold for the development of new P-gp inhibitors.
4-arylmercaptoquinazoline compound as well as preparation method and medical application thereof
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Paragraph 0024; 0026, (2021/01/24)
The invention discloses a 4-arylmercaptoquinazoline compound as well as a preparation method and medical application thereof. The 4-arylmercaptoquinazoline compound is reported for the first time. Research finds that the 4-arylmercaptoquinazoline compound has LSD1 inhibitory activity and has a prospect of being developed into antitumor drugs. Taking the compound 1 as an example, the IC50 value ofthe compound for inhibiting the LSD1 protein is 0.69 [mu]M and is remarkably superior to that of positive control; and in an anti-tumor test, the compound has relatively strong inhibitory activity ongastric cancer MGC-803, gastric cancer BGC-823, gastric cancer SGC-7901, breast cancer MCF-7, lung cancer H1650, lung cancer A549, lung cancer H1975, lung cancer H460, esophageal cancer EC-109, livercancer HepG2 and leukemia THP1 cells, and has a prospect of being developed into medicines for resisting gastric cancer, breast cancer, lung cancer, cancer of the esophagus, liver cancer and leukemia.
Discovery of quinazoline derivatives as a novel class of potent and in vivo efficacious LSD1 inhibitors by drug repurposing
Li, Zhonghua,Li, Zhongrui,Ma, Jinlian,Miao, Jinxin,Qin, Tingting,Yang, Nian,Zhang, Xinhui,Zhang, Zhenqiang,Zhao, Taoqian,Zhao, Xuan
, (2021/08/19)
Histone lysine-specific demethylase 1 (LSD1) is an important epigenetic modulator, and is implicated in malignant transformation and tumor pathogenesis in different ways. Therefore, the inhibition of LSD1 provides an attractive therapeutic target for cancer therapy. Based on drug repurposing strategy, we screened our in-house chemical library toward LSD1, and found that the EGFR inhibitor erlotinib, an FDA-approved drug for lung cancer, possessed low potency against LSD1 (IC50 = 35.80 μM). Herein, we report our further medicinal chemistry effort to obtain a highly water-soluble erlotinib analog 5k (>100 mg/mL) with significantly enhanced inhibitory activity against LSD1 (IC50 = 0.69 μM) as well as higher specificity. In MGC-803 cells, 5k suppressed the demethylation of LSD1, indicating its cellular activity against the enzyme. In addition, 5k had a remarkable capacity to inhibit colony formation, suppress migration and induce apoptosis of MGC803 cells. Furthermore, in MGC-803 xenograft mouse model, 5k treatment resulted in significant reduction in tumor size by 81.6% and 96.1% at dosages of 40 and 80 mg/kg/d, respectively. Our findings indicate that erlotinib-based analogs provide a novel structural set of LSD1 inhibitors with potential for further investigation, and may serve as novel candidates for the treatment of LSD1-overexpressing cancers.
Transition-metal and oxidant-free approach for the synthesis of diverse N-heterocycles by TMSCl activation of isocyanides
Chen, Fen-Er,Dong, Lin,Li, Hongyan,Liu, Jinxin,Luo, Liangliang,Xiao, You-Cai,Zhou, Yuan
, p. 29257 - 29262 (2020/10/02)
A highly efficient TMSCl-mediated addition of N-nucleophiles to isocyanides has been achieved. This transition-metal and oxidant-free strategy has been applied to the construction of various N-heterocyles such as quinazolinone, benzimidazole and benzothiazole derivatives by the use of distinct amino-based binucleophiles. The notable feature of this protocol includes its mild reaction condition, broad functional group tolerance and excellent yield. This journal is
Preparation method of erbtinib
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, (2020/06/16)
The invention discloses a preparation method of erbtinib. The method comprises the following steps: carrying out a cyclization reaction on a compound represented by formula 1 to obtain a compound represented by formula 2, carrying out a chlorination reaction on the compound of the formula 2 to obtain a compound represented by formula 3, and carrying out a substitution salification reaction on thecompound of the formula 3 to obtain the compound erbtinib represented by formula 4. The preparation method of erbtinib can greatly shorten the production cycle when used for preparing erbtinib hydrochloride, can effectively avoid the defects of long production cycle, serious environmental pollution, unstable intermediate, difficult product purification, complex operation and the like, and has theadvantages of short reaction steps, simple operation, easy reaction, high product purity, high yield and low cost. The addition amount of reactants is properly controlled, the environmental requirements are clear, and a clear and new production direction is provided for process production.
Erlotinib derivative with killing performance on wild type lung cancer tumor cells and preparation method thereof
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Paragraph 0034-0036, (2020/07/12)
The invention discloses an erlotinib derivative with killing performance on wild cells and a preparation method thereof, and belongs to the technical field of medicine synthesis. According to the technical scheme, the erlotinib derivative is characterized in that the erlotinib derivative has a structure shown in the specification, wherein n is 1 or 2, n is 1 or 2, and R1 and R2 as well as R3 and R4 are different substituents. According to the invention, 3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester is used as a raw material, and a series of erlotinib-1, 2, 3-triazole compounds with novel structures are obtained through six-step reaction; the compound has a good inhibition effect on IDO1, and a 1, 2, 3-triazole structure can form a relatively strong action effect with Fe ions in heme, sothat the enzyme activity of IDO1 is competitively inhibited; the compound has a good inhibition effect on wild lung cancer tumor cells, also has an inhibition effect on mutant lung cancer tumor cells, and has remarkable tumor cell inhibition activity universality by being compared with erlotinib.
Preparation method for high-purity erlotinib hydrochloride
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Paragraph 0026-0039, (2019/05/16)
The invention belongs to the field of pharmaceutical synthesis, and provides a method for preparing high-purity erlotinib hydrochloride. The method comprises the following steps: 6,7-di(2-methoxyethoxy)quinazoline-4-one is used as a raw material, chlorination is performed to obtain 4-chloro-6,7-di(2-methoxyethoxy)quinazoline (compound I), refining is performed on the compound I, the refined compound I is reacted with 3-aminophenylacetylene, and therefore the high-purity erlotinib hydrochloride is obtained, wherein the purity obtained by HPLC is 99.85% or more, and the content of an impurity 1and an impurity 2 is less than 0.06%. The method provided by the invention is suitable for industrial large-scale production.
Novel quinazoline EGFR inhibitor, and preparation method and application thereof
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Paragraph 0040, (2019/10/01)
A novel quinazoline EGFR inhibitor, and a preparation and an application thereof belong to the field of synthesis of medicines. The novel quinazoline EGFR inhibitor has a general formula shown in thedescription; and in the general formula, R is one from H, F, Cl, Br, and I, and R1 and R2 are same to or different from each other, and are respectively selected from H, a nitro group, an amino group,a hydroxyl group, a 2-methoxyethoxy group, a C1-C4 alkoxy group and a C1-C4 alkyl group. The novel quinazoline EGFR inhibitor is different from existing quinazoline inhibitors with the 4-position substituted with various anilines, and is designed and synthesized by substituting the 4-position of a quinazoline skeleton with a broadly bioactive thienylmethylamine and reasonably modifying the 6-position and the 7-position with groups not including an electrophilic acrylamide bond in order to avoid covalent bonds with EGFR. Compared with existing antitumor drugs, the above compound can significantly inhibit EGFR phosphorylation, and has excellent anti-proliferative activity against EGFR overexpressing tumor cells (such as A431 and MCF-7).
Design, synthesis, and biological study of 4-[(2-nitroimidazole-1h-alkyloxyl)aniline]-quinazolines as EGFR inhibitors exerting cytotoxicities both under normoxia and hypoxia
Cheng, Weiyan,Wang, Suhua,Yang, Zhiheng,Tian, Xin,Hu, Yongzhou
, p. 3079 - 3089 (2019/09/10)
Purpose: In order to get novel EGFR inhibitors exerting more potency in tumor hypoxia than in normoxia. Methods: A series of 4-[(2-nitroimidazole-1H-alkyloxyl)aniline]-quinazolines were designed and synthesized, and their in vitro cytotoxicity and EGFR inhibitory activity were evaluated. Molecule docking study was performed for the representative compound. Results: The structure-activity relationship (SAR) studies revealed that compounds bearing both meta-chloride and para-(2-nitroimidazole-1H-alkyloxy) groups on the aniline displayed potent inhibitory activities both in enzymatic and cellular levels. The most promising compound 16i potently inhibited EGFR with an IC50 value of 0.12 μM. Meanwhile, it manifested more potent cytotoxicity than the positive control lapatinib under tumor normoxia and hypoxia conditions (IC50 values of 1.59 and 1.09 μM against A549 cells, 2.46 and 1.35 μM against HT-29 cells, respectively). The proposed binding model of 16i in complex with EGFR was displayed by the docking results. Conclusion: This study provides insights for developing hypoxia-activated kinase inhibitors.
