13183-79-4Relevant articles and documents
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.
Antibiotic-improved cefmenoxime hydrochloride synthesis process
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Paragraph 0039-0041, (2021/02/06)
The invention discloses an antibiotic-improved cefmenoxime hydrochloride synthesis process, which comprises the following steps: step 1, preparation of 1-methyl-5-sulfydryl-1H-tetrazole, step 2, preparation of 2-(2-amino-4-azolyl)-2(Z)-methoxyimino ethyl acetate; step 3, preparation of 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino acetic acid; step 4, preparation of 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino acetic acid-2-benzothiazole thioester; step 5, preparation of 7-amino-3-(1-methyl-1H-tetrazole-5-thiomethyl)cephalosporanic acid hydrochloride (7-ACA-MMT. HC1); and step 6, preparation of cefmenoxime hydrochloride; domestic raw materials are adopted, the raw materials are cheap and easy to obtain in the synthesis route, the synthesis cost is reduced, and synthesis is improved; the improved process has the advantages of low raw material cost, simplicity in operation and suitability for industrial production.
Synthesis method of 1-methyl-5-mercaptotetrazole
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Paragraph 0018; 0020-0029, (2020/12/30)
The invention relates to a synthesis method of 1-methyl-5-mercaptotetrazole. The method comprises the following steps: (1) carrying out reflux reaction by using sodium methylamino dithiocarboxylate and sodium azide as reaction raw materials, water as a reaction solvent and an alkaline solution as a catalyst, neutralizing the reaction solution with a protonic acid after the reaction until the pH value is 6-7, and filtering to obtain a 1-methyl-5-mercaptotetrazole crude product; and (2) recrystallizing the 1-methyl-5-mercaptotetrazole crude product obtained in step (1) by using a recrystallization solution to obtain the 1-methyl-5-mercaptotetrazole finished product, wherein the recrystallization solution is a mixed solution of toluene and water. The synthesis method disclosed by the invention is high in yield, and the prepared 1-methyl-5-mercaptotetrazole is high in purity.