162012-67-1Relevant articles and documents
STEFs: Activated Vinylogous Protein-Reactive Electrophiles
Hansen, Bente K.,Loveridge, Christopher J.,Thyssen, Stine,W?rmer, Gustav J.,Nielsen, Andreas D.,Palmfeldt, Johan,Johannsen, Mogens,Poulsen, Thomas B.
, p. 3533 - 3537 (2019)
Reported here is the synthesis of a class of semi-oxamide vinylogous thioesters, designated STEFs, and the use of these agents as new electrophilic warheads. This work includes preparation of simple probes that contain this reactive motif as well as its installation on a more complex kinase inhibitor scaffold. A key aspect of STEFs is their reactivity towards both thiol and amine groups. Shown here is that amine conjugations in peptidic and proteinogenic samples can be facilitated by initial, fast conjugation to proximal thiol residues. Evidence that both the selectivity and the reactivity can be tuned by the structure of STEFs is provided, and given the unique ability of this functionality to conjugate by an addition-elimination mechanism, STEFs are electrophilic warheads that could find broad use in chemical biology.
Design, synthesis, and docking studies of quinazoline analogues bearing aryl semicarbazone scaffolds as potent EGFR inhibitors
Tu, Yuanbiao,Wang, Caolin,Xu, Shan,Lan, Zhou,Li, Wei,Han, Jiaqian,Zhou, Yuanzhang,Zheng, Pengwu,Zhu, Wufu
, p. 3148 - 3157 (2017)
Two series of quinazoline derivatives bearing aryl semicarbazone scaffolds (9a–o and 10a–o) were designed, synthesized and evaluated for the IC50 values against four cancer cell lines (A549, HepG2, MCF-7 and PC-3). The selected compound 9o was further evaluated for the inhibitory activity against EGFR kinases. Four of the compounds showed excellent cytotoxicity activity and selectivity with the IC50 values in single-digit μM to nanomole range. Two of them are equal to more active than positive control afatinib against one or more cell lines. The most promising compound 9o showed the best activity against A549, HepG2, MCF-7 and PC-3 cancer cell lines and EGFR kinase, with the IC50 values of 1.32?±?0.38?μM, 0.07?±?0.01?μM, 0.91?±?0.29?μM and 4.89?±?0.69?μM, which were equal to more active than afatinib (1.40?±?0.83?μM, 1.33?±?1.28?μM, 2.63?±?1.06?μM and 3.96?±?0.59?μM), respectively. Activity of the most promising compound 9o (IC50 56?nM) against EGFR kinase was slightly lower to the positive compound afatinib (IC50 1.6?nM) but more active than reference staurosporine (IC50 238?nM). The result of flow cytometry, with the dose of compound 9o increasing, which indicated the compound 9o could induce remarkable apoptosis of A549 and cells in a dose dependent manner. Structure–activity relationships (SARs) and docking studies indicated that replacement of the cinnamamide group by aryl semicarbazone scaffolds slightly decreased the anti-tumor activity. The results suggested that hydroxy substitution at C-4 had a significant impact on the activity and replacement of the tetrahydrofuran group by methyl moiety was not beneficial for the activity.
Clinical stage EGFR inhibitors irreversibly alkylate Bmx kinase
Hur, Wooyoung,Velentza, Anastasia,Kim, Sungjoon,Flatauer, Laura,Jiang, Xinnong,Valente, David,Mason, Daniel E.,Suzuki, Melissa,Larson, Brad,Zhang, Jianming,Zagorska, Anna,DiDonato, Michael,Nagle, Advait,Warmuth, Markus,Balk, Steven P.,Peters, Eric C.,Gray, Nathanael S.
, p. 5916 - 5919 (2008)
Irreversible HER/erbB inhibitors selectively inhibit HER-family kinases by targeting a unique cysteine residue located within the ATP-binding pocket. Sequence alignment reveals that this rare cysteine is also present in ten other protein kinases including all five Tec-family members. We demonstrate that the Tec-family kinase Bmx is potently inhibited by irreversible modification at Cys496 by clinical stage EGFR inhibitors such as CI-1033. This cross-reactivity may have significant clinical implications.
In vivo efficacy studies of novel quinazoline derivatives as irreversible dual EGFR/HER2 inhibitors, in lung cancer xenografts (NCI-H1975) mice models
Das, Debasis,Xie, Lingzhi,Wang, Jingbing,Shi, Jingli,Hong, Jian
, (2020)
Lung cancer is the most common cancer and leading cause of cancer-related deaths worldwide. The first-generation reversible, ATP-competitive inhibitors gefetinib and elotinib showed good clinical responses in lung adenocarcinoma tumors (NSCLC). But almost all patients developed resistance to these inhibitors over time. Such resistance of EGFR inhibitors was frequently linked to the acquired L858R and T790M point mutations in the kinase domain of EGFR. To overcome these resistance problems, the second and the third generation inhibitors have been discovered. FDA approved afatinib, the second generation irreversible inhibitor and osimitinib, the third generation irreversible EGFR inhibitors for the treatments of NSCLC. We identified new covalent quinazoline inhibitors (E)-N-(4-(3-chloro-4-fluorophenylamino)-7-(2-ethoxyethoxy)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide (6d) and (E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-7-(2-ethoxyethoxy)quinazolin-6-yl)-4-(dimethyl-amino)but-2-enamide (6h) that exhibited potent EGFR kinase inhibitory activities on L858R and T790M mutations. The compound 6 h showed selectivity similar to AZD9291 (osimertinib) in mutated and wild type tumor cell lines. In vitro cell assay 6d and 6h were better than afatinib and osimertinib. In vivo antitumor efficacy studies of these compounds were done in NCI-H1975 mice xenografts.
Preparation method of dcotinib
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Paragraph 0056-0059, (2021/04/17)
The invention discloses a preparation method of Dacomitinib. The preparation method comprises the following steps: methyl oxidation, reduction and condensation reaction. The preparation method disclosed by the invention is simple and effective in process, simple and reliable to operate, high in economic benefit and more suitable for industrial production; the prepared Dacomitinib is high in purity and high in overall yield.
Tyrosine kinase inhibitor and pharmaceutical application thereof
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, (2021/08/19)
The invention relates to a tyrosine kinase inhibitor containing a quinazoline derivative in the fields of tumor treatment medicines and the like, and application of the tyrosine kinase inhibitor in treatment medicines for inhibiting and treating diseases caused by overexpression of tyrosine kinase. The active ingredient of the tyrosine kinase inhibitor is a quinazoline derivative with a structure shown in the following formula: a functional group containing XCH2 (CH2) nC = O is introduced on the basis of a quinazoline structure, and the functional group is easily combined with cysteine sulfydryl through nucleophilic reaction to form a covalent bond so that the activity of tyrosine kinase is irreversibly inhibited.
Design, synthesis and evaluation of novel ErbB/HDAC multitargeted inhibitors with selectivity in EGFRT790M mutant cell lines
Zhao, Lei,Fan, Tingting,Shi, Zhichao,Ding, Chao,Zhang, Cunlong,Yuan, Zigao,Sun, Qinsheng,Tan, Chunyan,Chu, Bizhu,Jiang, Yuyang
, (2021/01/25)
Acquired resistance leads to the failure of EGFR TKIs in NSCLC treatment. A novel series of hydroxamic acid-containing 4-aminoquinazoline derivatives as irreversible ErbB/HDAC multitargeted inhibitors for NSCLC therapy had been designed and synthesized, which displayed weak anti-proliferative activity in several EGFR wild-type cancer cell lines (NCI–H838, SK-BR-3, A549, A431) yet retained moderate activity to EGFRT790M resistance mutation harboring NCI–H1975 cells. The mechanistic studies revealed that the representative compound 11e was able to inhibit the phosphorylation of EGFR, up-regulate hyperacetylation of histone H3 and even reduce the expression of EGFR and Akt in NCI–H1975 cells. In further assays, compound 11e also showed moderate anti-proliferative activity in other EGFRT790M harboring tumor cell lines (NCI–H820, Ba/F3_EGFR_Del19-T790M-C797S) and low toxicities in normal cell lines (HL-7702, FHC). This selectivity of designed multitargeted compounds could serve as a potential strategy to circumvent multiple mechanisms of acquired resistance to EGFR-targeted therapy without severe toxicities and side effects resulting from broad inhibition.
Production method of N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazoline amine
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Paragraph 0018-0062, (2020/08/27)
The invention discloses a production method of a targeted anti-tumor drug afatinib intermediate namely N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazoline amine. The preparation method comprises the following steps: in a non-proton organic solvent environment; carrying out chlorination reaction on a Vislmeier reagent prepared from a non-phosphorus reagent and 4-hydroxy-5-fluoro-6-nitro-quinazoline; after the reaction is finished, adding a 3-chloro-4-fluorine-aniline solution taking the non-proton organic solvent as a solvent to carry out a coupling reaction; after the coupling reactionis finished, adding water, uniformly mixing, standing for layering; sequentially washing, concentrating under reduced pressure, and drying to obtain a final product. No waste is generated in the wholeproduction process, and the used non-proton organic solvent can be recycled, so that the production method has the advantages that the production process is environment-friendly and conforms to cleanproduction, the yield of the finally obtained N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazoline amine can reach 83-89%, and the purity reaches 98% or above.
Novel method for preparing N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazolinamine
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Paragraph 0019-0024, (2019/01/24)
The invention discloses a novel method for preparing N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazolinamine. The method comprises the following steps: with 2-bromo-4-fluoro-5-nitrobenzonitrileas a starting material, subjecting 2-bromo-4-fluoro-5-nitrobenzonitrile and 3-chloro-4-fluoroaniline to addition under the promotion of a catalyst and microwaves; and then subjecting an addition product and methanamide to cascaded amination and condensation cyclization reactions to synthesize the key intermediate N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazolinamine used for the anticancer drugs, i.e., afatinib and dacomitinib, wherein overall yield is 90%. The method of the invention has the advantages of short synthetic route, mild reaction conditions, short reaction time, high product yield, no usage of highly-contaminating thionyl chloride and phosphorus oxychloride, and friendliness to environment; and the method provides a highly-efficient simple method approach for synthesis of 4-quinazolinamine compounds and has potential industrial application prospects.
Discovery of new quinazoline derivatives as irreversible dual EGFR/HER2 inhibitors and their anticancer activities – Part 1
Das, Debasis,Xie, Lingzhi,Wang, Jingbing,Xu, Xin,Zhang, Zonghua,Shi, Jingli,Le, Xiaoyong,Hong, Jian
, p. 591 - 596 (2019/01/04)
Overexpression of EGFR and HER2 are observed in many breast, ovarian, colon and prostate cancers. The second and third generation irreversible EGFR/HER2 dual kinase inhibitors became popular after the approval of Afatinib by FDA to overcome the mutation related problem. To find efficacious drug candidates, a series of novel quinazoline derivatives were designed, synthesized and evaluated as dual EGFR/HER2 tyrosine kinase (TK) inhibitors. Selected twenty four compounds were reported here with significant inhibitory activities against EGFR/HER2 tyrosine kinases. Several compounds showed nanomolar IC50 values. In vitro studies of quinazoline derivatives were done on NCI-H1975, HCC827, A431, MDA MB-453 cell lines. The compounds 1a, 1d and 1v were found more potent compared to standard drug afatinib. In vivo efficacy study of 1d on nude mice NCI-H1975 tumour xenograft model was discussed.
