21369-76-6Relevant academic research and scientific papers
Design, synthesis and 3D-QSAR analysis of novel thiopyranopyrimidine derivatives as potential antitumor agents inhibiting A549 and Hela cancer cells
Zhao, Bingbing,Zhao, Chengwu,Hu, Xiaohan,Xu, Shan,Lan, Zhou,Guo, Yuping,Yang, Zunhua,Zhu, Wufu,Zheng, Pengwu
, (2020)
Four series of thiopyranopyrimidine AZD9291 derivatives containing acrylamide structure were designed, synthesized and evaluated for their antiproliferative activity against A549 and Hela cancer cells. Most of the compounds exhibited excellent antiproliferative activity against A549 cells. Moreover, the compounds with indole ring fluorine substituted exhibited better antiproliferative activity against Hela cells. The most promising compound 23g exhibited excellent enzymatic inhibitory activity and selectivity for EGFRL858R/T790M double mutations. The IC50 value against EGFRL858R/T790M kinase was 16 nM. The compound 23g inhibits selectively against the mutated form of EGFR, with the selectivity more than 125-fold. Furthermore, compound 23g also inhibited A549 cells, Hela cells and H1975 cells proliferation at a low concentration, and the IC50 values were 0.057 μM, 0.104 μM and 0.916 μM, respectively. To further investigate the QSARs of thiopyranopyrimidine derivatives, the CoMFA (q [2] = 0.765, r2 = 0.965) and CoMSIA (q [2] = 0.875, r2 = 0.956) models on Hela cancer cells were established. The generated 3D-QSAR model was validated to be reliable and can be used for further design and optimization of novel and selective EGFR inhibitors.
Direct Regio- and Diastereoselective Synthesis of δ-Lactams from Acrylamides and Unactivated Alkenes Initiated by RhIII-Catalyzed C?H Activation
Lee, Sumin,Rovis, Tomislav,Semakul, Natthawat
supporting information, p. 4965 - 4969 (2020/02/20)
We report a RhIII-catalyzed regio- and diastereoselective synthesis of δ-lactams from readily available acrylamide derivatives and unactivated alkenes. The reaction provides a rapid route to a diverse set of δ-lactams in good yield and stereoselectivity, which serve as useful building blocks for substituted piperidines. The regioselectivity of the reaction with unactivated terminal alkene is significantly improved by using Cpt ligand on the RhIII catalyst. The synthetic utility of the reaction is demonstrated by the preparation of a potential drug candidate containing a trisubstituted piperidine moiety. Mechanistic studies show that the reversibility of the C?H activation depends on the choice of Cp ligand on the RhIII catalyst. The irreversible C?H activation is observed and becomes turnover-limiting with [CptRhCl2]2 as catalyst.
Design, synthesis and biological evaluation of AZD9291 derivatives as selective and potent EGFRL858R/T790M inhibitors
Zhao, Bingbing,Xiao, Zhen,Qi, Jianguo,Luo, Rong,Lan, Zhou,Zhang, Yanzhuo,Hu, Xiaohan,Tang, Qidong,Zheng, Pengwu,Xu, Shan,Zhu, Wufu
, p. 367 - 380 (2018/12/13)
Third-generation epidermal growth factor receptor (EGFR)L858R/T790M inhibitors are still the main drugs for the treatment of advanced non-small cell lung cancer (NSCLC), and these drugs have achieved remarkable clinical efficacy. However, there are still many patients suffering from drug-resistant mutations and drug side effects caused by NSCLC. In this study, guided by the molecular simulation, we applied a structure-based drug design strategy (SBDD) and optimized the structure to obtain a series of potent and selective EGFRL858R/T790M inhibitors. The most potent compound 18e demonstrated excellent kinase inhibitory activity and selectivity for EGFRL858R/T790M double mutants and the IC50 value reached nanomolar level. The selectivity of 18e against wild-type EGFR was near to 200-fold. In addition, compound 18e also inhibited H1975 cells proliferation at G2/M phase and induced apoptosis at a concentration of 0.25 μM, which makes it more valuable for potential lung cancer research.
Quinoline and quinazoline derivatives, preparation method, intermediate, composition and use thereof (by machine translation)
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Paragraph 0416; 0420, (2016/11/07)
The invention discloses a quinoline and quinazoline derivative I, a preparation method, an intermediate C, composition and an application. The preparation method comprises two methods, wherein the first method comprises steps as follows: 1, a compound A and a compound B react in a solvent under the action of alkali 1 to obtain a compound C; and 2, the product C obtained in the step 1 reacts with a compound D under the action of alkali 2; and the second comprises step as follows: the compound A and a compound E react in the solvent under the action of the alkali 1. The invention further provides the application of the compound represented in formula I or medicine composition in preparation of an EGFR (epidermal growth factor receptor) tyrosine kinase inhibitor, an A431 or H1975 cell proliferation inhibitor or medicine for preventing or treating tumor diseases. The provided compound has better antitumor activity.
Efficient synthesis of 6-amino-substituted pyridin-2(1H)-ones using in situ generated propiolic acid chloride
Schirok, Hartmut,Alonso-Alija, Cristina,Michels, Martin
, p. 3085 - 3094 (2007/10/03)
A regioselective and highly efficient synthesis of 6-amino-substituted pyridin-2(1H)-ones is presented. In situ generated propiolic acid chloride was used for the cyclization of acyclic β-keto N,S-acetals to afford the heterocyclic core. Substitution by a
Design and Synthesis of Naltrexone-Derived Affinity Labels with Nonequilibrium Opioid Agonist and Antagonist Activities. Evidence for the Existence of Different μ Receptor Subtypes in Different Tissues
Sayre, L. M.,Larson, D. L.,Takemori, A. E.,Portoghese, P. S.
, p. 1325 - 1335 (2007/10/02)
A series of β-funaltrexamine (2, β-FNA) analogues (3-14) were synthesized that contain a variety of electrophilic groups attached at the 6β-position of the opiate.The opioid agonist and antagonist activities of these ligands were evaluated in the guinea pig ileum (GPI) and mouse vas deferens (MVD) in vitro assays.Several of the compounds behaved like β-FNA in that they exhibited reversible agonist activity at κ opioid receptors and irreversible antagonist activity at μ opioid receptors.The rank order of irreversible antagonism for a series of related Michael acceptors did not parallel their intrinsic chemical reactivity, confirming that the degree of covalent binding is in part dependent on the spatial disposition of the electrophilic center relative to the receptor nucleophile (secondary recognition).The maleimidoacetamide 8 behaved very differently from β-FNA in that it exhibited considerably greater irreversible μ antagonism in MVD relative to the μ blockage in the GPI.This suggests that different proportions of μ receptor subtypes exist in the two tissues.Several of the agents tested, including some nonreactive control compounds, displayed an unusual type of persistent κ agonist activity in the GPI.This activity, which was reversed by addition of naxolone, reappeared upon washing.Receptor models have been presented to explain this effect.A few of the reactive ligands displayed a true nonreversible κ agonist activity, suggesting a covalent association with the receptor.Of note in this regard was the propiolamide 6, which appeared to be an irreversible mixed agonist-antagonist at κ and μ receptors.
Process for the preparing α-chloroacrylic acid chlorides
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, (2008/06/13)
α-Chloroacrylic acid chloride is obtained in a high yield by splitting off HCl from α,β-dichloropropionic acid chloride at an increased temperature and under reduced pressure in the presence of a tertiary phosphine, a quaternary phosphonium salt or a tertiary phosphine oxide, sulfide, halide or imine. α-Chloroacrylic acid chloride is important as a starting and intermediate material for further syntheses, especially as the starting material for the total synthesis of prostaglandins according to Corey.
Acid chloride synthesis
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, (2008/06/13)
α,β-Unsaturated carboxylic acid chlorides are advantageously produced in high yields and with minimal formation of by-products by reaction of the corresponding carboxylic acid with oxalyl chloride.
