2216-15-1Relevant academic research and scientific papers
Optimization of WZ4003 as NUAK inhibitors against human colorectal cancer
Yang, Huali,Wang, Xiaobing,Wang, Cheng,Yin, Fucheng,Qu, Lailiang,Shi, Cunjian,Zhao, Jinhua,Li, Shang,Ji, Limei,Peng, Wan,Luo, Heng,Cheng, Maosheng,Kong, Lingyi
, (2020/12/15)
NUAK, the member of AMPK (AMP-activated protein kinase) family of protein kinases, is phosphorylated and activated by the LKB1 (liver kinase B1) tumor suppressor protein kinase. Recent work has indicated that NUAK1 is a key component of the antioxidant stress response pathway, and the inhibition of NUAK1 will suppress the growth and survival of colorectal tumors. As a promising target for anticancer drugs, few inhibitors of NUAK were developed. With this goal in mind, based on NUAK inhibitor WZ4003, a series of derivatives has been synthesized and evaluated for anticancer activity. Compound 9q, a derivative of WZ4003 by removing a methoxy group, was found to be the most potential one with stronger inhibitory against NUAK1/2 enzyme activity, tumor cell proliferation and inducing apoptosis of tumor cells. By in vivo efficacy evaluations of colorectal SW480 xenografts, 9q suppresses tumor growth more effectively with an excellent safety profile in vivo and is therefore seen as a suitable candidate for further investigation.
Discovery of benzo[d]oxazole derivatives as the potent type-I FLT3-ITD inhibitors
Bao, Jiyin,Liu, Haichun,Zhi, Yanle,Yang, Wenqianzi,Zhang, Jiawei,Lu, Tao,Wang, Yue,Lu, Shuai
, (2019/09/30)
Fms-like tyrosine kinase 3 (FLT3) has been considered as a potential drug target for the treatment of acute myeloid leukemia (AML), because of its high and aberrant expression in AML patients, especially the patients with FLT3-ITD mutation. Initiating from a hit compound (IC50: 500 nM against FLT3-ITD), a series of compounds were designed and synthesized based on benzo[d]oxazole-2-amine scaffold to discover new potent FLT3-ITD inhibitors. During the medicinal chemistry works, flexible molecular docking was used to provide design rationale and study the binding modes of the target compounds. Through the mixed SAR exploration based on the enzymatic and cellular activities, compound T24 was identified with potent FLT3-ITD inhibitory (IC50: 0.41 nM) and anti-proliferative (IC50: 0.037 μM against MV4-11 cells) activities. And the binding mode of T24 with “DFG-in” FLT3 was simulated by a 20-ns molecular dynamics run, providing some insights into further medicinal chemistry efforts toward novel FLT3 inhibitors in AML therapy.
Cp*Co(iii) and Cu(OAc)2bimetallic catalysis for Buchwald-type C-N cross coupling of aryl chlorides and amines under base, inert gas & solvent-free conditions
Srivastava, Avinash K.,Sharma, Charu,Joshi, Raj K.
supporting information, p. 8248 - 8253 (2020/12/29)
A strategy involving bimetallic catalysis with a combination of Cp?Co(CO)I2 and Cu(OAc)2 was used for performing Buchwald-type C-N coupling reactions of aryl chlorides with amines. The reactions proceeded at 100 °C to produce excellent yields of many of the desired C-N coupled products, in 4 h, under aerobic reaction conditions. The reactions were shown to run under base-free and solvent-free conditions, enabling this strategy to work efficiently for electron-withdrawing and base-sensitive functionalities. The presented methodology was found to be equally efficient for electron-donating functionalities as well as for primary (1°) and secondary (2°) aromatic and aliphatic amines. Moreover, the products were easily separated through the extractions of the organic aqueous layer, with this process chromatographic separations is not required.
Half-sandwich (η5-Cp?)Rh(iii) complexes of pyrazolated organo-sulfur/selenium/tellurium ligands: Efficient catalysts for base/solvent free C-N coupling of chloroarenes under aerobic conditions
Joshi, Raj Kumar,Sharma, Charu,Sharma, Kamal Nayan,Srivastava, Avinash Kumar
supporting information, p. 3599 - 3606 (2020/06/10)
Three new pyrazolated chalcogenoether ligated Rh(iii) half-sandwich complexes (1-3) were synthesised by the thermal reaction of chalcogenoether (S, Se and Te) substituted 1H-pyrazole ligands (L1-L3) and [(η5-C5Me5)RhCl]2 in methanol. The complexes were fully characterised by various spectroscopic techniques, and the molecular structures of complexes 1 and2 were also established through single crystal X-ray crystallographic analysis, which indicates a pseudo-octahedral half-sandwich piano-stool geometry around the rhodium metal. All three complexes were found to be thermally stable and insensitive towards air and moisture. One mol% of Rh(iii) complexes (1-3) along with 10 mol% of Cu(OAc)2 were explored for the Buchwald-Hartwig type C-N coupling reactions of amine and aryl chloride. Good to excellent yields (89-92%) of the coupling products were obtained with seleno- and thio-ether functionalised pyrazolated Rh(iii) complexes (1 and 2), while an average yield (39%) was obtained with the telluro-ether functionalised complex (3). In contrast to the previously reported C-N coupling reactions the present reaction works under solvent- and base-free conditions, and the coupling reaction is accomplished in just 6 h with a high yield of the coupling product. The present methodology was also found to be efficient for a wide variety of functionalised aryl halides, and aliphatic or aromatic amines (1° and 2°). Moreover, the reaction also enables the C-N coupling of electron-withdrawing substrates and base-sensitive functionalities.
Amination of Aromatic Halides and Exploration of the Reactivity Sequence of Aromatic Halides
Yang, Chu,Zhang, Feng,Deng, Guo-Jun,Gong, Hang
, p. 181 - 190 (2019/01/10)
A base-promoted amination of aromatic halides has been developed using a limited amount of dimethylformamide (DMF) or amine as an amino source. Various aryl halides, including F, Cl, Br, and I, have been successfully aminated in good to excellent yields. Although the amination of aromatic halides with amines or DMF is usually considered as an aromatic nucleophilic substitution (SNAr) process, and the reactivity of an aromatic halide is F > Cl > Br > I, the reactivity of aromatic halides in this system was found to be I > Br a‰ F > Cl. This protocol also showed a good regioselectivity for multihalogenated aromatics. This protocol is valuable for industrial application due to the simplicity of operation, the unrestricted availability of amino sources and aromatic halides, transition metal-free conditions, no requirement for solvent, and scalability.
A palladium nanoparticle-catalyzed aryl-amine coupling reaction: High performance of aryl and pyridyl chlorides as the coupling partner
Nandi, Debkumar,Islam, Rafique Ul,Devi, Nishu,Siwal, Samarjeet,Mallick, Kaushik
supporting information, p. 812 - 816 (2018/02/06)
Carbon nitride (CN)-supported nanosized palladium particles, Pd-CN, have been found to be an active catalyst system for the amination of aryl and pyridyl chloride moieties in the presence of dialkyl amine under mild reaction conditions. The recyclability study of the reaction shows the stable performance of the catalyst without a significant loss of catalytic activity for a couple of cycles.
Discovery of Potent, Selective Stem Cell Factor Receptor/Platelet Derived Growth Factor Receptor Alpha (c-KIT/PDGFRα) Dual Inhibitor for the Treatment of Imatinib-Resistant Gastrointestinal Stromal Tumors (GISTs)
Lu, Yanli,Mao, Fei,Li, Xiaokang,Zheng, Xinyu,Wang, Manjiong,Xu, Qing,Zhu, Jin,Li, Jian
supporting information, p. 5099 - 5119 (2017/06/28)
Stem cell factor receptor (c-KIT) and platelet derived growth factor receptor alpha (PDGFRα) kinases play an important role in gastrointestinal stromal tumors (GISTs). Here, we have discovered an c-KIT/PDGFRα dual inhibitor, compound 31, with single-digit nanomolar potency against c-KIT and PDGFRα. Compared to Imatinib (1), 31 showed better antiproliferative efficacy against various TEL-c-KIT/PDGFRα-BaF3 isogenic cells, including three 1-resistant BaF3 cell lines, as well as against GIST-T1 and GIST-882 cell lines. Furthermore, compound 31 showed a good KinomeScan selectivity (468 kinases) (S score (1) = 0.01 at 1 μM concentration), good metabolic stability in liver microsomes, and no hERG inhibitory activity. It was worth noting that 31 inhibited GIST-T1 tumor growth (TGI = 81.5%) and even the BaF3-TEL-cKIT-T670I tumor progression (TGI = 41.9%, 1-resistant GISTs) at a dosage of 100 mg/kg/day without exhibiting apparent toxicity.
Synthesis of functionalized 4-nitroanilines by ring transformation of dinitropyridone with enaminones
Naito, Saki,Yokoyama, Soichi,Asahara, Haruyasu,Nishiwaki, Nagatoshi
supporting information, p. 4699 - 4702 (2017/11/21)
2-Functionalized 4-nitroanilines were readily synthesized by ring transformation using 3,5-dinitro-2-pyridone and enaminones prepared from 1,3-dicarbonyl compounds and amines. Modification of the amino group and the ortho-position could be achieved by sim
Combination of 4-anilinoquinazoline, arylurea and tertiary amine moiety to discover novel anticancer agents
Zuo, Sai-Jie,Zhang, Sai,Mao, Shuai,Xie, Xiao-Xiao,Xiao, Xue,Xin, Min-Hnag,Xuan, Wei,He, Yuan-Yuan,Cao, Yong-Xiao,Zhang, San-Qi
, p. 179 - 190 (2015/12/31)
In present study, 4-anilinoquinazolines scaffold, arylurea and tertiary amine moiety were combined to design, synthesize gefitinib analogs and discover novel anticancer agents. A series of 4-anilinoquinazoline derivatives (1, 2, 3 and 4) bearing arylurea and tertiary amine moiety at its 6-position were synthesized. Their antiproliferative activities in vitro were evaluated via MTT assay against A431 cell and A549 cell. The SAR of the title compounds was discussed. The compounds 2d, 2i and 2j with potent antiproliferative activities were evaluated their inhibitory activity against EGFR-TK. Compound 2j displayed potent inhibitory activity against EGFR-TK. In addition, compound 2j, at 50 mg/kg, can completely inhibit cancer growth in established nude mouse A549 xenograft model in vivo. These results suggest that the 4-anilinoquinazoline derivatives bearing diarylurea and tertiary amino moiety at its 6-position can serve as anticancer agents and EGFR inhibitors.
