20876-36-2Relevant articles and documents
Design, synthesis and biological evaluation of indole-2-one derivatives as potent BRD4 inhibitors
Xu, Yu,Zhang, Xiu-Juan,Li, Wen-Bo,Wang, Xing-Rong,Wang, Shuai,Qiao, Xue-Peng,Chen, Shi-Wu
, (2020)
Bromodomain protein 4 (BRD4) plays a crucial role in transcriptional regulation and is considered to be a viable drug target for cancer treatment. Herein, we designed and synthesized a series of indole-2-one derivatives through scaffold hopping drug desig
A novel small molecule, ZY354, inhibits dental caries-associated oral biofilms
Zhang, Chenzi,Kuang, Xinyi,Zhou, Yuanzheng,Peng, Xian,Guo, Qiang,Yang, Tao,Zhou, Xuedong,Luo, Youfu,Xu, Xin
, (2019)
Biofilm control is a critical approach to the better management of dental caries. Antimicrobial small molecules have shown their potential in the disruption of oral biofilm and control of dental caries. The objectives of this study were to examine the antimicrobial activity and cytotoxicity of a newly designed small-molecule compound, ZY354. ZY354 was synthesized, and its cytotoxicity was evaluated in human oral keratinocytes (HOK), human gingival epithelial cells (HGE), and macrophages (RAW) by CCK-8 assays. Minimal inhibitory concentrations (MICs), minimum bactericidal concentrations (MBCs), minimum biofilm inhibition concentrations (MBICs), and minimum biofilm reduction concentrations (MBRCs) of ZY354 against common oral streptococci (i.e., Streptococcus mutans, Streptococcus gordonii, and Streptococcus sanguinis) were determined by microdilution method. The exopolysaccharide (EPS)/bacterium ratio and the dead/live bacterium ratio in the ZY354-treated multispecies biofilms were determined by confocal laser scanning microscopy, and the microbial composition was visualized and quantified by fluorescent in situ hybridization and quantitative PCR (qPCR). The demineralizing activity of ZY354-treated biofilms was evaluated by transverse microradiography. The results showed that ZY354 exhibited low cytotoxicity in HOK, HGE, and RAW cells and exhibited potent antimicrobial activity against common oral streptococci. The EPS and the abundance of S. mutans were significantly reduced after ZY354 treatment, along with an increased dead/live microbial ratio in multispecies biofilms compared to the level with the nontreated control. The ZY354-treated multispecies biofilms exhibited reduced demineralizing activity at the biofilm/enamel interface. In conclusion, the small-molecule compound ZY354 exhibits low cytotoxicity and remarkable antimicrobial activity against oral streptococci, and it may have a great potential in anticaries clinical applications.
Synthesis of novel 3,5-disubstituted-2-oxindole derivatives as antitumor agents against human nonsmall cell lung cancer
Nesi, Giulia,Sestito, Simona,Mey, Valentina,Ricciardi, Simona,Falasca, Marco,Danesi, Romano,Lapucci, Annalina,Breschi, Maria C.,Fogli, Stefano,Rapposelli, Simona
, p. 1137 - 1141 (2013)
This study was aimed at investigating the antitumor activity of novel 2-oxindole derivatives against a well-characterized human nonsmall cell lung cancer (NSCLC) cell line. Test compounds produced an antiproliferative activity in the low micromolar/submicromolar range of concentrations and significantly induced typical apoptotic morphology with cell shrinkage, nuclear condensation and fragmentation, and rupture of cells into debris in a relatively low percentage of A549 cells. Cell cycle arrest occurred at the G1/S phase (1a and 2), and Akt phosphorylation was significantly inhibited at Thr308 and Ser473. The most active compound (1a) has an IC50 6-fold lower than the Akt inhibitor, perifosine. These data suggest that the new compounds may be cytostatic and may have maximum clinical effects in NSCLC patients who do not respond to EGFR inhibitors. These findings prompt us to further explore the oxindole structure as leading scaffold to design new molecules with potent antitumor activity against NSCLC.
Design, synthesis and biological evaluation of 3-substituted-2-oxindole hybrid derivatives as novel anticancer agents
Romagnoli, Romeo,Baraldi, Pier Giovanni,Prencipe, Filippo,Oliva, Paola,Baraldi, Stefania,Salvador, Maria Kimatrai,Lopez-Cara, Luisa Carlota,Bortolozzi, Roberta,Mattiuzzo, Elena,Basso, Giuseppe,Viola, Giampietro
, p. 258 - 270 (2017)
The 2-oxindole nucleus is the central core to develop new anticancer agents and its substitution at the 3-position can effect antitumor activity. Utilizing a pharmacophore hybridization approach, a novel series of antiproliferative agents was obtained by the modification of the structure of 3-substituted-2-oxindole pharmacophore by the attachment of the α-bromoacryloyl moiety, acting as a Michael acceptor, at the 5-position of 2-oxindole framework. The impact of the substituent at the 3-position of 2-oxindole core on the potency and selectivity against a panel of seven different cancer cell lines was examined. We found that these hybrid molecules displayed potent antiproliferative activity against a panel of four cancer cell lines, with one-to double digit nanomolar 50% inhibitory concentrations (IC50). A distinctive selective antiproliferative activity was obtained towards CCRF-CEM and RS4; 11 leukemic cell lines. In order to study the possible mechanism of action, we observed that the two most active compounds namely 3(E) and 6(Z) strongly induce apoptosis that follow the mitochondrial pathway. Interestingly a decrease of intracellular reduced glutathione content (GSH) and reactive oxygen species (ROS) production was detected in treated cells compared with controls suggesting that these effects may be involved in their mechanism of action.
A Unified Catalytic Asymmetric (4+1) and (5+1) Annulation Strategy to Access Chiral Spirooxindole-Fused Oxacycles
Gao, Min,Gong, Xiangnan,Hu, Lin,Luo, Yanshu,Xia, Yuanzhi,Xu, Qianlan,Zhao, Yukun
, p. 19813 - 19820 (2021/08/03)
A unified catalytic asymmetric (N+1) (N=4, 5) annulation reaction of oxindoles with bifunctional peroxides has been achieved in the presence of a chiral phase-transfer catalyst (PTC). This general strategy utilizes peroxides as unique bielectrophilic four- or five-atom synthons to participate in the C?C and the subsequent umpolung C?O bond-forming reactions with one-carbon unit nucleophiles, thus providing a distinct method to access the valuable chiral spirooxindole-tetrahydrofurans and -tetrahydropyrans with good yields and high enantioselectivities under mild conditions. DFT calculations were performed to rationalize the origin of high enantioselectivity. The gram-scale syntheses and synthetic utility of the resultant products were also demonstrated.
Structure–activity relationship study of DEL-22379: ERK dimerization inhibitors with increased safety
Yang, Yang,Zhou, Yuanzheng,Tao, Lei,Yang, Tao,Zhao, Yinglan,Luo, Youfu
, p. 1051 - 1075 (2020/05/25)
Abstract: Aberrant activation of ERK signaling pathway usually leads to oncogenesis, and small molecular agents targeting this pathway are impeded by the emergence of drug resistance due to reactivation of ERK signaling. Compound DEL-22379 has been reported to inhibit ERK dimerization which was unaffected by drug-resistant mechanism reactivating the ERK signaling. Here, we discussed a structure–activity relationship study of DEL-22379. Forty-seven analogues were designed and synthesized. Each synthesized compound was biologically evaluated for their inhibitory rates on several tumor cell lines and compounds with high inhibitory rates were further evaluated for IC50 values. The structure–activity relationship of idolin-2-one scaffold and the impact of Z/E configuration on potency were discussed. Potential safety of two synthesized analogues was investigated and in silico docking study of five compounds was performed to understand the structural basis of ERK dimerization inhibition. Graphic abstract: [Figure not available: see fulltext.]
Design, synthesis and biological evaluation of 2-indolinone derivatives as PAK1 inhibitors in MDA-MB-231 cells
Yao, Dahong,Ruhan,Jiang, Jin,Huang, Jian,Wang, Jinhui,Han, Weina
, (2020/07/03)
P21-activated kinase 1 (PAK1) plays a vital role in the proliferation, survival and migration of cancer cells, which has emerged as a promising drug target for cancer therapy. In this study, a series of 2-indolinone derivatives were designed and synthesized through a structure-based strategy. A potent PAK1 inhibitor (ZMF-005) was discovered, which presented an IC50 value of 0.22 μM against PAK1 with potent antiproliferative activity. Furthermore, we predicted the binding mode of ZMF-005 and PAK1 by molecule docking and dynamic (MD) simulation. In addition, ZMF-005 was documented to induce significant apoptosis and suppress migration in MDA-MB-231 cells. Collectively, these findings revealed that ZMF-005 is a novel potent PAK1 inhibitor for breast cancer treatment.
2-indolone PAK1 inhibitor and application of 2-indolone PAK1 inhibitor in anti-tumor treatment drugs
-
, (2020/09/30)
The invention relates to a 2-indolone PAK1 inhibitor and an application of the 2-indolone PAK1 inhibitor in anti-tumor treatment drugs, and belongs to the technical field of anti-tumor pharmacy. The technical problem to be solved by the invention is to provide a compound used as a PAK1 inhibitor. The compound comprises a compound as shown in the specification or pharmaceutically acceptable salt thereof, wherein X, n and R1 are described in the claims and the specification. The compound or the pharmaceutically acceptable salt thereof can be used as a PAK1 inhibitor for preparing antitumor drugs.
Indole-2-ketone derivative, preparation method and application thereof
-
Paragraph 0240; 0376-0379, (2020/07/06)
The invention belongs to the field of medicines, particularly relates to an indole-2-ketone derivative, a preparation method and application thereof, and provides a compound represented by the following formula (I), a stereoisomer, a racemate, a tautomer,
Synthesis and biological evaluation of 3-substituted 2-oxindole derivatives as new glycogen synthase kinase 3β inhibitors
Lozinskaya, Natalia A.,Babkov, Denis A.,Zaryanova, Ekaterina V.,Bezsonova, Elena N.,Efremov, Alexander M.,Tsymlyakov, Michael D.,Anikina, Lada V.,Zakharyascheva, Olga Yu.,Borisov, Alexander V.,Perfilova, Valentina N.,Tyurenkov, Ivan N.,Proskurnina, Marina V.,Spasov, Alexander A.
, p. 1804 - 1817 (2019/03/23)
Glycogen synthase kinase 3β (GSK-3β) is a widely investigated molecular target for numerous diseases including Alzheimer's disease, cancer, and diabetes mellitus. Inhibition of GSK-3β activity has become an attractive approach for treatment of diabetes and cancer. We report the discovery of novel GSK-3β inhibitors of 3-arylidene-2-oxindole scaffold with promising activity. The most potent compound 3a inhibits GSK-3β with IC50 4.19 nM. In a cell-based assay 3a shows no significant leucocyte toxicity at 10 μM and is moderately cytotoxic against A549 cells. Compound 3a demonstrated high antidiabetic efficacy in obese streptozotocin-treated rats improving glucose tolerance at a dose of 50 mg/kg body weight thus representing an interesting lead for further optimization.
