- Design, synthesis and biological evaluation of indole-2-one derivatives as potent BRD4 inhibitors
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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
- Xu, Yu,Zhang, Xiu-Juan,Li, Wen-Bo,Wang, Xing-Rong,Wang, Shuai,Qiao, Xue-Peng,Chen, Shi-Wu
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- A novel small molecule, ZY354, inhibits dental caries-associated oral biofilms
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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.
- Zhang, Chenzi,Kuang, Xinyi,Zhou, Yuanzheng,Peng, Xian,Guo, Qiang,Yang, Tao,Zhou, Xuedong,Luo, Youfu,Xu, Xin
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- Synthesis of novel 3,5-disubstituted-2-oxindole derivatives as antitumor agents against human nonsmall cell lung cancer
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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.
- Nesi, Giulia,Sestito, Simona,Mey, Valentina,Ricciardi, Simona,Falasca, Marco,Danesi, Romano,Lapucci, Annalina,Breschi, Maria C.,Fogli, Stefano,Rapposelli, Simona
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- Design, synthesis and biological evaluation of 3-substituted-2-oxindole hybrid derivatives as novel anticancer agents
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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.
- 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
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- A Unified Catalytic Asymmetric (4+1) and (5+1) Annulation Strategy to Access Chiral Spirooxindole-Fused Oxacycles
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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.
- Gao, Min,Gong, Xiangnan,Hu, Lin,Luo, Yanshu,Xia, Yuanzhi,Xu, Qianlan,Zhao, Yukun
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p. 19813 - 19820
(2021/08/03)
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- Structure–activity relationship study of DEL-22379: ERK dimerization inhibitors with increased safety
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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.]
- Yang, Yang,Zhou, Yuanzheng,Tao, Lei,Yang, Tao,Zhao, Yinglan,Luo, Youfu
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p. 1051 - 1075
(2020/05/25)
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- Design, synthesis and biological evaluation of 2-indolinone derivatives as PAK1 inhibitors in MDA-MB-231 cells
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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.
- Yao, Dahong,Ruhan,Jiang, Jin,Huang, Jian,Wang, Jinhui,Han, Weina
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- 2-indolone PAK1 inhibitor and application of 2-indolone PAK1 inhibitor in anti-tumor treatment drugs
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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.
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- Indole-2-ketone derivative, preparation method and application thereof
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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,
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Paragraph 0240; 0376-0379
(2020/07/06)
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- Virtual Screening Identifies Irreversible FMS-like Tyrosine Kinase 3 Inhibitors with Activity toward Resistance-Conferring Mutations
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The use of covalent irreversible binding inhibitors is an established concept for drug development. Usually, the discovery of new irreversible kinase inhibitors occurs serendipitously, showing that efficient rational approaches for the rapid discovery of new drugs are needed. Herein, we report a virtual screening strategy that led to the discovery of irreversible inhibitors of FMS-like tyrosine kinase 3 (FLT3) involved in the pathogenesis of acute myeloid leukemia. A virtual screening library was designed to target the highly conserved Cys828 residue preceding the DFG motif by modification of reported reversible inhibitors with chemically reactive groups. Prospective covalent docking allowed the identification of two lead series, resulting in a massive increase in inhibition of kinase activity and cell viability by irreversible inhibitors compared to the corresponding reversible scaffolds. Lead compound 4b (BSc5371) displays superior cytotoxicity in FLT3-dependent cell lines to compounds in recent clinical trials and overcomes drug-resistant mutations.
- Bensinger, Dennis,Stubba, Daniel,Cremer, Anjali,Kohl, Vanessa,Wa?mer, Theresa,Stuckert, Johanna,Engemann, Victoria,Stegmaier, Kimberly,Schmitz, Katja,Schmidt, Boris
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supporting information
p. 2428 - 2446
(2019/03/11)
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- Synthesis and biological evaluation of 3-substituted 2-oxindole derivatives as new glycogen synthase kinase 3β inhibitors
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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.
- 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.
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p. 1804 - 1817
(2019/03/23)
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- Discovery of hybrids of indolin-2-one and nitroimidazole as potent inhibitors against drug-resistant bacteria
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With antibiotics resistance developing rapidly, new antibacterial agents are needed to be discovered. We readily synthesized 11 indolin-2-one compounds and found a hybrid of indolin-2-one and nitroimidazole 3-((1-methyl-5-nitro-1H-imidazol-2-yl)methylene)
- Zhou, Yuanzheng,Ju, Yuan,Yang, Yang,Sang, Zitai,Wang, Zhenling,He, Gu,Yang, Tao,Luo, Youfu
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p. 887 - 897
(2018/07/13)
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- Fe-Catalyzed Amination of (Hetero)Arenes with a Redox-Active Aminating Reagent under Mild Conditions
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A novel and efficient Fe-catalyzed direct C?H amination (NH2) of arenes is reported using a new redox-active aminating reagent. The reaction is simple, and can be performed under air, mild, and redox-neutral conditions. This protocol has a broad substrate scope and could be used in the late-stage modification of bioactive compounds. Mechanistic studies demonstrate that a radical pathway could be involved in this transformation.
- Liu, Jianzhong,Wu, Kai,Shen, Tao,Liang, Yujie,Zou, Miancheng,Zhu, Yuchao,Li, Xinwei,Li, Xinyao,Jiao, Ning
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supporting information
p. 563 - 567
(2017/01/18)
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- 2-OXO-1,2-DIHYDROPYRIDINE-3-CARBOXAMIDE COMPOUNDS AND THEIR USE AS INHIBITORS OF PDK1
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The present invention concern a 2-oxo-1,2-dihydropyridine-3-carboxamide compound of Formula (I) and new 2-oxo-1,2-dihydropyridine-3-carboxamide compounds of Formula (II) in the treatment of pathologies which require an inhibitor of PDK1 enzyme such as diabetes, neurodegenerative diseases such as Alzheimer's and Prion Diseases, and tumours such as breast, and pancreatic cancers and glioblastoma, particularly glioblastoma.
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Page/Page column 18; 19
(2016/12/26)
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- PHARMACEUTICAL COMBINATION FOR THE TREATMENT OF TUMORS
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The invention concerns a combination comprising at least one 2-oxo-indole derivative of formula (I) in which R1 is selected from the group consisting of thienyl, imidazolyl and pyridyl, optionally substituted by (C1-C3) al
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Page/Page column 10; 11
(2016/05/02)
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- Synthesis, Biological, and Computational Evaluation of Novel 1,3,5-Substituted Indolin-2-one Derivatives as Inhibitors of Src Tyrosine Kinase
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Several substituted indolin-2-one derivatives were synthesized and evaluated for their activities against Src kinase. Several compounds showed activity against Src, with IC50 values in the low micromolar range. Among them, compound 2f showed the most significant activity with an IC50 value of 1.02 μM. Molecular docking studies have been performed for evaluation of the binding modes of compound 2f into the Src active site. The docking structure of compound 2f disclosed that the indole NH forms a hydrogen bond with the carbonyl of Met341. These results suggest that our novel compound 2f is a promising compound for the further development of indole-based drugs targeting Src kinase. A novel series of indole-2-one derivatives were synthesized and evaluated for their Src inhibitory activities. Compound 2f was found as the most promising compound with an IC50 value of 1.02 μM. Molecular docking studies were performed to disclose the binding mode for compound 2f.
- Kilic-Kurt, Zühal,Bakar, Filiz,?lgen, Süreyya
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p. 715 - 729
(2015/10/12)
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- Design and synthesis of 2-oxindole based multi-targeted inhibitors of PDK1/Akt signaling pathway for the treatment of glioblastoma multiforme
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Aggressive behavior and diffuse infiltrative growth are the main features of Glioblastoma multiforme (GBM), together with the high degree of resistance and recurrence. Evidence indicate that GBM-derived stem cells (GSCs), endowed with unlimited proliferative potential, play a critical role in tumor development and maintenance. Among the many signaling pathways involved in maintaining GSC stemness, tumorigenic potential, and anti-apoptotic properties, the PDK1/Akt pathway is a challenging target to develop new potential agents able to affect GBM resistance to chemotherapy. In an effort to find new PDK1/Akt inhibitors, we rationally designed and synthesized a small family of 2-oxindole derivatives. Among them, compound 3 inhibited PDK1 kinase and downstream effectors such as CHK1, GS3Kα and GS3Kβ, which contribute to GCS survival. Compound 3 appeared to be a good tool for studying the role of the PDK1/Akt pathway in GCS self-renewal and tumorigenicity, and might represent the starting point for the development of more potent and focused multi-target therapies for GBM.
- Sestito, Simona,Nesi, Giulia,Daniele, Simona,Martelli, Alma,Digiacomo, Maria,Borghini, Alice,Pietra, Daniele,Calderone, Vincenzo,Lapucci, Annalina,Falasca, Marco,Parrella, Paola,Notarangelo, Angelantonio,Breschi, Maria C.,Macchia, Marco,Martini, Claudia,Rapposelli, Simona
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p. 274 - 288
(2015/11/03)
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- Repurposing human Aurora kinase inhibitors as leads for anti-protozoan drug discovery
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Hesperadin, an established human Aurora B inhibitor, was tested against cultures of Trypanosoma brucei, Leishmania major, and Plasmodium falciparum, and was identified to be a potent proliferation inhibitor. A series of analogs was designed and tested to
- Patel, Gautam,Roncal, Norma E.,Lee, Patricia J.,Leed, Susan E.,Erath, Jessey,Rodriguez, Ana,Sciotti, Richard J.,Pollastri, Michael P.
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p. 655 - 658
(2014/05/06)
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- Substituted indolin-2-ones as p90 ribosomal S6 protein kinase 2 (RSK2) inhibitors: Molecular docking simulation and structure-activity relationship analysis
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A series of novel indolin-2-ones inhibitors against p90 ribosomal S6 protein kinase 2 (RSK2) were designed and synthesized and their structure-activity relationship (SAR) was studied. The most potent inhibitor, compound 3s, exhibited potent inhibition against RSK2 with an IC50 value of 0.5 μM and presented a satisfactory selectivity against 23 kinases. The interactions of these inhibitors with RSK2 were investigated based on the proposed binding poses with molecular docking simulation. Four compounds and six compounds exhibited moderate anti-proliferation activities against PC 3 cells and MCF-7 cells, respectively.
- Zhong, Ye,Xue, Mengzhu,Zhao, Xue,Yuan, Jun,Liu, Xiaofeng,Huang, Jin,Zhao, Zhenjiang,Li, Honglin,Xu, Yufang
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p. 1724 - 1734
(2013/05/08)
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- The design, synthesis, and biological evaluation of potent receptor tyrosine kinase inhibitors
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Variously substituted indolin-2-ones were synthesized and evaluated for activity against KDR, Flt-1, FGFR-1 and PDGFR. Extension at the 5-position of the oxindole ring with ethyl piperidine (compound 7i) proved to be the most beneficial for attaining both biochemical and cellular potencies. Further optimization of 7i to balance biochemical and cellular potencies with favorable ADME/ PK properties led to the identification of 8h, a compound with a clean CYP profile, acceptable pharmacokinetic and toxicity profiles, and robust efficacy in multiple xenograft tumor models.
- Kim, Moon H.,Tsuhako, Amy Lew,Co, Erick W.,Aftab, Dana T.,Bentzien, Frauke,Chen, Jason,Cheng, Wei,Engst, Stefan,Goon, Levina,Klein, Rhett R.,Le, Donna T.,Mac, Morrison,Parks, Jason J.,Qian, Fawn,Rodriquez, Monica,Stout, Thomas J.,Till, Jeffrey H.,Won, Kwang-Ai,Wu, Xiang,Michael Yakes,Yu, Peiwen,Zhang, Wentao,Zhao, Yeping,Lamb, Peter,Nuss, John M.,Xu, Wei
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scheme or table
p. 4979 - 4985
(2012/09/07)
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- PYRROLO-NITROGENOUS HETEROCYCLIC DERIVATIES,THE PREPARATION AND THE PHARMCETICAL USE THEEOF
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The invention provides new pyrrolo-nitrogenous heterocyclic derivatives represented by formula (I) or their salts, the preparation thereof, pharmaceutical compositions containing such derivatives and the use of such derivatives as therapeutic agents, especially as protein kinase inhibitors, wherein each substituent in formula (I) is same as defined in the description.
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Page/Page column 64
(2010/04/23)
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- PYRROLO-NITROGENOUS HETEROCYCLIC DERIVATIVES, THE PREPARATION AND THE PHARMACEUTICAL USE THEREOF
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The invention provides new pyrrolo-nitrogenous heterocyclic derivatives represented by formula (I) or their salts, the preparation thereof, pharmaceutical compositions containing such derivatives and the use of such derivatives as therapeutic agents, espe
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Page/Page column 62
(2010/04/23)
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- SUBSTITUTED ARYLSULFONYLAMINOMETHYLPHOSPHONIC ACID DERIVATIVES, THEIR PREPARATION AND THEIR USE IN THE TREATMENT OF TYPE I AND II DIABETES MELLITUS
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The present invention relates to substituted arylsulphonylaminomethylphosphonic acid derivatives of general formula (I) wherein R, X, Y and Z are defined as in claim 1, the tautomers, enantiomers, diastereomers, mixtures thereof and salts thereof which ha
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Page/Page column 54-55
(2009/03/07)
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- Methods for treating diseases and disorders related to unregulated angiogenesis and/or vasculogenesis
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The present invention relates to methods for treating diseases and disorders related to unregulated angiogenesis and/or vasculogenesis. More specifically, this invention relates to methods for treating diseases and disorders, such as rheumatoid arthritis,
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- Pyrimidine derivatives for the treatment of abnormal cell growth
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The present invention relates to a compound of the formula 1 wherein R1-R4 are as defined herein. Such novel pyrimidine derivatives are useful in the treatment of abnormal cell growth, such as cancer, in mammals. This invention also relates to a method of using such compounds in the treatment of abnormal cell growth in mammals, especially humans, and to pharmaceutical compositions containing such compounds.
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Page/Page column 43
(2008/06/13)
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- Pyrimidine derivatives for the treatment of abnormal cell growth
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The present invention relates to a compound of the formula 1 wherein A and Ar are as defined herein. Such novel pyrimidine derivatives are useful in the treatment of abnormal cell growth, such as cancer, in mammals. This invention also relates to a method of using such compounds in the treatment of abnormal cell growth in mammals, especially humans, and to pharmaceutical compositions containing such compounds.
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Page/Page column 19-20
(2010/02/14)
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- Indolinone derivatives and their use in treating disease-states such as cancer
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Indolinone derivatives, such as compounds of the formula (I): wherein A, m, n, R1, R2, R3, R5 and R6 are described herein, are disclosed herein as being useful in treating mammal having disease-states alleviated by the inhibition of PDK-1 activity.
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Page/Page column 31
(2010/02/11)
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- Selected anthranilaminde pyridinamides and their use as pharmaceutical agents
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Selected anthranilamide pyridinamines of general formula I in which R1 and R2 have the meanings that are indicated in the description, as VEGFR-2 and VEGFR-3 inhibitors, their production and use as pharmaceutical agents for treating
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Page/Page column 6
(2008/06/13)
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- COMPOUNDS FOR THE TREATMENT OF ABNORMAL CELL GROWTH
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The invention relates to compounds of the formula (1) and to pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein R1, R2, R3, R4, R5, n, A and B are as defined herein. The inventi
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- Prodrugs of a 3-(pyrrol-2-ylmethylidene)-2-indolinone derivatives
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The present invention relates to pyrrole substituted 2-indolinone compounds and their pharmaceutically acceptable salts which modulate the activity of protein kinases and therefore are expected to be useful in the prevention and treatment of protein kinase related cellular disorders such as cancer.
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- Combination therapy for the treatment of cancer
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The present invention relates to methods for treatment or prevention of neoplasia disorders using protein tyrosine kinase inhibitors in combination with cyclooxygenase inhibitors, in particular cyclooxygenase-2 selective inhibitors.
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- Methods of modulating protein tyrosine kinase function with substituted indolinone compounds
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The invention relates to certain indolinone compounds, their method of synthesis, and a combinatorial library consisting of the indolinone compounds. The invention also relates to methods of modulating the function of protein kinases using indolinone compounds and methods of treating diseases by modulating the function of protein kinases and related signal transduction pathways.
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- Pyrrole substituted 2-indolinone protein kinase inhibitors
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The present invention relates to pyrrole substituted 2-indolinone compounds and their pharmaceutically acceptable salts which modulate the activity of protein kinases and therefore are expected to be useful in the prevention and treatment of protein kinase related cellular disorders such as cancer.
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- 3-heteroarylidene-2-indolinone protein kinase inhibitors
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The present invention relates to novel 3-heteroarylidene-2-indolinone compounds and physiologically acceptable salts thereof which modulate the activity of protein kinases and therefore are expected to be useful in the prevention and treatment of protein kinase related cellular disorders such as cancer.
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- 3-(cycloalkanoheteroarylidenyl)-2-indolinone protein tyrosine kinase inhibitors
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The present invention relates to novel 3-(cycloalkano-heteroarylidenyl)-2-indolinone compounds and physiologically acceptable salts and prodrugs thereof which are expected to modulate the activity of protein tyrosine kinases and therefore to be useful in the prevention and treatment of protein tyrosine kinase related cellular disorders such as cancer.
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Page column 19
(2010/02/05)
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- Benzylidene-1,3-dihydro-indol-2-one derivatives a receptor tyrosine kinase inhibitors, particularly of Raf kinases
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Compounds of general formula (I) wherein: R1is H or optionally joined with R2to form a fused ring selected from the group consisting of five to ten membered aryl, heteroaryl or heterocyclyl rings, R2and R3are in
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- Substituted tetralylmethylen-oxindole analogues as tyrosine kinase inhibitors
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PCT No. PCT/EP97/02672 Sec. 371 Date Jan. 12, 1998 Sec. 102(e) Date Jan. 12, 1998 PCT Filed May 15, 1997 PCT Pub. No. WO97/45409 PCT Pub. Date Dec. 4, 1997A tetralylmethylene-2-oxindole derivative having the following formula (I) wherein one or two of R, R1, R2 and R3 the said two being the same or different, are selected from: a) -X-(CH2)m-NH2, -X-(CH2)m-NR4R5 or -X-(CH2)m-NHR6, in which X is -O-, -S- or -NH-, m is an integer of 2 to 4, one of R4 and R5 is hydrogen or C1-C6 alkyl and the other is C1-C6 alkyl or R4 and R5 taken together with the N atom to which they are linked form a 5 to 7 membered saturated heteromonocycle, and R6 is C2-C6 alkanoyl or a C-terminally linked peptidyl residue containing from 1 to 3 aminoacids wherein the terminal amino group is either free or protected or in an alkylated form to provide a -NR4R5 group in which R4 and R5 are as defined above.
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- 3-(cycloalkanoheteroarylidenyl)-2- indolinone protein tyrosine kinase inhibitors
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The present invention relates to novel 3-(cycloalkanoheteroarylidenyl)-2-indolinone compounds and physiologically acceptable salts and prodrugs thereof which are expected to modulate the activity of protein tyrosine kinases and therefore to be useful in the prevention and treatment of protein tyrosine kinase related cellular disorders such as cancer.
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- Indolinone combinatorial libraries and related products and methods for the treatment of disease
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The present invention relates to organic molecules capable of modulating, regulating and/or inhibiting protein kinase signal transduction. Such compounds are useful for the treatment of diseases related to unregulated protein kinase signal transduction, including cell proliferative diseases such as cancer, atherosclerosis, arthritis and restenosis and metabolic diseases such as diabetes. The present invention features indolinone compounds that potently inhibit protein kinases and related products and methods. Inhibitors specific to the FLK protein kinase can be obtained by adding chemical substituents to the 3-[(indole-3-yl)methylene]-2-indolinone, in particular at the 1' position of the indole ring. Indolinone compounds that specifically inhibit the FLK and platelet derived growth factor protein kinases can harbor a tetrahydroindole or cyclopentano-b-pyrrol moiety. Indolinone compounds that are modified with substituents, particularly at the 5 position of the oxindole ring, can effectively activate protein kinases. This invention also features novel hydrosoluble indolinone compounds that are tyrosine kinase inhibitors and related products and methods.
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- Substituted quinolymethylen-oxindole analogues as tyrosine kinase inhibitors
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Quinolylmethylen-oxindole derivatives having general formula (I), wherein R is H or --(CH2)n --COR7 group in which n is an integer of 1 to 4 and R7 is hydroxy, amino, C1 -C6 alkoxy or --NR
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