- KMU-1170, a novel multi-protein kinase inhibitor, suppresses inflammatory signal transduction in THP-1 cells and human osteoarthritic fibroblast-like synoviocytes by suppressing activation of NF-κB and NLRP3 inflammasome signaling pathway
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Protein kinases regulate protein phosphorylation, which are involved in fundamental cellular processes such as inflammatory response. In this study, we discovered a novel multi-protein kinase inhibitor, KMU-1170, a derivative of indolin-2-one, and investigated the mechanisms of its inflammation-inhibiting signaling in both THP-1 cells and human osteoarthritic fibroblast-like synoviocytes (FLS). We demonstrated that in THP-1 cells, KMU-1170 inhibited lipopolysaccharide (LPS)-induced upregulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and, furthermore, suppressed LPS-induced phosphorylation of transforming growth factor- β-activated kinase 1, JNK, ERK, inhibitor of NF-κB kinase α/β (IKKα/α), and NF-κB p65 as well as nuclear translocation of NF-κB p65. Moreover, KMU-1170 suppressed LPS-induced upregulation of proinflammatory cytokines such as IL-1β, TNF-α, and IL-6, and, notably, inhibited LPS-induced upregulation of the NLRP3 inflammasome in THP-1 cells. Importantly, KMU-1170 attenuated LPS-mediated inflammatory responses in human osteoarthritic FLS, such as the upregulation of IL-1β, TNF-α, IL-6, iNOS, and COX-2 and the phosphorylation of IKKα/β and NF-κB p65. Collectively, these results suggest that KMU-1170 inhibits inflammatory signal transduction and could be developed as a potential anti-inflammatory agent.
- Baek, Hye Suk,Hong, Victor Sukbong,Kim, Sang Hyon,Lee, Jinho,Kim, Shin
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Read Online
- Synthesis and Reactivity of 3,3-Diazidooxindoles
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The synthesis of previously unknown 3,3-diazidooxindoles as synthetically useful derivatives of isatins was accomplished through the direct oxidative diazidation of 2-oxindoles. The method yielded the diazido compounds from the starting oxindoles under mild and simple conditions with NaN3 and iodine, in good yields. The notable reactivity of this new class of compounds toward primary and secondary nucleophilic amines is also described, which gives access to either 4-imino-3,4-dihydroquinazolin-2(1H)-one derivatives or cyanophenylureas.
- Holzschneider, Kristina,Mohr, Fabian,Kirsch, Stefan F.
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- Selective tuning of activity in a multifunctional enzyme as revealed in the F21W mutant of dehaloperoxidase B from Amphitrite ornata
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Possessing both peroxidase and peroxygenase activities with a broad substrate profile that includes phenols, indoles, and pyrroles, the enzyme dehaloperoxidase (DHP) from Amphitrite ornata is a multifunctional catalytic hemoglobin that challenges many of the assumptions behind the well-established structure–function paradigm in hemoproteins. While previous studies have demonstrated that the F21W variant leads to attenuated peroxidase activity in DHP, here we have studied the impact of this mutation on peroxygenase activity to determine if it is possible to selectively tune DHP to favor one function over another. Biochemical assays with DHP B (F21W) revealed minimal decreases in peroxygenase activity of 1.2–2.1-fold as measured by 4-nitrophenol or 5-Br-indole substrate conversion, whereas the peroxidase activity catalytic efficiency for 2,4,6-trichlorophenol (TCP) was more than sevenfold decreased. Binding studies showed a 20-fold weaker affinity for 5-bromoindole (Kd?=?2960?±?940?μM) in DHP B (F21W) compared to WT DHP B. Stopped-flow UV/visible studies and isotope labeling experiments together suggest that the F21W mutation neither significantly changes the nature of the catalytic intermediates, nor alters the mechanisms that have been established for peroxidase and peroxygenase activities in DHP. The X-ray crystal structure (1.96??; PDB 5VLX) of DHP B (F21W) revealed that the tryptophan blocks one of the two identified TCP binding sites, specifically TCPinterior, suggesting that the other site, TCPexterior, remains viable for binding peroxygenase substrates. Taken together, these studies demonstrate that blocking the TCPinterior binding site in DHP selectively favors peroxygenase activity at the expense of its peroxidase activity. Graphical abstract: [Figure not available: see fulltext.].
- Carey, Leiah M.,Kim, Kyung Beom,McCombs, Nikolette L.,Swartz, Paul,Kim, Cheal,Ghiladi, Reza A.
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- Regiospecific synthesis of mono-n-substituted indolopyrrolocarbazoles
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(Chemical Equation Presented) Two complementary and efficient strategies have been developed for the regiospecific synthesis of unsymmetrical indolopyrrolocarbazoles (IPCs) mono-N-substituted with a pentacycle. A halogen in position 2 of the intermediate bisindolylmaleimides 3a-e allows a selective Mitsunobu coupling by exploiting the increased acidity of the 2-chloro-substituted indole nitrogen. It also promotes an easier cyclization of bisindolylmaleimides 4a-e and 7b-e to IPCs. Alkylation of the 2-unsubstituted indole-3-carboxamides 2a,b and further processing to the corresponding IPCs gives access to the opposite regioisomers.
- Froehner, Wolfgang,Monse, Barbara,Braxmeier, Tobias M.,Casiraghi, Laura,Sahagun, Heidi,Seneci, Pierfausto
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Read Online
- Following Nature’s Footprint: Mimicking the High-Valent Heme-Oxo Mediated Indole Monooxygenation Reaction Landscape of Heme Enzymes
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Pathways for direct conversion of indoles to oxindoles have accumulated considerable interest in recent years due to their significance in the clear comprehension of various pathogenic processes in humans and the multipotent therapeutic value of oxindole pharmacophores. Heme enzymes are predominantly responsible for this conversion in biology and are thought to proceed with a compound-I active oxidant. These heme-enzyme-mediated indole monooxygenation pathways are rapidly emerging therapeutic targets; however, a clear mechanistic understanding is still lacking. Additionally, such knowledge holds promise in the rational design of highly specific indole monooxygenation synthetic protocols that are also cost-effective and environmentally benign. We herein report the first examples of synthetic compound-I and activated compound-II species that can effectively monooxygenate a diverse array of indoles with varied electronic and steric properties to exclusively produce the corresponding 2-oxindole products in good to excellent yields. Rigorous kinetic, thermodynamic, and mechanistic interrogations clearly illustrate an initial rate-limiting epoxidation step that takes place between the heme oxidant and indole substrate, and the resulting indole epoxide intermediate undergoes rearrangement driven by a 2,3-hydride shift on indole ring to ultimately produce 2-oxindole. The complete elucidation of the indole monooxygenation mechanism of these synthetic heme models will help reveal crucial insights into analogous biological systems, directly reinforcing drug design attempts targeting those heme enzymes. Moreover, these bioinspired model compounds are promising candidates for the future development of better synthetic protocols for the selective, efficient, and sustainable generation of 2-oxindole motifs, which are already known for a plethora of pharmacological benefits.
- Mondal, Pritam,Rajapakse, Shanuk,Wijeratne, Gayan B.
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p. 3843 - 3854
(2022/02/16)
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- A novel methodology for the efficient synthesis of 3-monohalooxindoles by acidolysis of 3-phosphate-substituted oxindoles with haloid acids
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A novel method for the synthesis of 3-monohalooxindoles by acidolysis of isatin-derived 3-phosphate-substituted oxindoles with haloid acids was developed. This synthetic strategy involved the preparation of 3-phosphate-substituted oxindole intermediates and SN1 reactions with haloid acids. This new procedure features mild reaction conditions, simple operation, good yield, readily available and inexpensive starting materials, and gram-scalability.
- Liu, Li,Li, Yue,Huang, Tiao,Kong, Dulin,Wu, Mingshu
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p. 2321 - 2328
(2021/09/22)
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- Anti-inflammatory effects of the novel PIM kinase inhibitor KMU-470 in raw 264.7 cells through the TLR4-NF-κb-NLRP3 pathway
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PIM kinases, a small family of serine/threonine kinases, are important intermediates in the cytokine signaling pathway of inflammatory disease. In this study, we investigated whether the novel PIM kinase inhibitor KMU-470, a derivative of indolin-2-one, inhibits lipopolysaccharide (LPS)-induced inflammatory responses in RAW 264.7 cells. We demonstrated that KMU-470 suppressed the production of nitric oxide and inducible nitric oxide synthases that are induced by LPS in RAW 264.7 cells. Furthermore, KMU-470 inhibited LPS-induced up-regulation of TLR4 and MyD88, as well as the phosphorylation of IκB kinase and NF-κB in RAW 264.7 cells. Additionally, KMU-470 suppressed LPS-induced up-regulation at the transcriptional level of various proinflammatory cytokines such as IL-1β, TNF-α, and IL-6. Notably, KMU-470 inhibited LPS-induced up-regulation of a major component of the inflammasome complex, NLRP3, in RAW 264.7 cells. Importantly, PIM-1 siRNA transfection attenuated up-regulation of NLRP3 and pro-IL-1β in LPStreated RAW 264.7 cells. Taken together, these findings indicate that PIM-1 plays a key role in inflammatory signaling and that KMU-470 is a potential anti-inflammatory agent.
- Baek, Hye Suk,Hong, Victor Sukbong,Kim, Shin,Kwon, Taeg Kyu,Lee, Jinho,Min, Hyeon Ji,Park, Jong Wook
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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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- Design and Synthesis of DNA-Interactive β-Carboline–Oxindole Hybrids as Cytotoxic and Apoptosis-Inducing Agents
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A new series of (E)-3-[(1-aryl-9H-pyrido[3,4-b]indol-3-yl)methylene]indolin-2-one hybrids were synthesized and evaluated for their in vitro cytotoxic activity against a panel of selected human cancer cell lines, namely, HCT-15, HCT-116, A549, NCI-H460, and MCF-7, including HFL. Among the tested compounds, (E)-1-benzyl-5-bromo-3-{[1-(2,5-dimethoxyphenyl)-9H-pyrido[3,4-b]indol-3-yl]methylene}indolin-2-one (10 s) showed potent cytotoxicity against HCT-15 cancer cells with an IC50 value of 1.43±0.26 μm and a GI50 value of 0.89±0.06 μm. Notably, induction of apoptosis by 10 s on the HCT-15 cell line was characterized by using different staining techniques, such as acridine orange/ethidium bromide (AO/EB) and DAPI. Further, to understand the mechanism of anticancer effects, various assays such as annexin V-FITC/PI, DCFDA, and JC-1were performed. The flow cytometric analysis revealed that compound 10 s arrests the HCT-15 cancer cells at the G0/G1 phase of the cell cycle. Additionally, western blot analysis indicated that treatment of 10 s on HCT-15 cancer cells led to decreased expression of anti-apoptotic Bcl-2 and increased protein expression of both pro-apoptotic Bax and caspase-3, -8, and -9, and cleaved PARP with reference to actin. Next, a clonogenic assay revealed the inhibition of colony formation in HCT-15 cancer cells by 10 s in a dose-dependent manner. Moreover, upon testing on normal human lung cells (HFL), the compounds were observed to be safer with a low toxicity profile. In addition, viscosity and molecular-docking studies showed that compound 10 s has typical intercalation with DNA.
- Tokala, Ramya,Thatikonda, Sowjanya,Vanteddu, Usha Sree,Sana, Sravani,Godugu, Chandraiah,Shankaraiah, Nagula
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p. 1909 - 1922
(2018/09/14)
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- Method for synthesizing 2,5-dibromo phenylacetic acid
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The invention discloses a method for synthesizing 2,5-dibromo phenylacetic acid. The method comprises the following step: by taking isatin as a raw material, carrying out carbonyl reduction, 5-site bromo reactions and diazotization hydrolysis reactions, thereby obtaining 2,5-dibromo phenylacetic acid, wherein the step of carbonyl reduction is carried out through catalytic hydrogenation reduction;the step of 5-site bromo reactions is carried out with NBS (Bromo-Succinimide) as a bromo agent; and the step of diazotization is carried out with a sodium nitrite/hydrobromic acid system. HBr/cuprousbromide is adopted as a hydrolysis bromo agent. The method has the advantages of being wide in raw material source, mild in reaction condition, high in yield, excellent in quality, low in finished product cost, and the like.
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- Synthesis of novel 3-(benzothiazol-2-ylmethylene)indolin-2-ones
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A mild method for the synthesis of 3-(benzothiazol-2-ylmethylene)indolin-2-ones via the aldol condensation of substituted indolin-2-ones and benzothiazole-2-carbaldehyde is described. This new procedure has significant advantages, such as mild conditions, high yields and simple work-up.
- Zhang, Chao,Xu, Juan,Zhao, Xinyu,Kang, Congmin
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p. 537 - 540
(2017/10/03)
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- Spirotriazoline oxindoles: A novel chemical scaffold with in vitro anticancer properties
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The design and synthesis of a library of twenty-six spirotriazoline oxindoles and their in vitro evaluation as potential anticancer agents is reported. The antiproliferative activity of the synthesized compounds was assessed against four different cancer cell lines (HCT-116 p53 (+/+), HCT-116 p53 (?/?), MCF-7, and MDA-MB-231). Four spirotriazoline oxindoles showed selectivity against the four cancer cell lines tested over the non-cancer derived HEK 293T cell line. To characterize the molecular mechanisms involved in compound antitumoral activity, two spirotriazoline oxindoles were selected for further studies. Both compounds were able to induce apoptosis and cell cycle arrest at G0/G1 phase and upregulated p53 steady-state levels, while decreasing its main inhibitor MDM2, in HCT-116 cells. Importantly, cytotoxic effects induced by spirotriazoline oxindoles occurred in cancer cells without eliciting cell death in non-malignant CCD-18Co human colon fibroblasts. In addition, four spirotriazoline oxindoles showed selectivity against the triple-negative breast cancer cell line MDA-MB-231 with IC50 values of 3.5–6.7 μM. These results highlight the anticancer potential of spirotriazoline oxindoles, especially when dealing with aggressive and challenging triple-negative breast cancer.
- Ribeiro, Carlos J.A.,Nunes, Rute C.,Amaral, Joana D.,Gon?alves, Lídia M.,Rodrigues, Cecília M.P.,Moreira, Rui,Santos, Maria M.M.
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p. 494 - 509
(2017/10/10)
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- Natural α-methylenelactam analogues: Design, synthesis and evaluation of α-alkenyl-γ and δ-lactams as potential antifungal agents against Colletotrichum orbiculare
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In our continued efforts to improve the potential utility of the α-methylene-γ-lactone scaffold, 62 new and 59 known natural α-methylenelactam analogues including α-methylene-γ-lactams, α-arylidene-γ and δ-lactams, and 3-arylideneindolin-2-ones were synthesized as the bioisosteric analogues of the α-methylenelactone scaffold. The results of antifungal and cytotoxic activity indicated that among these derivatives compound (E)-1-(2, 6-dichlorobenzyl)-3-(2-fluorobenzylidene) pyrrolidin-2-one (Py51) possessed good selectivity with the highest antifungal activity against Colletotrichum orbiculare with IC50?=?10.4?μM but less cytotoxic activity with IC50?=?141.2?μM (against HepG2 cell line) and 161.2?μM (against human hepatic L02?cell line). Ultrastructural change studies performed by transmission electron microscope showed that Py51 could cause important cell morphological changes in C.?orbiculare, such as plasma membrane detached from cell wall, cell wall thickening, mitochondria disruption, a dramatic increase in vacuolation, and eventually a complete loss in the integrity of organelles. Significantly, mitochondria appeared one of the primary targets, as confirmed by their remarkably aberrant morphological changes. Analysis of structure–activity relationships revealed that incorporation of the aryl group into the α-exo-methylene and the N-benzyl substitution increased the activity. Meanwhile, the α-arylidene-γ-lactams have superiority in selectivity over the 3-arylideneindolin-2-ones. Based on the results, the N-benzyl substituted α-(2-fluorophenyl)-γ-lactam was identified as the most promising natural-based scaffold for further discovering and developing improved crop-protection agents.
- Delong, Wang,Lanying, Wang,Yongling, Wu,Shuang, Song,Juntao, Feng,Xing, Zhang
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p. 286 - 307
(2017/03/09)
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- A 2, 5 - di bromo acetic acid
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The invention belongs to the technical field of organic chemistry and particularly discloses a method for preparing 2, 5-dibromo-benzene acetic acid. The preparation method comprises the following steps: taking 5-bromoisatin (formula I) as a starting raw material and performing reduction reaction to obtain the bromo-indolone (formula II) and performing diazotized bromization on the bromo-indolone (formula II) to obtain the 2, 5-dibromo-benzene acetic acid (formula III), wherein the reaction process is as follows: FORMULA. By taking the 5-bromoisatin as the starting raw material, the method has the advantages that the 5-bromoisatin is a large-scale produced chemical product with sufficient market supply and low cost.
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Paragraph 0018-0022; 0028-0032; 0038-0042
(2017/08/25)
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- CYCLOPROPYL-AMIDE COMPOUNDS AS DUAL LSD1/HDAC INHIBITORS
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The present disclosure describes novel compounds of the general Formula (I), their analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts, pharmaceutical compositions, metabolites, and prodrugs thereof. These compounds can inhibit both LSD and HDAC and are useful as therpeautic or ameliorating agent for diseases that are involved in cellular growth such as malignant tumors, schizophrenia, Alzheimer's disease, parkinson's disease and the like.
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Page/Page column 157-158
(2017/12/01)
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- Design, synthesis and preliminary biological evaluation of novel benzyl sulfoxide 2-indolinone derivatives as anticancer agents
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In this work, a series of novel benzyl sulfoxide 2-indolinone derivatives was designed and synthesized as potent anticancer agents. Tyrosine kinase inhibitory activity assay indicated that most of the compounds showed significant activity. The in vitro antiproliferative activity of these compounds was further investigated against five human cancer cell lines (HeLa, HepG2, MCF-7, SCC-15, and A549). Several compounds exhibited evident activities. Among them, (Z)-3-(((4-bromobenzyl)sulfinyl)methylene)indolin-2-one (6j) and (Z)-3-((benzylsulfinyl) methylene)-5-bromoindolin-2-one (6o) were found to be effective tyrosine kinase inhibitors (IC50 = 1.34 and 2.69 μM, respectively) in addition to having noteworthy antitumor potential (the average IC50 value of 6j or 6o was less than 40 μM). This class of novel derivatives has promising potential for further development as anticancer agents.
- Tang, Lin,Peng, Tao,Wang, Gang,Wen, Xiaoxue,Sun, Yunbo,Zhang, Shouguo,Liu, Shuchen,Wang, Lin
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supporting information
(2017/12/05)
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- Design, synthesis and apoptosis inducing effect of novel (Z)-3-(3′-methoxy-4′-(2-amino-2-oxoethoxy)-benzylidene)indolin-2-ones as potential antitumour agents
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A series of new (Z)-3-(3′-methoxy-4′-(2-amino-2-oxoethoxy)benzylidene)indolin-2-one derivatives has been synthesized and evaluated for their cytotoxic activity against selected human cancer cell lines of prostate (PC-3 and DU-145), breast (BT-549 and MDA-MB-231) and non-tumorigenic prostate epithelial cells (RWPE-1). Among the tested, one of the compounds 4p exhibited potent cytotoxicity selectively on prostate cancer cell lines (PC-3 and DU-145; IC50: 1.89 ± 0.6 and 1.94 ± 0.2 μM, respectively). Further experiments were conducted with 4p on PC-3 cancer cells to study the mechanisms of growth inhibition and apoptosis inducing effect. Treatment of PC-3 cells with test compound 4p resulted in inhibition of cell migration through disorganization of F-actin protein. The flow-cytometry analysis results showed that the compound arrested PC-3 cancer cells in the G2/M phase of cell cycle in a dose dependent manner. Hoechst staining and annexin-V binding assay revealed that the compound 4p inhibited tumor cell proliferation through induction of apoptosis. Western blot studies demonstrated that the compound 4p treatment led to activation of caspase-3, increased expression of pro-apoptotic Bax and significantly decreased expression of anti-apoptotic Bcl-2 in human prostate cancer PC-3 cells. In addition, the mitochondrial membrane potential (ΔΦm) was also affected and the levels of intracellular Ca2+ were raised.
- Senwar, Kishna Ram,Reddy, T. Srinivasa,Thummuri, Dinesh,Sharma, Pankaj,Naidu,Srinivasulu, Gannoju,Shankaraiah, Nagula
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- New (E)-1-alkyl-1H-benzo[d]imidazol-2-yl)methylene)indolin-2-ones: Synthesis, in vitro cytotoxicity evaluation and apoptosis inducing studies
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A new series of (E)-benzo[d]imidazol-2-yl)methylene)indolin-2-one derivatives has been synthesized and evaluated for their in vitro cytotoxic activity against a panel of selected human cancer cell lines of prostate (PC-3 and DU-145) and breast (BT-549, MDA-MB-231, MCF-7, 4T1), non-small lung (A549) and gastric (HGC) cancer cells along with normal breast epithelial cells (MCF10A). Among the tested compounds, 8l showed significant cytotoxic activity against MDA-MB-231 and 4T1 cancer cells with IC50values of 3.26 ± 0.24 μM and 5.96 ± 0.67 μM respectively. The compounds 8f, 8i, 8l and 8o were also screened on normal human breast epithelial cells (MCF10A) and found to be safer with lesser cytotoxicity. The treatment of MDA-MB-231 cells with 8l led to inhibition of cell migration ability through disruption of F-actin protein assembly. The flow-cytometry analysis reveals that the cells arrested in G0/G1 phase of the cell cycle. Further, the compound 8l induced apoptosis of MDA-MB-231 cells was characterized by different staining techniques such as Acridine Orange/Ethidium Bromide (AO/EB), DAPI, annexin V-FITC/PI, Rhodamine-123 and MitoSOX red assay. Western blot studies demonstrated that the compound 8l treatment led to activation of caspase-3, increased expression of cleaved PARP, increased expression of pro-apoptotic Bax and decreased expression of anti-apoptotic Bcl-2 in MDA-MB-231 cancer cells.
- Sharma, Pankaj,Thummuri, Dinesh,Reddy, T. Srinivasa,Senwar, Kishna Ram,Naidu,Srinivasulu, Gannoju,Bharghava, Suresh K.,Shankaraiah, Nagula
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p. 584 - 600
(2016/07/22)
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- Design and synthesis of 4′-O-alkylamino-tethered-benzylideneindolin-2-ones as potent cytotoxic and apoptosis inducing agents
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A series of new 4′-O-alkylamino-tethered-benzylideneindolin-2-one derivatives has been synthesized and evaluated for their anti-proliferative activity against selected human cancer cell lines of lung (A549), prostate (DU-145), breast (BT549 and MDA-MB-231) and normal breast epithelial cells (MCF-10A). Gratifyingly, the compounds 5j, 5o and 5r exhibited potent cytotoxicity against breast cancer cell lines (BT549 and MDA-MB-231) with IC50values in the range of 1.26–2.77?μM, and are found to be safer with lesser cytotoxicity on normal breast epithelial cells (MCF-10A). Further, experiments were conducted with these compounds 5j, 5o and 5r on MDA-MB-231 cancer cells to study the mechanism of growth inhibition and apoptosis inducing effect. Treatment of MDA-MB-231 cells with test compounds resulted in inhibition of cell migration through disorganization and disruption of F-actin capping protein. The flow-cytometry analysis results showed that the compound 5o arrested MDA-MB-231 cells in G0/G1 phase of cell cycle in a dose dependent manner. Hoechst staining study revealed that the test compounds inhibited tumor cell proliferation through induction of apoptosis. In addition, the mitochondrial membrane potential (DΨm) was affected and the increased level of reactive oxygen species (ROS) was noted in MDA-MB-231 cells.
- Senwar, Kishna Ram,Reddy, T. Srinivasa,Thummuri, Dinesh,Sharma, Pankaj,Bharghava, Suresh K.,Naidu,Shankaraiah, Nagula
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supporting information
p. 4061 - 4069
(2016/08/01)
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- A quick, mild and efficient bromination using a CFBSA/KBr system
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Bromination is a fundamental transformation in organic chemistry and brominated compounds as building blocks are of paramount importance in organic synthesis. In our study, we have developed an efficient method of bromination by using a CFBSA/KBr system at room temperature in a short reaction time. Notably, this approach has been proven to be applicable to a range of substrates including 1,3-diketones and β-keto esters, phenols, aromatic amines and heteroarenes with good to excellent yields.
- Jiang, Pan-Pan,Yang, Xian-Jin
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p. 90031 - 90034
(2016/10/09)
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- PHOSPHOINOSITIDE 3-KINASE INHIBITORS WITH ZINC BINDING MOIETY
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PROBLEM TO BE SOLVED: To provide phosphoinositide 3-kinase inhibitors with a zinc binding moiety. SOLUTION: There is provided a compound represented by formula (I) in the figure. (X is S, O or the like; Y is CH, N or the like; G1 is optionally substituted N or the like; R1 and R2 are each independently H or the like; C is a substituted heterocycle or the like; B is a linear alkyl or the like; Ra and Rb together with the nitrogen atom coupled to them are morpholino or the like; G2 is an indazole ring or the like; q, r and s are independently from 0 to 1, provided that at least one of them is 1; t is from 0 to 1; n is from 0 to 4; and p is from 0 to 2.) COPYRIGHT: (C)2016,JPOandINPIT
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Paragraph 0507
(2016/10/07)
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- A cinchona alkaloid catalyzed enantioselective sulfa-Michael/aldol cascade reaction of isoindigos: Construction of chiral bispirooxindole tetrahydrothiophenes with vicinal quaternary spirocenters
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A cinchona alkaloid catalyzed diastereoselective and enantioselective sulfa-Michael/aldol cascade reaction between 1,4-dithiane-2,5-diol and isoindigos has been successfully developed to afford the highly congested bispirooxindole tetrahydrothiophenes with vicinal quaternary spirocenters in high yields (up to 91%), excellent diastereoselectivities (up to >20 : 1 dr), and good enantioselectivities (up to 98% ee). Some synthetic transformations of the reaction products were also studied.
- Gui, Yong-Yuan,Yang, Jian,Qi, Liang-Wen,Wang, Xiao,Tian, Fang,Li, Xiao-Nian,Peng, Lin,Wang, Li-Xin
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p. 6371 - 6379
(2015/06/08)
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- Design and synthesis of novel 3,5-substituted indolin-2-one derivatives
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In this paper, twelve novel 3,5-substituted indolin-2-one derivatives were designed and synthesized based on indolin-2-one. The structures of the new compounds have been confirmed by 1 H NMR, HR-MS and IR spectra analysis. This study provides a new method for development of indolin-2-one derivatives.
- Zhang, Yi-Ying,Liu, Yuan,Wang, Yu-Liang
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p. 491 - 495
(2015/02/05)
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- Selective reduction of carbonyl groups in the presence of low-valent titanium reagents
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The chemoselective reduction of several structurally diverse compounds containing carbonyl groups was achieved in the presence of low-valent titanium reagents. This novel synthetic method provides easy access to highly selective reduction of carbonyl groups, and possesses several advantages including one-step procedure, convenient manipulation, good to excellent yields, and short reaction times.
- Lin, Wei,Hu, Ming-Hua,Feng, Xian,Fu, Lei,Cao, Cheng-Pao,Huang, Zhi-Bin,Shi, Da-Qing
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p. 2238 - 2242
(2014/04/17)
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- Peroxygenase and oxidase activities of dehaloperoxidase-hemoglobin from Amphitrite ornata
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The marine globin dehaloperoxidase-hemoglobin (DHP) from Amphitrite ornata was found to catalyze the H2O2-dependent oxidation of monohaloindoles, a previously unknown class of substrate for DHP. Using 5-Br-indole as a representative substrate, the major monooxygenated products were found to be 5-Br-2-oxindole and 5-Br-3-oxindolenine. Isotope labeling studies confirmed that the oxygen atom incorporated was derived exclusively from H2O2, indicative of a previously unreported peroxygenase activity for DHP. Peroxygenase activity could be initiated from either the ferric or oxyferrous states with equivalent substrate conversion and product distribution. It was found that 5-Br-3-oxindole, a precursor of the product 5-Br-3-oxindolenine, readily reduced the ferric enzyme to the oxyferrous state, demonstrating an unusual product-driven reduction of the enzyme. As such, DHP returns to the globin-active oxyferrous form after peroxygenase activity ceases. Reactivity with 5-Br-3-oxindole in the absence of H2O2 also yielded 5,5′-Br2-indigo above the expected reaction stoichiometry under aerobic conditions, and O2-concentration studies demonstrated dioxygen consumption. Nonenzymatic and anaerobic controls both confirmed the requirements for DHP and molecular oxygen in the catalytic generation of 5,5′-Br2-indigo, and together suggest a newly identified oxidase activity for DHP.
- Barrios, David A.,D'Antonio, Jennifer,McCombs, Nikolette L.,Zhao, Jing,Franzen, Stefan,Schmidt, Andreas C.,Sombers, Leslie A.,Ghiladi, Reza A.
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supporting information
p. 7914 - 7925
(2014/06/23)
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- Unexpected approach to the synthesis of 2-phenylquinoxalines and pyrido[2,3-b]pyrazines via a regioselective reaction
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An unexpected approach to the preparation of quinoxaline and pyrido[2,3-b]pyrazine derivatives 5 is described. The reaction between 1H-indole-2,3-diones 1, 1-phenyl-2-(triphenylphosphoranylidene)ethanone (2), and benzene-1,2- or pyridine-2,3-diamines 3 proceeds in MeOH under reflux in good to excellent yields (Scheme 1 and Table). No co-catalyst or activator is required for this multi-component reaction (MCR), and the reaction is, from an experimental point of view, simple to perform. The structures of 5, 5′, and 6 were corroborated spectroscopically (IR, 1H- and 13C-NMR, and EI-MS) and were confirmed by comparison with reference compounds. A plausible mechanism for this type of reaction is proposed (Scheme 2). Copyright
- Alizadeh, Abdolali,Mokhtari, Javad
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p. 124 - 129
(2013/03/14)
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- Novel oxindole based sensitizers: Synthesis and application in dye-sensitized solar cells
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Two novel oxindole sensitizers have been synthesized for dye-sensitized solar cell applications. These new dyes can provide an additional pathway to inject electrons into the photoanode through the partial chelation of their amide carbonyl groups to the TiO2 surface. Incorporation of an electron deficient pyridine in the acceptor of the TI125 dye was found to enhance the photovoltage and conversion efficiency of the cell.
- Tingare, Yogesh S.,Shen, Ming-Tai,Su, Chaochin,Ho, Shih-Yu,Tsai, Sheng-Han,Chen, Bo-Ren,Li, Wen-Ren
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supporting information
p. 4292 - 4295
(2013/09/24)
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- TREATMENT OF CANCERS HAVING K-RAS MUTATIONS
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The present invention provides a method of treating a cancer associated with a K-ras mutation in a subject in need thereof. The method comprises the steps of: (1) identifying a subject with a cancer associated with a K-ras mutation; and (2) administering to the subject (i) an inhibitor of PI3 kinase and (ii) an HDAC inhibitor, wherein the PI3 kinase inhibitor and the HDAC inhibitor are administered in amounts which together are therapeutically effective.
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Paragraph 0597
(2013/05/08)
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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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- Synthesis, structure, and properties of new spirooxindolodibenzodiazepine derivatives
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An acid-catalyzed reaction of 3-(2-aminophenylamino)-5,5- dimethylcyclohexen-1-one with isatines leads to the formation of the earlier undescribed 3,3-dimethyl-2,3,4,5,10,11- hexahydrospiro[1H-dibenzo[b,e][1,4] diazepine-11,3-2H-indole]-1,2-dione derivati
- Orlova,Ukhin,Suponitskii,Shepelenko,Belousova,Borodkin,Popova
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p. 1409 - 1416
(2014/05/06)
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- Discovery of di-indolinone as a novel scaffold for protein tyrosine phosphatase 1B inhibitors
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A series of di-indolinone derivatives was designed and synthesized to optimize our lead compounds basing on molecular docking study as PTP1B inhibitors. Successive enzymatic assay identified the synthetic di-indolinone as novel PTP1B inhibitors with low micromole-ranged inhibitory activity and at least several-fold selectivity over other tested homologous PTPs.
- Dai, Hou-Ling,Gao, Li-Xin,Yang, Ying,Li, Jing-Ya,Cheng, Jia-Gao,Li, Jia,Wen, Ren,Peng, Yan-Qing,Zheng, Jian-Bin
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p. 7440 - 7443
(2013/02/22)
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- Synthesis of paullone and kenpaullone derivatives by photocyclization of 2-(2-chloro-1H-indol-3-yl)-N-arylacetamides
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An efficient synthesis of paullone and kenpaullone derivatives in moderate to high yields has been achieved through photocyclizations of (2-chloro-1H-indole-3-yl)-N-arylacetamides in acetone at room temperature. Paullone and kenpaullone have been obtained
- Li, Zhanshan,Lu, Nianhong,Wang, Lihong,Zhang, Wei
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supporting information; experimental part
p. 1019 - 1024
(2012/03/27)
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- Synthesis of spiro[furan-3,3′-indolin]-2′-ones by PET-catalyzed [3+2] reactions of spiro[indoline-3,2′-oxiran]-2-ones with electron-rich olefins
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An efficient procedure for the synthesis of spiro[furan-3,3′-indolin] -2-ones and dispiro[cycloalkane-1,2′-furan-3′,3″-indolin]- 2″-ones has been achieved in high yields and stereoselectivity by photoinduced electron transfer-catalyzed [3+2] reactions of substituted spiro[indoline-3,2′-oxiran]-2-ones with olefins. The reactions proceed by ring opening of spiro[indoline-3,2′-oxiran]-2-ones via C β-O bond cleavage and subsequent cycloaddition with olefins by using 2,4,6-triphenylpyrylium tetarfluoroborate (TPT) as a sensitizer.
- Wang, Lihong,Li, Zhanshan,Lu, Lianhong,Zhang, Wei
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supporting information; experimental part
p. 1483 - 1491
(2012/03/09)
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- TREATMENT OF CANCERS HAVING K-RAS MUTATIONS
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The present invention provides a method of treating a cancer associated with a K- ras mutation in a subject in need thereof. The method comprises the steps of (1) identifying a subject with a cancer associated with a K-ras mutation; and (2) adminsiterign to the subject (i) an inhibitor of PI3 kinase and (ii) an HDAC inhibitor, wherein the PI3 kinase inhibitor and the HDAC inhibitor are administered in amounts which together are therapeutically effective.
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Page/Page column 232
(2011/11/01)
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- Ultrasound promoted clay catalyzed efficient and one pot synthesis of substituted oxindoles
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A simple facile, one-pot synthesis of oxindoles in reasonable purity is reported via intramolecular Friedal-Craft cyclization. Clay KSF is an inexpensive, efficient and mild catalyst for the synthesis of substituted oxindoles by the reaction of chloroacetyl chloride and various anilines under the influence of ultrasonic irradiation under solvent-free conditions. The remarkable advantages of this method are the simple experimental procedures, short reaction times, high yields of products, suitability for a wide variety of substituents, and the green aspects through the avoidance of toxic catalyst and solvents.
- Dandia,Bhati,Jain,Sharma
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experimental part
p. 1143 - 1147
(2012/03/10)
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- Synthesis and biological evaluation of novel indolin-2-one derivatives as protein tyrosine phosphatase 1b inhibitors
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3-Substituted indolin-2-one derivatives had been designed and synthesized as a novel class ofprotein tyrosine phosphatase 1B (PTP1B) inhibitors. These compounds had been evaluated for their inhibitory activities against PTP1B in vitro with IC50 values in a low micromolar range.Compound 36, the lowest, bore an IC50 value of 3.48 μM. Preliminary structure-activity relationship was summarized.
- Dai, Hou-Ling,Shen, Qiang,Zheng, Jian-Bin,Lib, Jing-Ya,Wen, Ren,Li, Jia
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p. 526 - 530
(2012/04/23)
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- INDOLE DERIVATIVES AS CRAC MODULATORS
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Compounds of the formula I: or pharmaceutically acceptable salts thereof, wherein R1, R2, R3 and R4 are as defined herein. Also disclosed are methods of making the compounds and using the compounds for treatment of diseases associated with calcium release-activated calcium channels (CRAC).
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Page/Page column 60
(2012/01/30)
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- Synthesis, structure-activity relationship and crystallographic studies of 3-substituted indolin-2-one RET inhibitors
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The synthesis, structure-activity relationships (SAR) and structural data of a series of indolin-2-one inhibitors of RET tyrosine kinase are described. These compounds were designed to explore the available space around the indolinone scaffold within RET active site. Several substitutions at different positions were tested and biochemical data were used to draw a molecular model of steric and electrostatic interactions, which can be applied to design more potent and selective RET inhibitors. The crystal structures of RET kinase domain in complex with three inhibitors were solved. All three compounds bound in the ATP pocket and formed two hydrogen bonds with the kinase hinge region. Crystallographic analysis confirmed predictions from molecular modelling and helped refine SAR results. These data provide important information for the development of indolinone inhibitors for the treatment of RET-driven cancers.
- Mologni, Luca,Rostagno, Roberta,Brussolo, Stefania,Knowles, Phillip P.,Kjaer, Svend,Murray-Rust, Judith,Rosso, Enrico,Zambon, Alfonso,Scapozza, Leonardo,McDonald, Neil Q.,Lucchini, Vittorio,Gambacorti-Passerini, Carlo
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experimental part
p. 1482 - 1496
(2010/04/29)
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- Synthesis and biological evaluation of 3-[4-(amino/methylsulfonyl)phenyl] methylene-indolin-2-one derivatives as novel COX-1/2 and 5-LOX inhibitors
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Fourteen new 3-[4-(amino/methylsulfonyl)phenyl]methylene-indolin-2-one derivatives were synthesized. Six compounds displayed potent inhibitory activities against COX-1/2 and 5-LOX with IC50 in the range of 0.10-9.87 μM. Particularly, 10f exhibited well balanced inhibitory action on these enzymes (IC50 = 0.10-0.56 μM). More importantly, 10f and several other compounds had comparable or stronger anti-inflammatory and analgesic activities, but better gastric tolerability in vivo, as compared with darbufelone mesilate and tenidap sodium. Therefore, our findings may aid in the design of new and safe anti-inflammatory reagents for the intervention of painful inflammatory diseases, such as rheumatoid arthritis at clinic.
- Lai, Yisheng,Ma, Lin,Huang, Wenxing,Yu, Xing,Zhang, Yihua,Ji, Hui,Tian, Jide
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p. 7349 - 7353
(2011/01/12)
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- Osmium (VII)-catalyzed oxidation of indoles by potassium hexacyanoferrate (III) in alkaline media: A kinetic and mechanistic study
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THE REACTION of indoles with Os(VIIl) catalyzed hexacyanoferrate (III) in alkaline media to produce the corresponding oxindole has been studied at constant temperature and ionic strength. The reaction followed first order kinetics with respect to [indole], [OH] and [Os(VIII)], fractional order in [Fe(CN)63-]. The effects of added electrolytes, potassium hexacyanoferrate(II), relative permitivity and temperature have also been studied. A mechanism consistent with the kinetic data is proposed. Furthermore, the structural influence of the indoles on the reactivity has been discussed.
- Taha,Abu-Zuhri,EI Hadi,Amer
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experimental part
p. 1 - 13
(2010/02/28)
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- Kinetics and mechanism of the oxidation of indoles by alkaline potassium hexacyanoferrate (III)
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THE REACTION of indoles with hexacyanoferrate(III) in alkaline media to produce the corresponding oxindoie has been studied at constant temperature and ionic strength. The reaction followed first order kinetics with respect to [indole] and [OH-], whereas fractional order with respect to [Fe(CN)63-] was found. The effects of added electrolytes, potassium hexacyanoferrate(Π), relative permitivity and temperature have also been studied. On the basis of experimental observations, a probable reaction mechanism has been proposed.
- Taha,Abu-Zuhrf,El Hadi,Amer
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experimental part
p. 15 - 27
(2010/03/25)
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- KINASE INHIBITOR COMPOUNDS
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Pyridine and pyridazine derivatives have unexpected drug properties as inhibitors of protein kinases and are useful in treating disorders related to abnormal protein kinase activities such as cancer.
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Page/Page column 53
(2008/12/07)
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- In vivo active aldosterone synthase inhibitors with improved selectivity: Lead optimization providing a series of pyridine substituted 3,4-dihydro-1H-quinolin-2-one derivatives
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Pyridine substituted naphthalenes (e.g., I-III) constitute a class of potent inhibitors of aldosterone synthase (CYP11B2). To overcome the unwanted inhibition of the hepatic enzyme CYP1A2, we aimed at reducing the number of aromatic carbons of these molecules because aromaticity has previously been identified to correlate positively with CYP1A2 inhibition. As hypothesized, inhibitors with a tetrahydronaphthalene type molecular scaffold (1-11) exhibit a decreased CYP1A2 inhibition. However, tetralone 9 turned out to be cytotoxic to the human cell line U-937 at higher concentrations. Consequent structural optimization culminated in the discovery of heteroaryl substituted 3,4-dihydro-1H-quinolin-2-ones (12-26), with 12, a bioisostere of 9, being nontoxic up to 200 μM. The investigated molecules are highly selective toward both CYP1A2 and a wide range of other cytochrome P450 enzymes and show a good pharmacokinetic profile in vivo (e.g., 12 with a peroral bioavailability of 71%). Furthermore, isoquinoline derivative 21 proved to significantly reduce plasma aldosterone levels of ACTH stimulated rats.
- Lucas, Simon,Heim, Ralf,Ries, Christina,Schewe, Katarzyna E.,Birk, Barbara,Hartmann, Rolf W.
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scheme or table
p. 8077 - 8087
(2009/12/07)
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- Synthesis and biological evaluation of 3-ethylidene-1,3-dihydro-indol-2- ones as novel checkpoint 1 inhibitors
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Chk1 inhibitors have emerged as a novel class of neoplastic agents for abrogating the G2 DNA damage checkpoint arrest. Analogs of the Chk1 inhibitor, 3-ethylidene-1,3-dihydro-indol-2-one, were synthesized and tested in vitro for their inhibitory activitie
- Lin, Nan-Horng,Xia, Ping,Kovar, Peter,Park, Chang,Chen, Zehan,Zhang, Haiying,Rosenberg, Saul H.,Sham, Hing L.
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p. 421 - 426
(2007/10/03)
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- Monofluoroalkyl derivatives
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The present invention provides certain monofluoroalkyl derivatives useful for potentiating glutamate receptor function in a mammal and therefore, useful for treating a wide variety of conditions, such as psychiatric and neurological disorders.
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Page/Page column 91
(2010/10/20)
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- Concise syntheses of the cruciferous phytoalexins brassilexin, sinalexin, wasalexins, and analogues: Expanding the scope of the Vilsmeier formylation
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(Chemical Equation Presented) Efficient syntheses of the phytoalexins brassilexin, sinalexin, and analogues are demonstrated through the application of the Vilsmeier formylation to indoline-2-thiones followed by a new aqueous ammonia workup procedure. Similarly, a very concise two-pot synthesis of the phytoalexins wasalexins using sequential formylation-amination of indolin-2-ones is described. Remarkably, this novel aqueous ammonia workup allows the sequential one-pot formylation-amination, expanding substantially the scope of the Vilsmeier formylation of both indoline-2-thiones and indolin-2-ones. The examination of the formylation-amination reaction and optimization of conditions, as well as the syntheses and antifungal activities of several brassilexin analogues, are reported.
- Pedras, M. Soledade C.,Jha, Mukund
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p. 1828 - 1834
(2007/10/03)
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- Thienopyridine and furopyridine kinase inhibitors
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Compounds having the formula are useful for inhibiting protein tyrosine kinases. The present invention also discloses methods of making the compounds, compositions containing the compounds, and methods of treatment using the compounds.
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- Hexahydro-cyclohepta-pyrrole oxindole as potent kinase inhibitors
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The present invention is directed to a class indolinone compounds, hexahydro-cyclohepta-pyrrole oxindoles, which are useful as protein kinase inhibitors.
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Page/Page column 20
(2010/02/08)
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