- Ambipolar organic field-effect transistors based on N-Unsubstituted thienoisoindigo derivatives
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To investigate a hybrid of isoindigo and thienoisoindigo (TIIG), a new series of unsymmetrical TIIG analogs, in which one of the outer thiophene rings of TIIG is replaced by benzene (CS) or pyridine (NS) are prepared. In addition, the π-skeleton extension
- Ashizawa, Minoru,Hasegawa, Tsukasa,Hikima, Takaaki,Kawamoto, Tadashi,Kohara, Akihiro,Masunaga, Hiroyasu,Matsumoto, Hidetoshi,Mori, Takehiko,Ohta, Noboru,Sugiyama, Haruki,Uekusa, Hidehiro,Yoo, Dongho
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- Molybdenum hexacarbonyl mediated synthesis of indolin-2-one & azaindolin-2-one under catalyst free conditions
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Syntheses of indolin-2-ones and azaindolin-2-ones have been realized. The strategy involves the formation of tosylhydrazone from tosylhydrazine and 2-amino aryl or pyridyl aldehydes/ketones which then undergo intramolecular aminocarbonylation to afford indolin-2-ones and azaindolin-2-ones. The generality of the method was demonstrated by synthesizing C3 substituted and unsubstituted indolin-2-one and azaindolin-2-one derivatives.
- Patil, Vikas S.,Pal, Shyam S.,Pathare, Ramdas S.,Reddy,Pathak, Arunendra
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supporting information
p. 6370 - 6372
(2015/11/16)
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- 7,7′-Diazaindirubin - A small molecule inhibitor of casein kinase 2 in vitro and in cells
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Aza- and diaza-bisindoles were synthesized by coupling of 7-azaisatin, 7-azaoxindol, 7-azaindoxyl acetate, and their non-aza counterparts, respectively. Whereas 7,7′-diazaindigo (10) and 7,7′-diazaisoindigo (11) did not show antiproliferative activity in several human tumor cell lines up to 100 μM, 7-azaindirubin (12) and 7′-azaindirubin (13) were more active than the parent molecule, indirubin, in LXFL529L cells (human large cell lung tumor xenograft), and 7,7′-diazaindirubin (14) was exhibiting substantially enhanced growth inhibitory activity in these cells. In the NCI 60 cell line panel, 14 displayed antiproliferative activity preferentially in certain melanoma and non-small cell lung cancer cells. In contrast to the potent serine/threonine/tyrosine kinase inhibition observed for indirubins, kinase inhibition profiling of 14 in 220 kinases revealed largely a loss of kinase inhibitory activity towards most kinases, with retained inhibitory activity for just a few kinases. At 1 μM concentration, especially casein kinases CK1γ3, CK2α, CK2α2, and SIK were inhibited by more than 50%. In cell-based assays, 14 markedly affected CK2-mediated signaling in various human tumor cells. In MCF7 cells, 14 induced cell cycle arrest at G1 and G2/M and apoptosis, whereas CK2-deficient MCF7 cells were resistant. These findings reveal a novel key mechanism of action for 14, suggesting primarily CK2 inhibition to be causally related to growth inhibition of human tumor cells.
- Cheng, Xinlai,Merz, Karl-Heinz,Vatter, Sandra,Christ, Jochen,W?lfl, Stefan,Eisenbrand, Gerhard
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p. 247 - 255
(2014/01/17)
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- Exploring the Anticancer Activity of Functionalized Isoindigos: Synthesis, Drug-like Potential, Mode of Action and Effect on Tumor-Induced Xenografts
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Meisoindigo has been used as an indirubin substitute for the treatment of chronic myeloid leukemia (CML) for several years. In view of its poor solubility and erratic absorption, several investigations have focused on developing analogues with more desirable physicochemical profiles. Here, we investigated the structure-activity relationship (SAR) of meisoindigo with respect to its antiproliferative activity on leukemic K562 cells and found that appending a phenalkyl side chain onto the lactam NH resulted in analogues that retained good activity. Furthermore, analogues in which the phenyl ring was substituted with a basic heterocycle were significantly more soluble than meisoindigo while retaining acceptable antiproliferative profiles. The most promising analogue (E)-1-(2-(4-methylpiperazin-1-yl)ethyl)-[3,3′-biindolinylidene]-2,2′-dione (5-4) is more potent than meisoindigo across a panel of malignant cells, with at least 40 times greater solubility than meisoindigo, little or no tendency to aggregate in solution and capable of significantly extending the lifespans of animals with K562 induced xenografts. Mechanistically, it induced apoptotic cell death and disrupted the progression of K562 cells from the G1 to G2 phase. Taken together, our findings highlighted the feasibility of addressing the physicochemical deficits of the isoindigo scaffold by systematic modifications which was achieved without overt loss of growth inhibitory activity.
- Wee, Xi Kai,Yang, Tianming,Go, Mei Lin
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experimental part
p. 777 - 791
(2012/07/17)
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- Synthesis and biological evaluation of 2-indolinone derivatives as potential antitumor agents
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Three series of 3-substituted-indolin-2-ones and azaindolin-2-ones have been synthesized and showed potential antiproliferative activity to cancer cell lines. The inhibition activities on VEGF-induced VEGFR phosphorylation were observed for selected 2-indolinones. Among the compounds synthesized, 5-fluoroindolin-2-one derivative 23 with a pyridone unit showed the most significant enzymatic and cellular activities. Flow cytometric analysis indicates that 23 plays a role in suppressing HCT-116 cell proliferation via G1 phase arrest and apoptosis in a dose dependent manner. The binding mode of compound 23 complexed with VEGFR-2 was predicted using FlexX algorithm. Described here are the chemistry and biological testing for these series which will guide the design and optimization of novel 2-indolione antitumor agents.
- Zou, Hongbin,Zhang, Liang,Ouyang, Jingfeng,Giulianotti, Marc A.,Yu, Yongping
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p. 5970 - 5977
(2012/01/04)
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- CYCLOHEXYL AMIDE DERIVATIVES AS CRF RECEPTOR ANTAGONISTS
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There are described cydohexyl amide derivatives useful as corticotropin releasing factor (CRF) receptor antagonists
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- 7-azaindirubins, 7'-azaindirubins, 7-7'-diazaindirubin and the corresponding 3'-oxime ether derivates: production thereof, their production and use as a medicament
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The present invention relates to 7-azaindirubins (1), 7'-azaindirubins (2), and 7,7'-diaza-indirubins (3), wherein E, R1 and R2 have the meanings detailed in the description, their production and use as a medicament for treating cancer, neurodegenerative diseases, bipolar disorders, inflammatory and infectious diseases, including viral diseases. Depending on structure, these indirubins act as inhibitors of various kinases involved in tumor cell growth, and, most notably, as inhibitors of human tumor cell proliferation. As compared to indirubins bearing identical substituents but no hetero atoms in position 7 and 7', the activity of the compounds according to the present invention is increased and the propensity to get metabolized by CYP450s is reduced, resulting in improved metabolic stability.
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Page/Page column 10
(2010/07/06)
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- MONOCYCLIC CGRP RECEPTOR ANTAGONISTS
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The present invention is directed to compounds of the formula (I) : (wherein variables A1, A2, A3, A4, A5, A6, A7, A8, G1, G2, G3, G4, J, Q, Ea, Eb, Ec, R6, R7, RPG and Y are as described herein) which are antagonists of CGRP receptors and which are useful in the treatment or prevention of diseases in which CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.
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Page/Page column 82
(2009/10/22)
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- SUBSTITUTED PIPERIDINES HAVING PROTEIN KINASE INHIBITING ACTIVITY
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The invention provides PKA and PKB kinase-inhibiting compounds of the formula (I); or salts, solvates, tautomers or N-oxides thereof, wherein E is a five membered heteroaryl ring containing 1, 2, 3 or 4 heteroatoms selected from O, N and S provided that no more than 1 heteroatom may be other than N; q and r are each is 0 or 1; provided that q+r is 1 or 2; T is N or a group CR5; J1-J2 is N=C(R6), (R7)C=N, (R8)N- C(O), (R8)2C-C(O), N=N or (R7)C=C(R6); Q3 is a bond or a saturated C1-3 hydrocarbon linker group optionally substituted by fluorine and hydroxy; G is NR2R3, CN or OH; m and n are each 0 or 1, provided that m+n is 1 or 2, and provided also that m or n are each 0 when the adjacent ring member of ring E is S or O; R1a and R1b are the same or different and each is hydrogen or a substituent R10; or R1a and R1b together with the carbon atoms or heteroatoms to which they are attached form a 5 or 6-membered aryl or heteroaryl ring, wherein the aryl or heteroaryl rings are optionally substituted by one or more substituents R10; and R2, R3, R4, R5, R7, R6, R8, and R10 are as defined in the claims.
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Page/Page column 114
(2008/12/06)
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- SUBSTITUTED PIPERIDINES CONTAINING A HETEROARYLAMIDE OR HETEROARYLPHENYL MOIETY
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The invention provides compounds of the formula (I) having PKA and PKB kinase inhibiting compounds of the formula (I): GP 1 J T 2 J N 4 R N H (I) or salts, solvates, tautomers or N-oxides thereof, wherein (1) GP is a group GP1: HET 2a a Q G (HNCO)f 7 (R )x N * (GP1) (2) GP is a group GP2: 10 (R )r O 2a a QG (CH2)w N V H N * (GP2) wherein HET is a monocyclic or bicyclic heterocyclic group containing up to 4 heteroatom ring members; the ring V is a monocyclic or bicyclic heteroaryl group of 5 to 10 ring members; and J1, J2, R4, R7, R10, Q2a, Ga, x, w and f are as defined in the claims
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Page/Page column 104-105
(2008/12/06)
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- PHARMACEUTICAL COMPOUNDS
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The invention provides compounds of the formula (I): or salts, solvates, tautomers or N-oxides thereof, wherein J1-J2 is CH=CH, N=CH, CH=N, HN-C(O) or CH2CO; T is N or CH and GP is as defined in the claims. The compounds have activity as inhibitors of PKA and PKB kinases and are useful in the treatment of cancers.
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Page/Page column 124
(2008/06/13)
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- Substituted aza-oxindole derivatives
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Substituted aza-oxindole derivatives useful as cyclin dependent kinase 11 inhibitors, for preventing/reducing the severity of epithelial cytotoxicity side-effects (e.g., alopecia, plantar-palmar syndrome, mucositis) induced by chemoptherapy and/or radiati
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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 26
(2010/02/05)
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- 3-(anilinomethylene) oxindoles
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The present invention relates generally to novel amine substituted oxindole compounds and compositions. Such compounds and compositions have utility as pharmacological agents in treating diseases or conditions alleviated by the inhibition or antagonism of
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Page column 71
(2010/02/04)
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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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- Synthesis and Unexpected Reactions of 2-Hydroxy-3-pyridinylacetic Hydrazides. Formation of 2H-Pyrrolo[2,3-b]pyridin-2-ones
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Treatment of 2-hydroxy-3-pyridinylacetic hydrazides under mild mesylation conditions provided 2H-pyrrolo[2,3-b]pyridin-2-ones as unexpected products. This rearrangement is believed to result from an intramolecular attack of the hydrazide on a reactive pyridinium species formed under the reaction conditions.
- Teleha, Christopher A.,Greenberg, Roger A.,Chorvat, Robert J.
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p. 145 - 149
(2007/10/03)
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- Substituted 1,3-Dihydro-2H-pyrrolopyridin-2-ones as Potential Antiinflammatory Agents
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A series of analogues based on the 1,3-dihydro-2H-pyrrolopyridin-2-one ring system have been synthesized and shown to possess oral antiinflammatory activity in both the reverse passive Arthus reaction (RPAR) pleural cavity assay in rats and in the adjuvant-induced arthritic rat model (AAR).Several members of this series additionally exhibit an inhibitory effect on the in vivo production of prostaglandin- and leukotriene-derived products or arachidonic acid metabolism although these compounds exhibit no significant inhibitory activity against the cyclooxygenase and 5-lipoxygenase enzymes in vitro.Structure-activity relationships in this series are discussed.
- Ting, Pauline C.,Kaminski, James J.,Sherlock, Margaret H.,Tom, Wing C.,Lee, Joe F.,et al.
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p. 2697 - 2706
(2007/10/02)
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- OXIDATION OF INDOLES WITH PYRIDINIUM BROMIDE PERBROMIDE. A SIMPLE AND EFFICIENT SYNTHESIS OF 7-AZAOXINDOLES
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Indoles and azaindoles on treatment with pyridinium bromide perbromide (PBPB) in t-butanol give 3,3-dibromooxindoles which, upon further reduction, yield the corresponding oxindoles.
- Marfat, Anthony,Carta, Michael P.
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p. 4027 - 4030
(2007/10/02)
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