- Design, synthesis, and biological evaluation of 4-Methyl quinazoline derivatives as anticancer agents simultaneously targeting phosphoinositide 3-kinases and histone deacetylases
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Polypharmacology is a promising paradigm in modern drug discovery. Herein, we have discovered a series of novel PI3K and HDAC dual inhibitors in which the hydroxamic acid moiety as the zinc binding functional group was introduced to a quinazoline-based PI3K pharmacophore through an appropriate linker. Systematic structure-activity relationship studies resulted in lead compounds 23 and 36 that simultaneously inhibited PI3K and HDAC with nanomolar potencies and demonstrated favorable antiproliferative activities. Compounds 23 and 36 efficiently modulated the expression of p-AKT and Ac-H3, arrested the cell cycle, and induced apoptosis in HCT116 cancer cells. Following pharmacokinetic studies, 23 was further evaluated in HCT116 and HGC-27 xenograft models to show significant in vivo anticancer efficacies with tumor growth inhibitions of 45.8% (po, 150 mg/kg) and 62.6% (ip, 30 mg/kg), respectively. Overall, this work shows promise in discovering new anticancer therapeutics by the approach of simultaneously targeting PI3K and HDAC pathways with a single molecule.
- Zhang, Kehui,Lai, Fangfang,Lin, Songwen,Ji, Ming,Zhang, Jingbo,Zhang, Yan,Jin, Jing,Fu, Rong,Wu, Deyu,Tian, Hua,Xue, Nina,Sheng, Li,Zou, Xiaowen,Li, Yan,Chen, Xiaoguang,Xu, Heng
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- QUINAZOLINE DERIVATIVES AS PDE10A ENZYME INHIBITORS
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This invention is directed to compounds, which are PDE10A enzyme inhibitors. The invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier. The pr
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- SUBSTITUTED 1-ALKYLCINNOLIN-4(1H)-ONE DERIVATIVES, PREPARATION THEREOF AND THERAPEUTIC APPLICATION OF SAME
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The subject of the present invention is compounds corresponding to the formula (I) in which: X represents a divalent (C2-C5)alkylene radical which is unsubstituted or substituted one or more times by an Alk group; R1 represents a phenyl, a naphthyl, a pyridyl, a 1-benzothienyl or a 1,3-benzodioxolyl; R2 represents a hydrogen atom, a halogen atom, an Alk group, an OAlk group or else a group chosen from —S-Alk, —SO-Alk, —SO2-Alk, —CO—N(R4)-Alk, —N(R4)SO2-Alk, —N(R4)CO-Alk, —N(R4)SO2—N(Alk)2; R3 represents a hydrogen atom, a halogen atom, an Alk group or an OAlk group; R4 represents a hydrogen atom or a (C1-C4)alkyl; Alk represents an unsubstituted or substituted (C1-C4)alkyl. Preparation process and therapeutic application.
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- Ionic diamine rhodium complex catalyzed reductive N-heterocyclization of 2-nitrovinylarenes
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Ionic diamine rhodium complex (1) catalyzes the reductive N-cyclization of 2-vinylnitroarenes using carbon monoxide as a reducing agent to afford functionalized indoles. The catalytic system allows direct access to indoles with ester and ketone groups at the 2- or 3-position, in good yields.
- Okuro, Kazumi,Gurnham, Joanna,Alper, Howard
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experimental part
p. 4715 - 4720
(2011/07/08)
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- SUBSTITUTED 1-BENZYL-CINNOLIN-4(1H)-ONE DERIVATIVES, PREPARATION THEREOF, AND THERAPEUTIC USE THEREOF
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The present invention is related to novel substituted 1-benzylcinnolin-4(1H)-one derivatives having affinity for cannabinoid CB2 receptors, their preparation and their therapeutic application.
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- Novel and convenient synthesis of substituted quinolines by copper- or palladium-catalyzed cyclodehydration of 1-(2-aminoaryl)-2-yn-1-ols
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(Chemical Equation Presented) A general and convenient synthesis of substituted quinolines by regioselective copper- or palladium-catalyzed 6-endo-dig cyclization-dehydration of 1-(2-aminoaryl)-2-yn-1-ols is reported. The crude substrates were easily obtained by the Grignard reaction between the appropriate alkynylmagnesium bromide and 2-aminoaryl ketones and could be used without further purification for the subsequent cyclization step. Heteroannulation reactions were carried out in MeOH or DME as the solvent at 60 or 100°C in the presence of CuCl2 or PdX2 (in conjunction with 10 equiv of KX, X = Cl, I) as the catalyst to afford the quinoline derivatives in good to excellent isolated yields based on starting 1-(2-aminoaryl)-2-yn-1-ols (66-90%).
- Gabriele, Bartolo,Mancuso, Raffaella,Salerno, Giuseppe,Ruffolo, Giuseppe,Plastina, Pierluigi
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p. 6873 - 6877
(2008/02/10)
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- Pyrrolidine-3-carboxylic acids as endothelin antagonists. 4. Side chain conformational restriction leads to ET(B) selectivity
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When the dialkylacetamide side chain of the ETA-selective antagonist ABT-627 is replaced with a 2,6-dialkylacetanilide, the resultant analogues show a complete reversal of receptor selectivity, preferring ETB over ETA. By optimizing the aniline substitution pattern, as well as the alkoxy group on the 2-aryl substituent, it is possible to prepare antagonists with subnanomolar affinity for ETB and with selectivities in excess of 4000-fold. A number of these compounds also show promising pharmacokinetic profiles; a useful balance of properties is found in A-192621 (38). Pharmacology studies with A-192621 serve to reveal the role of the ETB receptor in modulating blood pressure; the observed hypertensive response to persistent ETB blockade is consistent with previous postulates and indicates that ETB-selective antagonists may not be suitable as agents for long-term systemic therapy.
- Von Geldern, Thomas W.,Tasker, Andrew S.,Sorensen, Bryan K.,Winn, Martin,Szczepankiewicz, Bruce G.,Dixon, Douglas B.,Chiou, William J.,Wang, Liming,Wessale, Jerry L.,Adler, Andy,Marsh, Kennan C.,Nguyen, Bach,Opgenorth, Terry J.
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p. 3668 - 3678
(2007/10/03)
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- Structure-activity relationship of a series of phenylureas linked to 4- phenylimidazole. Novel potent inhibitors of acyl-CoA:cholesterol O- acyltransferase with antiatherosclerotic activity. 2
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In our continuing search to find systemically bioavailable ACAT (acyl- CoA:cholesterol O-acyl-transferase) inhibitors with more potent antiatherosclerotic effect than N-[2-(dimethylamino)-6-[3-(5-methyl-4- phenyl-1H-imidazol-1-yl)propoxy]phenyl]-N'-pentyl
- Kimura,Watanabe,Matsui,Hayashi,Tanaka,Ohtsuka,Saeki,Kogushi,Kabayashi,Akasaka,Yamagishi,Saitou,Yamatsu
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p. 1641 - 1653
(2007/10/02)
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- Herbicidal 2 methyl-4-phosphinylcinnolinium hydroxide inner salts
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Certain 2-methyl-4-phosphinylcinnolinium hydroxide inner salts, useful for controlling unwanted plants.
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- Method for preparing 4-hydroxycinnolines in a pH controlled system
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In the preparation of a 4-hydroxycinnoline wherein the diazonium salt of a 2-aminoacetophenone in aqueous solution is allowed to undergo cyclocondensation, the improvement that comprises maintaining the pH of the solution between about 4.0 and 8.5 during the cyclocondensation.
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