- N'-Alkylaminosulfonyl Analogues of 6-Fluorobenzylideneindolinones with Desirable Physicochemical Profiles and Potent Growth Inhibitory Activities on Hepatocellular Carcinoma
-
The benzylideneindolinone 6-chloro-3-(3′-trifluoromethylbenzylidene)-1,3-dihydroindol-2-one (4) was reported to exhibit potent and selective growth inhibitory effects on hepatocellular carcinoma (HCC). Corroborative evidence supported multi-receptor tyrosine kinase (RTK) inhibition as a possible mode of action. However, the poor physicochemical properties of 4 limited its furtherance as a lead compound. In this study, the modification of 4 was investigated with the aim of improving its potency and physicochemical profile. The 6-fluorobenzylideneindolinone 3-12 bearing a 3′-N-propylaminosulfonyl substituent was found to be a promising substitute. Compound 3-12 [6-fluoro-3-(3′-N-propylaminosulfonylbenzylidene)-1,3-dihydroindol-2-one] was found to be tenfold more soluble than 4 and to have sub-micromolar growth inhibitory activities on HCC cells. It is apoptogenic and inhibits the phosphorylation of several RTKs in HuH7, of which the inhibition of FGFR4 and HER3 are prominent. Compound 3-12 decreased the tumor load in a physiologically relevant orthotopic HCC xenograft murine model. Structure-activity relationships support pivotal roles for the fluoro and N′-propylaminosulfonyl moieties in enhancing cell-based activity and moderating the physicochemical profile (solubility, permeability) of 3-12.
- Chen, Xiao,Yang, Tianming,Deivasigamani, Amudha,Shanmugam, Muthu K.,Hui, Kam-Man,Sethi, Gautam,Go, Mei-Lin
-
p. 1548 - 1558
(2015/09/07)
-
- SUBSTITUTED DICYANOPYRIDINES AND USE THEREOF
-
The present application relates to novel substituted dicyanopyridines, to processes for their preparation, to their use for the treatment and/or prophylaxis of diseases and to their use for preparing medicaments for the treatment and/or prophylaxis of diseases, preferably for the treatment and/or prophylaxis of cardiovascular disorders.
- -
-
Paragraph 0563-0565
(2013/08/28)
-
- HETEROARYL COMPOUNDS, COMPOSITIONS THEREOF, AND USE THEREOF AS PROTEIN KINASE INHIBITORS
-
Provided herein are Heteroaryl Compounds having the following structure: (I) wherein R1, R2, L, X, Y, Z, Q, A and B are as defined herein, compositions comprising an effective amount of a Heteroaryl Compound and methods for treating or preventing cancer, inflammatory conditions, immunological conditions, metabolic conditions and conditions treatable or preventable by inhibition of a kinase pathway comprising administering an effective amount of a Heteroaryl Compound to a patient in need thereof.
- -
-
Page/Page column 119
(2008/12/05)
-
- AN AGENT FOR PLASMINOGEN-ACTIVATION AND MATRIX METALLOPROTEINASE ASSOCIATED CONDITIONS AND METHODS OF USE
-
The present invention provides methods and compounds useful in the treatment of conditions such as metastatic cancer spread and atherosclerosis using oxamflatin and derivatives thereof. It has been found that oxamflatin and derivatives thereof are able to
- -
-
Page/Page column 36
(2010/02/11)
-
- HYDROXAMIC ACIDS USEFUL IN THE TREATMENT OF HYPER-PROLIFERATIVE DISORDERS
-
This invention relates to a compound of Formula (I) and its use in treating hyper-proliferative disorders.
- -
-
-
- Crystalline beta-lactam solvate
-
The crystalline 2.5 hydrate of 7β-[2?-(R)-2?--(m-(methylsulfonamido)phenyl)-2?-aminoacetamido]-3--chloro-3-(1-carbadethiacephem)-4-carboxylic acid is an antibiotic with superior pharmaceutical elegance. Pharmaceutical formulations of the crystalline 2.5 hydrate are also described.
- -
-
-
- 7-( (Meta-substituted) phenylglycine) 1-carba-1-dethiacephalosporins
-
Compounds of the Formula I wherein R1 is C1 to C4 alkyl,and their pharmaceutically-acceptable salts are valuable antibiotics.
- -
-
-
- Substituent effects in infrared spectroscopy-VII. Meta and para substituted methanesulphonanilides
-
Substituent effects on the NH frequencies of the conformers of methanesulphonanilides, their cyclic dimers and their hydrogen bonded complexes with acetonitrile have been analysed by means of the Hammet equation.An electron-withdrawing substituent may either increase or decrease ν(NH) in the XC6H4NHY series according to the electronic nature of the Y group.This can be explained by the non-monotonic dependence of the NH stretching frequency on the ionic character of the NH bond.
- Laurence, C.,Berthelot, M.,Lucon, M.,Tsuno, Y.
-
p. 791 - 796
(2007/10/02)
-