ABSTRACT
A previously developed 1,8-hydrogen atom transfer (HAT) reaction promoted by 6-O-yl alkoxyl radicals between the two pyranose units in Hexp-(1â4)-Hexp disaccharides has been extended to other systems containing at least a furanose ring in their structures. In Penf-(1â3)-Penf (A) and Hexp-(1â3)-Penf (B) disaccharides, the 1,8-HAT reaction and concomitant cyclization to a 1,3,5-trioxocane ring are in competition with radical ß-scission of the C4-C5 bond and formation of dehomologated products. The influence of the stereoelectronic ß-oxygen effect on the ß-scission and consequently on the 1,8-HAT reaction has been studied using the four possible isomeric d-furanoses. d-xylo- and d-lyxo-derivatives afforded preferentially 1,8-HAT products, whereas d-arabino- and d-ribo-derivatives gave exclusively direct ß-scission of the alkoxyl radical. When the 6-O-yl radical is on a pyranose ring, as occurs in Penf-(1â4)-Hexp (C), it has been shown to provide the cyclized products exclusively.
Subject(s)
Disaccharides/chemical synthesis , Furans/chemistry , Hydrogen/chemistry , Cyclization , Disaccharides/chemistry , Molecular Structure , StereoisomerismABSTRACT
From a set of weakly potent lead compounds, using in silico screening and small library synthesis, a series of 2-alkyl-3-aryl-3-alkoxyisoindolinones has been identified as inhibitors of the MDM2-p53 interaction. Two of the most potent compounds, 2-benzyl-3-(4-chlorophenyl)-3-(3-hydroxypropoxy)-2,3-dihydroisoindol-1-one (76; IC(50) = 15.9 +/- 0.8 microM) and 3-(4-chlorophenyl)-3-(4-hydroxy-3,5-dimethoxybenzyloxy)-2-propyl-2,3-dihydroisoindol-1-one (79; IC(50) = 5.3 +/- 0.9 microM), induced p53-dependent gene transcription, in a dose-dependent manner, in the MDM2 amplified, SJSA human sarcoma cell line.
Subject(s)
Antineoplastic Agents/chemical synthesis , Indoles/chemical synthesis , Proto-Oncogene Proteins c-mdm2/metabolism , Tumor Suppressor Protein p53/metabolism , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Combinatorial Chemistry Techniques , Drug Screening Assays, Antitumor , Humans , Indoles/chemistry , Indoles/pharmacology , Models, Molecular , Protein Binding , Stereoisomerism , Structure-Activity Relationship , Transcription, Genetic , Tumor Suppressor Protein p53/geneticsABSTRACT
A series of 2-N-alkyl-3-aryl-3-alkoxyisoindolinones has been synthesised and evaluated as inhibitors of the MDM2-p53 interaction. The most potent compound, 3-(4-chlorophenyl)-3-(4-hydroxy-3,5-dimethoxybenzyloxy)-2-propyl-2,3-dihydroisoindol-1-one (NU8231), exhibited an IC50 of 5.3 +/- 0.9 microM in an ELISA assay, and induced p53-dependent gene transcription in a dose-dependent manner, in the SJSA human sarcoma cell line.
