ABSTRACT
Solid-phase syntheses of 1,2,4-trisubstituted urazole and thiourazole derivatives have been accomplished. The synthesis began with the coupling of carbonylimidazole-Wang resin with a disubstituted hydrazine. The resultant carbazate was coupled with an isocyanate or isothiocyanate. Subsequent heating of the resin in the presence of triethylamine or potassium t-butoxide induced cyclization and released the desired (thio)urazole into solution. Most of the products were obtained in high yields and purities. Structural diversity can be further expanded at the R(2) substituent by performing the palladium-mediated Suzuki coupling reaction.
ABSTRACT
Streptonigrin (1) and its novel natural derivative 7-(1-methyl-2-oxopropyl)streptonigrin (2) were isolated from an actinomycete strain, Micromonospora sp. IM 2670. The inductions for 1 and 2 are more potent in the human neuroblastoma SH-SY5Y cells that contain wild-type p53 than in SH-SY5Y-5.6 cells that overexpress a dominant negative mutant of p53, thus suggesting that they induce apoptosis through a p53-dependent pathway.
Subject(s)
Apoptosis/drug effects , Genes, p53/physiology , Micromonospora/chemistry , Neuroblastoma/pathology , Streptonigrin/isolation & purification , Tumor Suppressor Protein p53/metabolism , Cell Nucleus/metabolism , Chromatography, High Pressure Liquid , Genes, p53/genetics , Humans , Inhibitory Concentration 50 , Molecular Conformation , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Streptonigrin/analogs & derivatives , Streptonigrin/chemistry , Streptonigrin/pharmacology , Tumor Cells, Cultured/drug effectsABSTRACT
Harmine (3), 7-fluoro-1-methyl beta-carboline (35) and 1-(5-methyl-imidazol-4-yl) beta-carboline (41) were potent and specific inhibitors of cyclin-dependent kinases. The degree of aromaticity of the tricyclic ring and the positioning of substituents are important for inhibitory activity. While most beta-carbolines inhibited CDK2 and CDK5 to the same extent, selective inhibition against CDK2 was observed in 1-(2-chlorophenyl)- (12), 1-(2-fluorophenyl)- (15), and 1-(2-chloro-5-nitrophenyl)- (28) beta-carbolines.
Subject(s)
CDC2-CDC28 Kinases , Carbolines/pharmacology , Cyclin-Dependent Kinases/antagonists & inhibitors , Cyclins/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Cyclin-Dependent Kinase 2 , Cyclin-Dependent Kinase 5 , Cyclin-Dependent Kinase Inhibitor p21ABSTRACT
Benzylidene rhodanines are novel inhibitors of UDP N-acetylmuramate/L-alanine ligase. They showed selective whole-cell activity against the Gram-positive MRSA but not against the Gram-negative Escherichia coli. Their cytotoxic effect on mammalian CHO cells was also evaluated.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Peptide Synthases/antagonists & inhibitors , Animals , Anti-Bacterial Agents/pharmacology , Benzylidene Compounds/chemical synthesis , Benzylidene Compounds/pharmacology , CHO Cells/drug effects , Cell Survival/drug effects , Cricetinae , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Microbial Sensitivity Tests , Rhodanine/chemical synthesis , Rhodanine/pharmacologyABSTRACT
An efficient one-pot three-component synthesis of thiohydantoins was developed. In the first step, amino acid esters were alkylated by imine formation with aldehydes and reduction by sodium triacetoxyborohydride. In the second step, an isothiocyanate was added together with a molar equivalent of triethylamine, leading to the thiohydantoin product in high yield and purity after an extractive aqueous workup. This procedure was used to generate a combinatorial library of over 600 discrete thiohydantoins on a 0.1 mmol scale. Sampling of 10% of this library showed the thiohydantoin to be the major product in all cases, with purities of 52-98% by HPLC analysis. The cyclization conditions can also be adapted to the synthesis of hydantoins.
