ABSTRACT
The treatment of cancer through the development of new therapies is one of the most important challenges of our time. The decoding of the human genome has yielded important insights into the molecular basis of physical disorders, and in most cases a connection between failures in specific genes and the resulting clinical symptoms can be made. The modulation of epigenetic mechanisms enables, by definition, the alteration of cellular phenotype without altering the genotype. The information content of a single gene can be crucial or harmful, but the prerequisite for a cellular effect is active gene transcription. To this end, epigenetic mechanisms play a very important role, and the transcription of a given gene is directly influenced by the modification pattern of the surrounding histone proteins as well as the methylation pattern of the DNA. These processes are effected by different enzymes which can be directly influenced through the development of specific modulators. Of course, all genetic information is written as a four-character code in DNA. However, epigenetics describes the art of reading between the lines.
Subject(s)
Epigenesis, Genetic , Gene Expression Regulation , Histone Acetyltransferases/metabolism , Histones/physiology , Acetylation , Animals , DNA Methylation , Histone Acetyltransferases/chemistry , Histones/chemistry , Humans , Methylation , Phosphorylation , Poly Adenosine Diphosphate Ribose/metabolism , Yeasts/enzymology , Yeasts/geneticsSubject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Lactones/chemistry , Lactones/pharmacology , Sphingomyelin Phosphodiesterase/antagonists & inhibitors , Ceramides/chemical synthesis , Ceramides/chemistry , Dose-Response Relationship, Drug , Enzyme Activation/drug effects , Enzyme Inhibitors/chemical synthesis , Lactones/chemical synthesis , Molecular Conformation , Sphingomyelins/chemistry , Stereoisomerism , Structure-Activity Relationship , Time FactorsABSTRACT
A general enantioselective organocatalytic conjugate addition procedure of a variety of malonates to alpha,beta-unsaturated enone systems is presented. The reaction is efficiently catalysed by the pyrrolidinyl tetrazole catalyst 1. Cyclic, acyclic and aromatic enones can be used and the reaction with ethyl malonates 3 b provides the Michael addition products in high yields with good to excellent enantioselectivities. Since only 1.5 equivalents of malonate are used as a reagent, the reaction is readily scaled and practical to operate. Furthermore, the malonate addition products can be easily mono decarboxylated without loss in enantiomeric excess by enzymatic or sodium hydroxide mediated methods.
Subject(s)
Malonates/chemistry , Catalysis , Esterification , Ethylenes/chemistry , Molecular Structure , Solvents , StereoisomerismABSTRACT
Inspired by the combination of unique structure and potent bioactivities exhibited by several family members of the caged Garcinia xanthones, we developed a synthesis of simplified analogues that maintain the overall caged motif. The caged structure of these compounds was constructed via a site-selective Claisen/Diels-Alder reaction cascade. We found that the fully substituted caged structure, in which are included the C18 and C23 geminal methyl groups, is necessary to maintain bioactivity. Analogue had comparable activity to the natural products of this family, such as gambogic acid. These compounds exhibit cytotoxicity in a variety of tumor cell lines at low micromolar concentrations and were found to induce apoptosis in HUVE cells. In addition, studies with HL-60 and HL-60/ADR cells indicate that these compounds are not affected by the mechanisms of multidrug resistance, conferred by P glycoprotein expression, typical of relapsed cancers and thus represent a new and potent pharmacophore.