ABSTRACT
To find promising analogues of naturally occurring enediyne antibiotics with a sufficient reactivity in the Bergman cyclization and moderately stable under isolation and storage, a scale of relative enediynes reactivity was created on the basis of calculated free activation energies for the Bergman cyclization within 12 known and new benozothiophene, benzene, and cinnoline annulated 9- and 10-membered enediynes. To verify the predicted reactivity/stability balance, three new carbocyclic enediynes fused to a benzothiophene core bearing 3,4,5-trimethoxybenzene, fluoroisopropyl, and isopropenyl substituents were synthesized using the Nicholas-type macrocyclization. It was confirmed that annulation of a 3,4,5-trimethoxybenzene moiety to a 10-membered enediyne macrocycle imparts high reactivity to an enediyne while also conferring instability under ambient temperature. Fluoroisopropyl-substituted 10-membered enediyne from the opposite end of the scale was found to be stable while moderately reactive in the Bergman cyclization. Along with the experimentally confirmed moderate reactivity (DSC kinetic studies), (fluoroisopropyl)enediyne showed a significant DNA damaging activity in plasmid cleavage assays comparable with the known anticancer drug Zeocin.
Subject(s)
Enediynes/chemistry , Thiophenes/chemistry , Cyclization , DNA Damage , Drug Stability , Enediynes/pharmacology , Models, Molecular , Molecular Conformation , Quantum TheoryABSTRACT
Acid phosphatases of budding yeast have been studied for more than forty years. This paper covers biochemical characteristics of acid phosphatases and different aspects in expression regulation of eukaryotic genes, which were researched using acid phosphatases model. A special focus is devoted to cyclin-dependent kinase Pho85p, a negative transcriptional regulator, and its role in maintaining mitochondrial genome stability and to pleiotropic effects of pho85 mutations.