Isoindoles and their fused derivates represent a very important class of compounds with a wide scope of applications and biological activity, ranging from effects on the cardiovascular and cerebral systems to dopamine agonist, anticancer, antibiotic, anti-convulsive and anti-inflammatory effects. In this paper we described the application of activated carbon (Darco® KB) for the acceleration and direction of the transformation of various 2H-pyran-2-ones with N-substituted maleimides toward isoindole derivatives through the reaction sequence cycloaddition-elimination-dehydrogenation. We found that the combination of Darco® KB, as the metal-free catalyst, and decalin, as the solvent in a closed vessel, represents the most successful conditions. The catalyst could easily be recycled.
COBISS.SI-ID: 35801349
1,4-Diazabicyclo[2.2.2]octane (DABCO) has been evaluated as a starting material for the synthesis of 1-alkyl-4-(2-phenoxyethyl)piperazines and related derivatives. This type of heterocyclic moieties can be considered particularly promising for medicinal chemistry. We found that 1-alkyl-1,4-diazabicyclo[2.2.2]octan-1-ium salts, resulting from the alkylation of the DABCO, efficiently react with a variety of nucleophiles in polyethyleneglycol (PEG) or diglyme at high temperatures to give piperazine products resulting from the nucleophilic ring-opening reaction. This protocol was exemplified by the facile one-pot synthesis of ether isostere of Vanoxerine (GBR-12909), as a prototype of potential dopamine reuptake inhibitors.
COBISS.SI-ID: 35543813
A series of analogs of FDDNP, a well established molecular probe for the detection of changes in the CNS of Alzheimer disease patients, has been synthesized and characterized using spectroscopic and computational methods. The binding affinities of these molecules have been measured experimentally and explained through the use of a computational model. The analogs were created by systematically modifying the donor and the acceptor sides of FDDNP to learn the structural requirements for optimal binding to Aβ aggregates. FDDNP and its analogs are neutral, environmentally sensitive, fluorescent molecules with high dipole moments, as evidenced by their spectroscopic properties and dipole moment calculations. The preferred solution-state conformation of these compounds is directly related to the binding affinities. The extreme cases were a nonplanar analog tert-butyl-FDDNP, which shows low binding affinity for Aβ aggregates (520 nM Ki) in vitro and a nearly planar tricyclic analog cDDNP, which displayed the highest binding affinity (10 pM Ki). Using a previously published X-ray crystallographic model of DDNP bound to an amyloidogenic Aβ peptide model, we show that the binding affinity is inversely related to the distortion energy necessary to avoid steric clashes along the internal surface of the binding channel.
COBISS.SI-ID: 36232965
An eight-carbon chain constitutes the basic skeleton of Aliskiren molecule, which emerged as a potent nonpeptide renin inhibitor known to regulate blood pressure. We described an efficient strategy for the formation of 12-membered macrocyclic systems containing an eight-carbon alkene unit via alkene metathesis reaction by employing ruthenium catalysts. This study revealed that the formation of medium ring sizes via ring-closing metathesis is less favorable. We have also shown that the opening of the synthesized 12-membered rings with nucleophilic reagents can lead to the asymmetric acyclic alkene system that could possibly be further converted to the aliskiren derivatives.
COBISS.SI-ID: 35927045
Nitroxolin is a potent inibitor of cathepsin B, which is a promising therapeutic target as it participates in the degradation of extracellular matrix proteins in tumor tissues. We described a simple methodology to prepare 8-amino analogues of pharmacologically interesting nitroxoline. The reaction of O-cyanomethylated nitroxoline with various primary and secondary amines led selectively to the 8-quinolylamines by microwave-assisted displacement of cyanomethoxy group. Thus, we have demonstrated for the first time that a cyanomethoxy group can serve as a good leaving group in nucleophilic aromatic substitutions in a quinoline system.
COBISS.SI-ID: 3200625