Identification, Structure-Activity Relationship, and Biological Characterization of 2,3,4,5-Tetrahydro-1-pyrido[4,3-]indoles as a Novel Class of CFTR Potentiators.

Cystic fibrosis (CF) is a life-threatening autosomal recessive disease, caused by mutations in the CF transmembrane conductance regulator (CFTR) chloride channel. CFTR modulators have been reported to address the basic defects associated with CF-causing mutations, partially restoring the CFTR function in terms of protein processing and/or channel gating. Small-molecule compounds, called potentiators, are known to ameliorate the gating defect.

Discovery of a picomolar potency pharmacological corrector of the mutant CFTR chloride channel.

F508del, the most frequent mutation causing cystic fibrosis (CF), results in mistrafficking and premature degradation of the CFTR chloride channel. Small molecules named correctors may rescue F508del-CFTR and therefore represent promising drugs to target the basic defect in CF. We screened a carefully designed chemical library to find F508del-CFTR correctors.

Thermal stabilization of the deglycating enzyme Amadoriase I by rational design.

Amadoriases are a class of FAD-dependent enzymes that are found in fungi, yeast and bacteria and that are able to hydrolyze glycated amino acids, cleaving the sugar moiety from the amino acidic portion. So far, engineered Amadoriases have mostly found practical application in the measurement of the concentration of glycated albumin in blood samples. However, these engineered forms of Amadoriases show relatively low absolute activity and stability levels, which affect their conditions of use.

An efficient one-pot two catalyst system in the construction of 2-substituted benzimidazoles: synthesis of benzimidazo[1,2-c]quinazolines.

The benzimidazole core is a common moiety in a large number of natural products and pharmacologically active small molecules. The synthesis of novel benzimidazole derivatives remains a main focus in medicinal research. In continuation of the efforts towards Ce(III) catalysts for organic transformations, we observed for the first time the activity of the iodide ion and copper cation in activating CeCl3·7H2O in the selective formation of prototypical 2-substituted benzimidazoles.

Preparation and biological evaluation of synthetic and polymer-encapsulated congeners of the antitumor agent pactamycin: insight into functional group effects and biological activity.

The synthesis and biological analysis of a number of novel congeners of the aminocyclopentitol pactamycin is described. Specific attention was paid to the preparation of derivatives at crucial synthetic branch points of the parent structure, and biological assays revealed a number of insights into the source of pactamycin's biological activity. Additionally, the encapsulation of pactamycin and select derivatives into the PRINT© nanoparticle technology was investigated as a proof-of-concept, and evidence of bioactivity modulation through nanoparticle delivery is demonstrated.

Reactions of nitric oxide and nitrogen dioxide with coenzyme Q: involvement of the isoprenic chain.

The formation of a di-tert-alkyl nitroxide has been observed by Electron Spin Resonance during the exposure of coenzyme CoQ(10), in both the oxidized and reduced forms, to nitrogen dioxide (˙NO(2)) or to nitric oxide (˙NO) in the presence of oxygen. The same kind of nitroxide has been observed also with CoQ(1), CoQ(3) or with 1-phenyl-3-methyl-2-butene, chosen as model compounds. In all cases, the formation of the nitroxide may be justified only by admitting the involvement of the isoprenic chain of the coenzymes and in particular the addition of ˙NO(2) to the double bond.