Nickel Nanoparticle Catalyzed Mono- and Di-Reductions of gem-Dibromocyclopropanes Under Mild, Aqueous Micellar Conditions.

Mild mono- and di-hydrodehalogenative reductions of gem-dibromocyclopropanes are described, providing an easy and green approach towards the synthesis of cyclopropanes. The methodology utilizes 0.5-5 mol % TMPhen-nickel as the catalyst, which, when activated with a hydride source such as sodium borohydride, cleanly and selectively dehalogenates dibromocyclopropanes. Double reduction proceeds in a single operation at temperatures between 20-45 °C and at atmospheric pressure in an aqueous designer surfactant medium. At lower loading and either in the absence of ligand or in the presence of 2,2'-bipyridine, this new technology can also be used to gain access to not only monobrominated cyclopropanes, interesting building blocks for further use in synthesis, but also mono- or di-deuterated analogues. Taken together, this base-metal-catalyzed process provides access to cyclopropyl-containing products and is achieved under environmentally responsible conditions.

Cyanoquinolines with independent corrector and potentiator activities restore ΔPhe508-cystic fibrosis transmembrane conductance regulator chloride channel function in cystic fibrosis.

The ΔPhe508 mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) protein impairs its folding, stability, and chloride channel gating. Although small molecules that separately correct defective ΔPhe508-CFTR folding/cellular processing ("correctors") or chloride channel gating ("potentiators") have been discovered and are in clinical trials, single compounds with bona fide dual corrector and potentiator activities have not been identified. Here, screening of ∼110,000 small molecules not tested previously revealed a cyanoquinoline class of compounds with independent corrector and potentiator activities (termed CoPo). Analysis of 180 CoPo analogs revealed 6 compounds with dual corrector and potentiator activities and 13 compounds with only potentiator activity. N-(2-((3-Cyano-5,7-dimethylquinolin-2-yl)amino)ethyl)-3-methoxybenzamide (CoPo-22), which was synthesized in six steps in 52% overall yield, had low micromolar EC(50) for ΔPhe508-CFTR corrector and potentiator activities by short-circuit current assay. Maximal corrector and potentiator activities were comparable with those conferred by the bithiazole Corr-4a and the flavone genistein, respectively. CoPo-22 also activated wild-type and G551D CFTR chloride conductance within minutes in a forskolin-dependent manner. Compounds with dual corrector and potentiator activities may be useful for single-drug treatment of cystic fibrosis caused by ΔPhe508 mutation.

Coolade. A Low-Foaming Surfactant for Organic Synthesis in Water.

Several types of reduction reactions in organic synthesis are performed under aqueous micellar-catalysis conditions (in water at ambient temperature), which produce a significant volume of foam owing to the combination of the surfactant and the presence of gas evolution. The newly engineered surfactant "Coolade" minimizes this important technical issue owing to its low-foaming properties. Coolade is the latest in a series of designer surfactants specifically tailored to enable organic synthesis in water. This study reports the synthesis of this new surfactant along with its applications to gas-involving reactions.

Expedient synthesis of a 72-membered isoxazolino-ß-ketoamide library by a 2·3-component reaction.

An efficient 2·3-component reaction (2·3CR; a 2-component reaction followed, in one pot, by a3-component reaction) is presented for the synthesis of isoxazolino-ß-ketoamides. This 2·3CR proceeds by (i) a Meldrum's acid-generated acyl ketene, which is trapped by an amine to form a ß-ketoamide intermediate in a 2CR followed, in one pot, by (ii) a Mannich reaction followed by elimination of dimethyl amine·HCl to generate an α,ß-unsaturated ß-ketoamide dipolarophile that reacts in a nitrile oxide 1,3-dipolar cycloaddition reaction. This one-pot 2·3CR process delivers the targeted isoxazolino-ß-ketoamide product. A total of 72 compounds are presented, all of which have been submitted to the NIH Molecular Libraries Small Molecule Repository for high-throughput biological screening.

Structure-activity relationships of cyanoquinolines with corrector-potentiator activity in ΔF508 cystic fibrosis transmembrane conductance regulator protein.

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. The most common CF-causing mutation, ΔF508-CFTR, produces CFTR loss-of-function by impairing its cellular targeting to the plasma membrane and its chloride channel gating. We recently identified cyanoquinolines with both corrector ("Co", normalizing ΔF508-CFTR targeting) and potentiator ("Po", normalizing ΔF508-CFTR channel gating) activities. Here, we synthesized and characterized 24 targeted cyanoquinoline analogues to elucidate the conformational requirements for corrector and potentiator activities. Compounds with potentiator-only, corrector-only, and dual potentiator-corrector activities were found. Molecular modeling studies (conformational search ⇒ force-field lowest energy assessment ⇒ geometry optimization) suggest that (1) a flexible tether and (2) a relatively short bridge between the cyanoquinoline and arylamide moieties are important cyanoquinoline-based CoPo features. Further, these CoPo's may adopt two distinct π-stacking conformations to elicit corrector and potentiator activities.