ABSTRACT
The synthesis of new enantiopure syn- and anti-3-(α-aminobenzyl)-benzo-γ-sultam ligands 6 and their application in the ruthenium(ii)-catalyzed asymmetric transfer hydrogenation (ATH) of ketones using formic acid/triethylamine is described. In particular, benzo-fused cyclic ketones afforded excellent enantioselectivities in reasonable time employing a low loading of the syn ligand-containing catalyst. A never-before-seen dynamic kinetic resolution (DKR) during reduction of a γ-keto carboxylic ester (S7) derivative of 1-indanone is realized leading as well to excellent induction.
ABSTRACT
A highly enantioselective synthesis of unsubstituted 1-phenyl-phosphindane and its P-borane and P-oxide derivatives was effectively established via a new fluoride-triggered desilylative carbocyclization strategy. Preparation of the "oxygen atom-doped" 1-phenyl-3-oxa-1-phosphindane-P-borane analogue was otherwise achieved via a tandem P-α-iodination-intra-O-alkylation.
ABSTRACT
A conjugate of pyridine-4-aldoxime and atropine (ATR-4-OX) was synthesized and its antidotal efficiency was tested in vitro on tabun- or paraoxon-inhibited acetylcholinesterase (AChE) of human erythrocytes as well as in vivo using soman-, tabun- or paraoxon-poisoned mice. Its genotoxic profile was assessed on human lymphocytes in vitro and was found acceptable for further research. ATR-4-OX showed very weak antidotal activity, inadequate for soman or tabun poisoning. Conversely, it was effective against paraoxon poisoning both in vitro and in vivo. All animals treated with 5 % or 25 % LD(50) doses of the new oxime survived after administration of 10.0 or 16.0 LD(50) doses of paraoxon, respectively. Based on the persistence of toxicity symptoms in mice, the atropine moiety had questionable effects in attenuating such symptoms. It appears that ATR-4-OX has a therapeutic effect related to the reactivation of phosphylated AChE, but not to receptor antagonization.
Subject(s)
Antidotes/pharmacology , Atropine Derivatives/pharmacology , Cholinesterase Inhibitors/poisoning , Cholinesterase Reactivators/pharmacology , Organophosphate Poisoning , Paraoxon/poisoning , Pralidoxime Compounds/pharmacology , Soman/poisoning , Acetylcholinesterase , Adult , Animals , Atropine Derivatives/chemical synthesis , Cell Death/drug effects , Cell Survival/drug effects , Enzyme Assays , Erythrocytes/drug effects , Erythrocytes/enzymology , Humans , Lymphocytes/drug effects , Male , Mice , Organophosphates , Pralidoxime Compounds/chemical synthesisABSTRACT
Histamine H(1) and serotonin 5-HT(2A) receptors mediate two different mechanisms involved in sleep regulation: H(1) antagonists are sleep inducers, while 5-HT(2A) antagonists are sleep maintainers. Starting from 9'a, a novel spirotetracyclic compound endowed with good H(1)/5-HT(2A) potency but poor selectivity, very high Cli, and a poor P450 profile, a specific optimization strategy was set up. In particular, we investigated the possibility of introducing appropriate amino acid moieties to optimize the developability profile of the series. Following this zwitterionic approach, we were able to identify several advanced leads (51, 65, and 73) with potent dual H(1)/5-HT(2A) activity and appropriate developability profiles. These compounds exhibited efficacy as hypnotic agents in a rat telemetric sleep model with minimal effective doses in the range 3-10 mg/kg po.
