50262-48-1Relevant articles and documents
Formulating a new basis for the treatment against botulinum neurotoxin intoxication: 3,4-Diaminopyridine prodrug design and characterization
Zakhari, Joseph S.,Kinoyama, Isao,Hixon, Mark S.,Di Mola, Antonia,Globisch, Daniel,Janda, Kim D.
supporting information; experimental part, p. 6203 - 6209 (2011/12/02)
Botulism is a disease characterized by neuromuscular paralysis and is produced from botulinum neurotoxins (BoNTs) found within the Gram positive bacterium Clostridium botulinum. This bacteria produces the most deadliest toxin known, with lethal doses as low as 1 ng/kg. Due to the relative ease of production and transport, the use of these agents as potential bioterrorist weapons has become of utmost concern. No small molecule therapies against BoNT intoxication have been approved to date. However, 3,4-diaminopyridine (3,4-DAP), a potent reversible inhibitor of voltage-gated potassium channels, is an effective cholinergic agonist used in the treatment of neuromuscular degenerative disorders that require cholinergic enhancement. 3,4-DAP has also been shown to facilitate recovery of neuromuscular action potential post botulinum intoxication by blocking K+ channels. Unfortunately, 3,4-DAP displays toxicity largely due to blood-brain-barrier (BBB) penetration. As a dual-action prodrug approach to cholinergic enhancement we have designed carbamate and amide conjugates of 3,4-DAP. The carbamate prodrug is intended to be a slowly reversible inhibitor of acetylcholinesterase (AChE) along the lines of the stigmines thereby allowing increased persistence of released acetylcholine within the synaptic cleft. As a secondary activity, cleavage of the carbamate prodrug by AChE will afford the localized release of 3,4-DAP, which in turn, will enhance the pre-synaptic release of additional acetylcholine. Being a competitive inhibitor with respect to acetylcholine, the activity of the prodrug will be greatest at the synaptic junctions most depleted of acetylcholine. Here we report upon the synthesis and biochemical characterization of three new classes of prodrugs intended to limit previously reported stability and toxicity issues. Of the prodrugs examined, compound 32, demonstrated the most clinically relevant half-life of 2.76 h, while selectively inhibiting AChE over butyrylcholinesterase-a plasma-based high activity esterase. Future in vivo studies could provide validation of prodrug 32 as a potential treatment against BoNT intoxication as well as other neuromuscular disorders.
Liquid-Crystalline Heterocycloalkanes. III. Synthesis and Liquid-Crystalline Properties of Substituted 1,3-Dioxadecalines
Tschierske, C.,Zaschke, H.
, p. 1 - 14 (2007/10/02)
Liquid-crystalline 2-substituted and 2,6-disubstituted 1,3-dioxadecalines (4-6) were synthesized by acid-catalyzed acetalization of trans-2-hydroxymethylcyclohexanol (1) or trans-4-alkyl-trans-2-hydroxymethylcyclohexanoles (2) with aldehydes 3 whereby the desired trans-isomers were formed only.The syntheses of the various aldehydes are also described.Special attention is drawn on the evolution of mesogenic properties of the title compounds 4-6 in comparison with known decalines and 1,3-dioxanes.It was found that the clearing temperatures of the synthesized 1,3-dioxadecalines are always lower than those of the corresponding decaline derivatives, due to the deformation of the decaline-ringsystem by the introduction of two oxygen-atoms.The comparison of 1,3-dioxanes and 1,3-dioxadecalines shows that the dioxadecaline ringsystem tends to suppress smectic mesophases in favour of nematics.A first example of a liquid crystalline cis-fused 1,3-dioxadecaline (8) is described, too.
