Isomeric Carborane Neuromuscular Blocking Agents

Abstract

We synthesized a family of neuromuscular blocking agents (NMB) based on decamethonium, but containing a carborane cluster in the methylene chain between the two quaternary ammonium groups. The carborane cluster isomers o‐NMB, m‐NMB, and p‐NMB were tested in animals for neuromuscular block and compared with agents used clinically: rocuronium and decamethonium. All three isomers caused reversible muscle weakness in mice as determined by grip strength and inverted screen tests, with a potency rank of p‐NMB > rocuronium > decamethonium > m‐NMB > o‐NMB. The mechanism of action of the compounds was determined by using the in vitro rat phrenic nerve hemi‐diaphragm preparation and electrophysiologic measurements in cells. Neostigmine reversed hemi‐diaphragm weakness caused by the three isomers and rocuronium, but not succinylcholine. In electrophysiologic recordings of currents through acetylcholine receptor channels, the carborane compounds did not activate channel activity but did inhibit channel activation by acetylcholine. These results demonstrate that the carborane neuromuscular blocking agents are non‐depolarizers in contrast to the depolarizing action of the parent compound.

Direct Introduction of an Alkylsulfonamido Group on C‐sites of Isomeric Dicarba‐closo‐dodecaboranes: The Influence of Stereochemistry on Inhibitory Activity against the Cancer‐Associated Carbonic Anhydrase IX Isoenzyme

“…It should be noted that this systematic trend is demonstrated on a panel of three isomeric series of compounds, of which each has identical substitution but different positions of carbon atoms. As a result of the significant alterations of K i and S I influenced by isomerism presented here as well as in other recently published studies, [6–9] it seems that the interactions with CH groups or dipole moments of the dicarba‐ closo ‐dodecaborane cages might play an important role in biological activity. The results are complemented with high resolution crystal structures of CA IX mimic enzyme‐inhibitor complexes covering all the isomers.…”

“…Again, the S I values decrease gradually when moving from the ortho ‐, meta ‐, and, para ‐positions of carbon atoms. Thus, besides the previously published papers covering other targets, [6, 7, 9] these data represent another striking and rare example of the biological activity of isomeric dicarba‐ closo ‐dodecaboranes and dicarba‐ nido ‐undecaborate ions being clearly dependent on the stereochemistry of skeletal carbon atoms and/or substituents on the cage.…”

“…The first step, that is, the introduction of a hydroxypropyl group by reaction of lithiated 1,2‐dicarba‐ closo ‐dodecaorane with trimethylene oxide, leading to monosubstituted derivatives ortho ‐, meta , para ‐ 2 and to diols ortho ‐, meta , para ‐ 3 was adapted from a known protocol, [7, 10, 15] while the second step, that is, synthesis of corresponding disubstituted mesyl esters ortho ‐, meta ‐, and para ‐ 5 , has appeared in the very recent literature [7] (see also Supporting Information). The reaction conditions were optimized for the synthesis of the monosubstituted cages.…”

“…For example, boronicaine, a cluster analogue of lidocaine, displayed different analgesic activities for boron‐substituted ortho ‐, meta ‐, and para ‐dicarba‐ closo ‐dodecaborane [6] . The isomeric effect of dicarba‐ closo ‐dodecaboranes was also recently described by Kracke and co‐workers on the neuromuscular‐blocking activity of isomeric dicarba‐ closo ‐dodecaboranes that were incorporated into central part of an alkyl chain interconnecting two dimethylamine groups, like in the known muscle relaxant and neuromuscular blocking agent decamethonium [7] . In that study, the increased potency was found experimentally in a mouse model to be in the order ortho < meta < para .…”

The Rise of Boron-Containing Compounds: Advancements in Synthesis, Medicinal Chemistry, and Emerging Pharmacology

“…Some other molecules containing carboranyl clusters were described as potential biomolecule-interacting agents, some of which were designed by a previous docking analysis, including compound 168 (Figure ), which targets the neuromuscular junction to prevent muscle contraction and cause paralysis; compounds 169 and 170 (Figure ), which inhibit nicotinamide phosphoribosyltransferase and show potential use in cancer, AD, diabetes, and arthritis; , compounds 171 and 172 (Figure ), which displaying selective and differential affinity for the estrogen receptors α and β are involved in depression, AD, multiple sclerosis, metabolic disorders, cardiovascular diseases, and various types of cancers; and compound 173 (Figure ), which inhibits the formation of β-amyloid aggregates and enhances fibril disaggregation and could serve as a potential treatment for Alzheimer’s disease …”