Human carbonic anhydrase IX (CA IX), a protein specifically expressed on the surface of solid tumour cells, represents a validated target both for anticancer therapy and diagnostics. We recently identified sulfonamide dicarbaboranes as promising inhibitors of CA IX with favourable activities both in vitro and in vivo. To explain their selectivity and potency, we performed detailed X-ray structural analysis of their interactions within the active sites of CA IX and CA II. Series of compounds bearing various aliphatic linkers between the dicarbaborane cluster and sulfonamide group were examined. Preferential binding towards the hydrophobic part of the active site cavity was observed. Selectivity towards CA IX lies in the shape complementarity of the dicarbaborane cluster with a specific CA IX hydrophobic patch containing V131 residue. The bulky side chain of F131 residue in CA II alters the shape of the catalytic cavity, disrupting favourable interactions of the spherical dicarbaborane cluster.
- MeSH
- antigeny nádorové genetika MeSH
- antitumorózní látky chemie farmakologie MeSH
- HEK293 buňky MeSH
- hydrofobní a hydrofilní interakce MeSH
- inhibitory karboanhydras chemie farmakologie MeSH
- karboanhydrasa IX antagonisté a inhibitory genetika MeSH
- katalytická doména MeSH
- krystalografie rentgenová MeSH
- léky antitumorózní - screeningové testy MeSH
- lidé MeSH
- sekvence aminokyselin MeSH
- sloučeniny boru chemie MeSH
- sulfonamidy chemie farmakologie MeSH
- vazba proteinů MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Ring cleavage of cyclic ether substituents attached to a boron cage via an oxonium oxygen atom are amongst the most versatile methods for conjoining boron closo-cages with organic functional groups. Here we focus on much less tackled chemistry of the 11-vertex zwitterionic compound [10-(O-(CH2-CH2)2O)-nido-7,8-C2B9H11] (1), which is the only known representative of cyclic ether substitution at nido-cages, and explore the scope for the use of this zwitterion 1 in reactions with various types of nucleophiles including bifunctional ones. Most of the nitrogen, oxygen, halogen, and sulphur nucleophiles studied react via nucleophilic substitution at the C1 atom of the dioxane ring, followed by its cleavage that produces six atom chain between the cage and the respective organic moiety. We also report the differences in reactivity of this nido-cage system with the simplest oxygen nucleophile, i.e., OH-. With compound 1, reaction proceeds in two possible directions, either via typical ring cleavage, or by replacement of the whole dioxane ring with -OH at higher temperatures. Furthermore, an easy deprotonation of the hydrogen bridge in 1 was observed that proceeds even in diluted aqueous KOH. We believe this knowledge can be further applied in the design of functional molecules, materials, and drugs.
We report the first amperometric method for the simultaneous determination of tert-butylhydroquinone (tBHQ), propyl gallate (PG), and butylated hydroxyanisole (BHA) using flow injection analysis coupled to multiple-pulse amperometry. A sequence of potential pulses was selected in order to detect tBHQ, PG, and BHA separately in a single injection step at a glassy carbon electrode without the need of a preliminary separation. A mixture of methanol and 0.040M Britton-Robinson buffer was used both as a carrier solution and for dilution of analyzed solutions before injection. The method is precise (RSD < 5%, n = 10), fast (a frequency of 140 injections h-1), provides sufficiently low quantification limits (2.51, 1.45, and 0.85μmolL-1 for tBHQ, PG, and BHA, respectively) and can be easily applied without high demands on instrumentation. As a practical application, the determination of these antioxidants contained in commercial chewing gum samples was carried out by applying a simple extraction procedure.
