Polyhedral boranes and heteroboranes appear almost exclusively as neutral or anionic species, while the cationic ones are protonated at exoskeletal heteroatoms or they are instable. Here we report the reactivity of 10-vertex closo-dicarbadecaboranes with one or two equivalents of N-heterocyclic carbene to 10-vertex nido mono- and/or bis-carbene adducts, respectively. These complexes easily undergo a reaction with HCl to give cages of stable and water soluble 10-vertex nido-type cations with protonation in the form of a BHB bridge or 10-vertex closo-type cations containing one carbene ligand when originating from closo-1,10-dicarbadecaborane. The reaction of a 10-vertex nido mono-carbene adduct with phosphorus trichloride gives nido-11-vertex 2-phospha-7,8-dicarbaundecaborane, which undergoes an oxidation of the phosphorus atom to P = O, while the product of a bis-carbene adduct reaction is best described as a distorted C2B6H8 fragment bridged by the (BH)2PCl2+ moiety.

• Publication type
• Journal Article MeSH

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.

• Keywords
• Carbonic anhydrase IX, carborane, enzyme inhibitors, structure-activity relationship,
• MeSH
• Antigens, Neoplasm genetics   MeSH
• HEK293 Cells MeSH
• Hydrophobic and Hydrophilic Interactions MeSH
• Carbonic Anhydrase Inhibitors chemistry   pharmacology   MeSH
• Carbonic Anhydrase IX antagonists & inhibitors   genetics   MeSH
• Catalytic Domain MeSH
• Crystallography, X-Ray MeSH
• Humans MeSH
• Antineoplastic Agents chemistry   pharmacology   MeSH
• Drug Screening Assays, Antitumor MeSH
• Amino Acid Sequence MeSH
• Boron Compounds chemistry   MeSH
• Sulfonamides chemistry   pharmacology   MeSH
• Protein Binding MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Antigens, Neoplasm MeSH
• CA9 protein, human MeSH Browser
• decaborane MeSH Browser
• Carbonic Anhydrase Inhibitors MeSH
• Carbonic Anhydrase IX MeSH
• Antineoplastic Agents MeSH
• Boron Compounds MeSH
• Sulfonamides 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.

• Keywords
• borane, carborane, dicarbollide ion, nucleophilic substitution, oxonium atom,
• MeSH
• Boron chemistry   MeSH
• Boranes chemistry   MeSH
• Dioxanes chemistry   MeSH
• Nitrogen chemistry   MeSH
• Halogens chemistry   MeSH
• Temperature MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 1,4-dioxane MeSH Browser
• Boron MeSH
• Boranes MeSH
• Dioxanes MeSH
• Nitrogen MeSH
• Halogens MeSH

Human diseases are often diagnosed by determining levels of relevant enzymes and treated by enzyme inhibitors. We describe an assay suitable for both ultrasensitive enzyme quantification and quantitative inhibitor screening with unpurified enzymes. In the DNA-linked Inhibitor ANtibody Assay (DIANA), the target enzyme is captured by an immobilized antibody, probed with a small-molecule inhibitor attached to a reporter DNA and detected by quantitative PCR. We validate the approach using the putative cancer markers prostate-specific membrane antigen and carbonic anhydrase IX. We show that DIANA has a linear range of up to six logs and it selectively detects zeptomoles of targets in complex biological samples. DIANA's wide dynamic range permits determination of target enzyme inhibition constants using a single inhibitor concentration. DIANA also enables quantitative screening of small-molecule enzyme inhibitors using microliters of human blood serum containing picograms of target enzyme. DIANA's performance characteristics make it a superior tool for disease detection and drug discovery.

• MeSH
• Biological Assay * MeSH
• DNA * MeSH
• Enzymes metabolism   MeSH
• Enzyme Inhibitors pharmacology   MeSH
• Humans MeSH
• Drug Discovery * MeSH
• Reproducibility of Results MeSH
• Sensitivity and Specificity MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• DNA * MeSH
• Enzymes MeSH
• Enzyme Inhibitors MeSH

Carborane-based compounds are promising lead structures for development of inhibitors of carbonic anhydrases (CAs). Here, we report structural and computational analysis applicable to structure-based design of carborane compounds with selectivity toward the cancer-specific CAIX isoenzyme. We determined the crystal structure of CAII in complex with 1-methylenesulfamide-1,2-dicarba-closo-dodecaborane at 1.0 Å resolution and used this structure to model the 1-methylenesulfamide-1,2-dicarba-closo-dodecaborane interactions with CAIX. A virtual glycine scan revealed the contributions of individual residues to the energy of binding of 1-methylenesulfamide-1,2-dicarba-closo-dodecaborane to CAII and CAIX, respectively.

• MeSH
• Glycine chemistry   MeSH
• Carbonic Anhydrase Inhibitors chemistry   pharmacology   MeSH
• Carbonic Anhydrases chemistry   MeSH
• Catalytic Domain MeSH
• Crystallography, X-Ray MeSH
• Quantum Theory * MeSH
• Humans MeSH
• Models, Molecular * MeSH
• Boron Compounds chemistry   pharmacology   MeSH
• Substrate Specificity drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• dodecaborate MeSH Browser
• Glycine MeSH
• Carbonic Anhydrase Inhibitors MeSH
• Carbonic Anhydrases MeSH
• Boron Compounds MeSH