Size and Polarizability of Boron Cluster Carriers Modulate Chaotropic Membrane Transport.

Perhalogenated closo-borates represent a new class of membrane carriers. They owe this activity to their chaotropicity, which enables the transport of hydrophilic molecules across model membranes and into living cells. The transport efficiency of this new class of cluster carriers depends on a careful balance between their affinity to membranes and cargo, which varies with chaotropicity. However, the structure-activity parameters that define chaotropic transport remain to be elucidated. Here, we have studied the modulation of chaotropic transport by decoupling the halogen composition from the boron core size. The binding affinity between perhalogenated decaborate and dodecaborate clusters carriers was quantified with different hydrophilic model cargos, namely a neutral and a cationic peptide, phalloidin and (KLAKLAK)2. The transport efficiency, membrane-lytic properties, and cellular toxicity, as obtained from different vesicle and cell assays, increased with the size and polarizability of the clusters. These results validate the chaotropic effect as the driving force behind the membrane transport propensity of boron clusters. This work advances our understanding of the structural features of boron cluster carriers and establishes the first set of rational design principles for chaotropic membrane transporters.

Structurally rigidified cobalt bis(dicarbollide) derivatives, a chiral platform for labelling of biomolecules and new materials.

We report the difunctional modification of an anionic cobalta bis(dicarbollide)(1-) cluster with a B(8,8')-oxygen bridging unit that provides structural rigidity and an organic alkylazide substituent(s) on the carbon atoms of the metallacarborane cage. These ions present a good binding motif for incorporation into organic molecules using Huisgen-Sharpless (2+3) cycloaddition reactions. In addition, the compounds are chiral, as verified by separation of enantiomers using HPLC on chiral stationary phases (CSPs) and provide a high electrochemical peak in the window located outside of typical signals of biomolecules.

Inhibitors of CA IX Enzyme Based on Polyhedral Boron Compounds.

This review describes recent progress in the design and development of inhibitors of human carbonic anhydrase IX (CA IX) based on space-filling carborane and cobalt bis(dicarbollide) clusters. CA IX enzyme is known to play a crucial role in cancer cell proliferation and metastases. The new class of potent and selective CA IX inhibitors combines the structural motif of a bulky inorganic cluster with an alkylsulfamido or alkylsulfonamido anchor group for Zn2+ ion in the enzyme active site. Detailed structure-activity relationship (SAR) studies of a large series containing 50 compounds uncovered structural features of the cluster-containing inhibitors that are important for efficient and selective inhibition of CA IX activity. Preclinical evaluation of selected compounds revealed low toxicity, favorable pharmacokinetics and ability to reduce tumor growth. Cluster-containing inhibitors of CA IX can thus be considered as promising candidates for drug development and/or for combination therapy in boron neutron capture therapy (BNCT).

Cobalt Bis(dicarbollide) Alkylsulfonamides: Potent and Highly Selective Inhibitors of Tumor Specific Carbonic Anhydrase IX.

Carbonic anhydrase IX (CAIX) is an enzyme expressed on the surface of cells in hypoxic tumors. It plays a role in regulation of tumor pH and promotes thus tumor cell survival and occurrence of metastases. Here, derivatives of the cobalt bis(dicarbollide)(1-) anion are reported that are based on substitution at the carbon sites of the polyhedra by two alkylsulfonamide groups differing in the length of the aliphatic connector (from C1 to C4, n=1-4), which were prepared by cobalt insertion into the 7-sulfonamidoalkyl-7,8-dicarba-nido-undecaborate ions. Pure meso- and rac-diastereoisomeric forms were isolated. The series is complemented with monosubstituted species (n=2). Synthesis by a direct method furnished similar derivatives (n=2, 3), which are chlorinated at the B(8,8') boron sites. All compounds inhibited CAIX with subnanomolar inhibition constants and showed high selectivity for CAIX. The best inhibitory properties were observed for the compound with n= 3 and two substituents present in rac-arrangement with Ki =20 pM and a selectivity index of 668. X-ray crystallography was used to study interactions of these compounds with the active site of CAIX on the structural level.

Cobalt Bis(dicarbollide) Alkylsulfonamides: Potent and Highly Selective Inhibitors of Tumor Specific Carbonic Anhydrase IX.

Invited for this month's cover is a collaboration from three institutes from the Czech Academy of Sciences: Institute of Inorganic Chemistry, Institute of Organic Chemistry and Biochemistry, and Institute of Molecular Genetics, and the University of Pardubice. The cover picture shows a family of potent and selective CA IX inhibitors that combines the structural motif of a bulky inorganic cobalt bis(dicarbollide) polyhedral ion with a propylsulfonamido anchor group. Read the full text of the article at 10.1002/cplu.202000574.

Tetrazole Ring Substitution at Carbon and Boron Sites of the Cobalt Bis(dicarbollide) Ion Available via Dipolar Cycloadditions.

Herein, we describe the synthesis of two families of compounds accessible from [3 + 2] cycloaddition reactions of known B8-substituted isonitrilium and new C1-alkylnitrile and C(1,1')-dialkylnitrile derivatives of the [(1,2-C2B9H11)2-3,3'-Co(III)]- ion with an azide ion that produce a tetrazole ring substitution at the cobaltacarborane cage. In addition, we outline the important differences in reactivity observed for the two types [B-isonitrilium/C-(alkyl)nitrile] of cobaltacarborane derivatives. The first family of compounds described corresponds to C5-atom-boronated tetrazole rings, with the five-membered moiety in the second type being doubly substituted at the N1 and C5 positions. This substitution opens cobaltacarborane chemistry to a new type of functional group at the cage of potential utility as structural blocks for use in medicinal chemistry or materials science. Our study includes single-crystal X-ray structures of the starting nitriles and both families of tetrazole derivatives, and the structural features that arise from the substitutions are discussed.

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.

Carbonic anhydrase IX (CA IX), a tumor-associated metalloenzyme, represents a validated target for cancer therapy and diagnostics. Herein, we report the inhibition properties of isomeric families of sulfonamidopropyl-dicarba-closo-dodecaboranes group(s) prepared using a new direct five-step synthesis from the corresponding parent cages. The protocol offers a reliable solution for synthesis of singly and doubly substituted dicarba-closo-dodecaboranes with a different geometric position of carbon atoms. The closo-compounds from the ortho- and meta-series were then degraded to corresponding 11-vertex dicarba-nido-undecaborate(1-) anions. All compounds show in vitro enzymatic activity against CA IX in the low nanomolar or subnanomolar range. This is accompanied by clear isomer dependence of the inhibition constant (Ki ) and selectivity towards CA IX. Decreasing trends in Ki and selectivity index (SI ) values are observed with increasing separation of the cage carbon atoms. Interactions of compounds with the active sites of CA IX were explored with X-ray crystallography, and eight high-resolution crystal structures uncovered the structural basis of inhibition potency and selectivity.

Sulfonamido carboranes as highly selective inhibitors of cancer-specific carbonic anhydrase IX.

Carbonic anhydrase IX (CA IX) is a transmembrane enzyme overexpressed in hypoxic tumors, where it plays an important role in tumor progression. Specific CA IX inhibitors potentially could serve as anti-cancer drugs. We designed a series of sulfonamide inhibitors containing carborane clusters based on prior structural knowledge of carborane binding into the enzyme active site. Two types of carborane clusters, 12-vertex dicarba-closo-dodecaborane and 11-vertex 7,8-dicarba-nido-undecaborate (dicarbollide), were connected to a sulfonamide moiety via aliphatic linkers of varying lengths (1-4 carbon atoms; n = 1-4). In vitro testing of CA inhibitory potencies revealed that the optimal linker length for selective inhibition of CA IX was n = 3. A 1-sulfamidopropyl-1,2-dicarba-closo-dodecaborane (3) emerged as the strongest CA IX inhibitor from this series, with a Ki value of 0.5 nM and roughly 1230-fold selectivity towards CA IX over CA II. X-ray studies of 3 yielded structural insights into their binding modes within the CA IX active site. Compound 3 exhibited moderate cytotoxicity against cancer cell lines and primary cell lines in 2D cultures. Cytotoxicity towards multicellular spheroids was also observed. Moreover, 3 significantly lowered the amount of CA IX on the cell surface both in 2D cultures and spheroids and facilitated penetration of doxorubicin. Although 3 had only a moderate effect on tumor size in mice, we observed favorable ADME properties and pharmacokinetics in mice, and preferential presence in brain over serum.

Focus on Chemistry of the 10-Dioxane-nido-7,8-dicarba-undecahydrido Undecaborate Zwitterion; Exceptionally Easy Abstraction of Hydrogen Bridge and Double-Action Pathways Observed in Ring Cleavage Reactions with OH- as Nucleophile.

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.

Versatile, one-pot introduction of nonahalogenated 2-ammonio-decaborate ions as boron cluster scaffolds into organic molecules; host-guest complexation with γ-cyclodextrin.

We report the modification of the 2-ammonio group at halogenated decaborate ions with 2,3-epoxypropane, the product of which reacts readily with nucleophiles to form previously inaccessible coupling of polyhedra with organic molecules and materials. We demonstrate that these ions present a good binding motif in supramolecular chemistry.