Organic amines are found to be abundant in natural living systems. They also constitute an inestimable family of building blocks available in drug design. Considering the man-made cluster [(1,2-C2B9H11)2-3,3'-Co(III)]- ion (1-) and its application as an emerging unconventional pharmacophore, the availability of the corresponding amines has been limited and those with amino groups attached directly to carbon atoms have remained unknown. This paper describes the synthesis of compounds containing one or two primary amino groups attached to the carbon atoms of the cobaltacarborane cage that are accessible via the reduction of newly synthesized azides or via the Curtius rearrangement of the corresponding acyl azide. This substitution represents the first members of the series of azides and primary amines with functional groups bound directly to the carbon atoms of the cage. As expected, the absence of the linker along with the presence of the bulky anionic polyhedral ion leads to a significant alteration of the chemical and physicochemical properties. On a broader series of amines of the ion 1- we have thus observed significant differences in the acidity of the amino groups, depending on whether these are attached to the carbon or boron atoms of the cage, or the C-substituted amines contain an aliphatic linker of variable length. The compounds are relevant for potential use as cobalt bis(dicarbollide) structural blocks in medicinal chemistry and material science. Our study includes single-crystal X-ray diffraction (XRD) structures of both amines and a discussion of their stereochemical and structural features.

• Publikační typ
• časopisecké články MeSH

The emergence of antibiotic resistance in opportunistic pathogens represents a huge problem, the solution for which may be a treatment with a combination of multiple antimicrobial agents. Sodium salt of cobalt bis-dicarbollide (COSAN.Na) is one of the very stable, low-toxic, amphiphilic boron-rich sandwich complex heteroboranes. This compound has a wide range of potential applications in the biological sciences due to its antitumor, anti-HIV-1, antimicrobial and antibiofilm activity. Our study confirmed the ability of COSAN.Na (in the concentration range 0.2-2.48 µg/mL) to enhance tetracycline, erythromycin, and vancomycin action towards Staphylococcus epidermidis planktonic growth with an additive or synergistic effect (e.g., the combination of 1.24 µg/mL COSAN.Na and 6.5 µg/mL TET). The effective inhibitory concentration of antibiotics was reduced up to tenfold most efficiently in the case of tetracycline (from 65 to 6.5 µg/mL). In addition, strong effect of COSAN.Na on disruption of the cell envelopes was determined using propidium iodide uptake measurement and further confirmed by transmission electron microscopy. The combination of amphiphilic COSAN.Na with antibiotics can therefore be considered a promising way to overcome antibiotic resistance in Gram-positive cocci.

• Klíčová slova
• Gram-positive bacterium, additive effect, antibiotics, antimicrobial activity, carborane, erythromycin, metallacarboranes, synergistic effect, tetracycline, vancomycin,
• Publikační typ
• časopisecké články MeSH

In this study we explore the effect on the electrochemical signals in aqueous buffers of the presence of hydrophilic alkylhydroxy and carboxy groups on the carbon atoms of cobalta bis(dicarbollide) ions. The oxygen-containing exo-skeletal substituents of cobalta bis(dicarbollide) ions belong to the perspective building blocks that are considered for bioconjugation. Carbon substitution provides wider versatility and applicability in terms of the flexibility of possible chemical pathways. However, until recently, the electrochemistry of compounds substituted only on boron atoms could be studied, due to the unavailability of carbon-substituted congeners. In the present study, electrochemistry in aqueous phosphate buffers is considered along with the dependence of electrochemical response on pH and concentration. The compounds used show electrochemical signals around -1.3 and +1.1 V of similar or slightly higher intensities than in the parent cobalta bis(dicarbollide) ion. The signals at positive electrochemical potential correspond to irreversible oxidation of the boron cage (the C2B9 building block) and at negative potential correspond to the reversible redox process of (CoIII/CoII) at the central atom. Although the first signal is typically sharp and its potential can be altered by a number of substituents, the second signal is complex and is composed of three overlapping peaks. This signal shows sigmoidal character at higher concentrations and may be used as a diagnostic tool for aggregation in solution. Surprisingly enough, the observed effects of the site of substitution (boron or carbon) and between individual groups on the electrochemical response were insignificant. Therefore, the substitutions would preserve promising properties of the parent cage for redox labelling, but would not allow for the further tuning of signal position in the electrochemical window.

• Klíčová slova
• cobalta bis(dicarbollide) ions, differential pulse voltammetry, glassy carbon electrode, metallacarborane,
• MeSH
• bor * chemie   MeSH
• elektrochemie MeSH
• hydrofobní a hydrofilní interakce MeSH
• uhlík * MeSH
• voda MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• bor * MeSH
• uhlík * MeSH
• voda MeSH

Platinum compounds remain the first-line drugs for the treatment of most lethal gynecological malignancies and ovarian cancers. Acquired platinum resistance remains a major challenge in gynecological oncology. Considering the unique physicochemical properties of the metallacarboranes modifier and the significant role of nucleoside derivatives as anticancer antimetabolites, we designed and synthesized a set of adenosine conjugates with metallacarboranes containing iron, cobalt, or chromium as semi-abiotic compounds that influence the cisplatin sensitivity of ovarian cancer cells. Adherent cultures of ovarian carcinoma cell lines and multicellular spheroids, ranging from sensitive to highly resistant including experimental cell lines "not responding" to platinum drugs were used. Iron-containing metallacarborane conjugates showed the best anticancer activity, especially against resistant cells. Compound modified at the C2' nucleoside position showed the best activity in resistant cancer cells and highly resistant cancer spheroids exposed to cisplatin, increasing cell cycle arrest, apoptosis or necrosis, and reactive oxygen species production. Moreover, it showed high cellular accumulation and did not induce cross-resistance to cisplatin, carboplatin, doxorubicin, paclitaxel, or gemcitabine in long-term cultures. The reference nido-carborane derivative (no metal ions) and unmodified nucleosides were not as effective. These findings indicate that metallacarborane modification of adenosine may sensitize ovarian cancer cells to cisplatin in combination treatment.

• Klíčová slova
• apoptosis, cancer spheroids, chemoresistance, cisplatin, metallacarboranes, nucleoside derivatives, ovarian cancer, reactive oxygen species,
• 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.

• Klíčová slova
• borane, carborane, dicarbollide ion, nucleophilic substitution, oxonium atom,
• MeSH
• bor chemie   MeSH
• borany chemie   MeSH
• dioxany chemie   MeSH
• dusík chemie   MeSH
• halogeny chemie   MeSH
• teplota MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 1,4-dioxane MeSH Prohlížeč
• bor MeSH
• borany MeSH
• dioxany MeSH
• dusík MeSH
• halogeny 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
• glycin chemie   MeSH
• inhibitory karboanhydras chemie   farmakologie   MeSH
• karboanhydrasy chemie   MeSH
• katalytická doména MeSH
• krystalografie rentgenová MeSH
• kvantová teorie * MeSH
• lidé MeSH
• molekulární modely * MeSH
• sloučeniny boru chemie   farmakologie   MeSH
• substrátová specifita účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• dodecaborate MeSH Prohlížeč
• glycin MeSH
• inhibitory karboanhydras MeSH
• karboanhydrasy MeSH
• sloučeniny boru MeSH

A small library of boron-cluster- and metallacarborane-cluster-based ligands was designed, prepared, and tested for isoform-selective activation or inhibition of the three nitric oxide synthase isoforms. On the basis of the concept of creating a hydrophobic analogue of a natural substrate, a stable and nontoxic basic boron cluster system, previously used for boron neutron capture therapy, was modified by the addition of positively charged moieties to its periphery, providing hydrophobic and nonclassical hydrogen bonding interactions with the protein. Several of these compounds show efficacy for inhibition of NO synthesis with differential effects on the various nitric oxide synthase isoforms.

• MeSH
• chemické modely MeSH
• kobalt chemie   MeSH
• lidé MeSH
• molekulární struktura MeSH
• organokovové sloučeniny chemická syntéza   farmakologie   MeSH
• protein - isoformy MeSH
• sloučeniny boru chemická syntéza   farmakologie   MeSH
• synthasa oxidu dusnatého antagonisté a inhibitory   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• kobalt MeSH
• organokovové sloučeniny MeSH
• protein - isoformy MeSH
• sloučeniny boru MeSH
• synthasa oxidu dusnatého MeSH

During the last few decades, the treatment of HIV-infected patients by highly active antiretroviral therapy, including protease inhibitors (PIs), has become standard. Here, we present results of analysis of a patient-derived, multiresistant HIV-1 CRF02_AG recombinant strain with a highly mutated protease (PR) coding sequence, where up to 19 coding mutations have accumulated in the PR. The results of biochemical analysis in vitro showed that the patient-derived PR is highly resistant to most of the currently used PIs and that it also exhibits very poor catalytic activity. Determination of the crystal structure revealed prominent changes in the flap elbow region and S1/S1' active site subsites. While viral loads in the patient were found to be high, the insertion of the patient-derived PR into a HIV-1 subtype B backbone resulted in reduction of infectivity by 3 orders of magnitude. Fitness compensation was not achieved by elevated polymerase (Pol) expression, but the introduction of patient-derived gag and pol sequences in a CRF02_AG backbone rescued viral infectivity to near wild-type (wt) levels. The mutations that accumulated in the vicinity of the processing sites spanning the p2/NC, NC/p1, and p6pol/PR proteins lead to much more efficient hydrolysis of corresponding peptides by patient-derived PR in comparison to the wt enzyme. This indicates a very efficient coevolution of enzyme and substrate maintaining high viral loads in vivo under constant drug pressure.

• MeSH
• buněčné linie MeSH
• genové produkty gag - virus lidské imunodeficience genetika   MeSH
• genové produkty pol - virus lidské imunodeficience genetika   MeSH
• geny gag MeSH
• geny pol MeSH
• HEK293 buňky MeSH
• HIV infekce farmakoterapie   virologie   MeSH
• HIV-1 genetika   izolace a purifikace   fyziologie   MeSH
• HIV-proteasa chemie   genetika   metabolismus   MeSH
• inhibitory HIV-proteasy terapeutické užití   MeSH
• krystalografie rentgenová MeSH
• lidé MeSH
• molekulární sekvence - údaje MeSH
• mutace MeSH
• peptidové fragmenty genetika   MeSH
• virová léková rezistence genetika   MeSH
• virová nálož MeSH
• vysoce aktivní antiretrovirová terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• gag protein p1, Human immunodeficiency virus MeSH Prohlížeč
• genové produkty gag - virus lidské imunodeficience MeSH
• genové produkty pol - virus lidské imunodeficience MeSH
• HIV-proteasa MeSH
• inhibitory HIV-proteasy MeSH
• p2 gag peptide, Human immunodeficiency virus 1 MeSH Prohlížeč
• peptidové fragmenty MeSH

Cross-metathesis between allylcarboranes and O-allylcyclodextrins was catalyzed by Hoveyda-Grubbs 2(nd) generation catalyst in toluene. The corresponding carboranyl-cyclodextrin conjugates were isolated in 15-25% yields.

• Klíčová slova
• carborane, catalysis, cross-metathesis, cyclodextrin, ruthenium,
• Publikační typ
• časopisecké články MeSH

The design, development and clinical success of HIV protease inhibitors represent one of the most remarkable achievements of molecular medicine. This review describes all nine currently available FDA-approved protease inhibitors, discusses their pharmacokinetic properties, off-target activities, side-effects, and resistance profiles. The compounds in the various stages of clinical development are also introduced, as well as alternative approaches, aiming at other functional domains of HIV PR. The potential of these novel compounds to open new way to the rational drug design of human viruses is critically assessed.

• Klíčová slova
• HAART, HIV protease, alternative inhibitors, pharmacokinetic boosting, protease dimerization, protease inhibitors, resistance development,
• Publikační typ
• časopisecké články MeSH