cobalt bis(dicarbollide)
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In the field of medicinal chemistry, cobalt bis(dicarbollide) derivatives are promising therapeutic agents. The potential pharmaceutical utilization of metallacarboranes is complicated due to spontaneous self-assembling in water. This problem can be solved by using suitable deaggregating agent. We present here the comprehensive screen of substituted cobalt bis(dicarbollide) derivatives with cyclodextrin derivatives, classical surfactants and amphiphilic copolymers to find general biocompatible excipients. Preliminary results are obtained by using UV/Vis spectroscopy as the technique with the best ratio of applicable information to time and source dependence.
- MeSH
- kobalt analýza chemie MeSH
- lidé MeSH
- pomocné látky analýza chemie MeSH
- rozpustnost MeSH
- voda analýza chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
Cobalt bis(dicarbollide) derivatives are promising therapeutic agents however their utilization is complicated due to their low solubility and self-assembling in water. Earlier we have shown that their solubility can be increased by using of suitable biocompatible excipients--carriers of pharmaceutically active compounds. Expected mechanism of solubilization was disassembling of self-assemblies and complexation of unimers. Newly our results of time-dependent light scattering study correct this presumption. Poor solubility of all derivatives can be easily improved by using various excipients, however only heptakis(2,6-di-O-methyl)-β-cyclodextrin displays ability to disassemble self-assemblies of all derivatives and suppress their self-assembling. Surprisingly, the other excipients participate on formation of mixed assemblies of derivative/excipient complex or cover assemblies to make them more soluble without decreasing their size.
- MeSH
- biologická dostupnost MeSH
- hydrodynamika MeSH
- kobalt chemie MeSH
- molekulární konformace MeSH
- molekulární modely MeSH
- organokovové sloučeniny chemie farmakokinetika MeSH
- radiační rozptyl MeSH
- rozpustnost MeSH
- světlo MeSH
- voda chemie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Tetraphenylporphyrin conjugates with one (PB1) and four (PB4) cobalt(III) bis(1,2-dicarbollide) substituents were synthesized and the physicochemical and photophysical properties as well as inhibition of HIV-1 protease were described. In methanol, both PB1 and PB4 were monomeric producing the triplet states and singlet oxygen after excitation. The triplet states of PB4 were quickly protonated. Porphyrins exhibited a small decrease of the quantum yields of the singlet oxygen formation (17% for PB4 and 13% for PB1) as compared with 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrin. On the contrary, no singlet oxygen was detected in aqueous solutions because of strong aggregation. Light scattering and atomic force microscopy (AFM) measurements documented that the behavior of aggregates in aqueous solutions is fairly complex and depends on pH, concentration, and aging. The aggregation started from spherical particles in neutral solutions. In acidic solutions, extended aggregation occurred because of slow protonation of the porphyrin pyrrole nitrogen atoms. Both PB1 and PB4 are new representatives of nonpeptide HIV-1 protease inhibitors. Their activity increased with the increasing number of the cobalt(III) bis(1,2-dicarbollide) substituents and was characterized with the IC50 values of 290+/-44 nM for PB1 and 77+/-13 nM for PB4.
- MeSH
- financování organizované MeSH
- HIV-proteasa metabolismus MeSH
- inhibiční koncentrace 50 MeSH
- inhibitory HIV-proteasy farmakologie chemie MeSH
- kyslík chemie MeSH
- mikroskopie atomárních sil MeSH
- molekulární modely MeSH
- molekulární struktura MeSH
- organokovové sloučeniny chemie MeSH
- porfyriny farmakologie chemie MeSH
- sloučeniny boru chemie MeSH
- substrátová specifita 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.
- Publikační typ
- časopisecké články MeSH
HIV protease (HIV PR) is a primary target for anti-HIV drug design. We have previously identified and characterized substituted metallacarboranes as a new class of HIV protease inhibitors. In a structure-guided drug design effort, we connected the two cobalt bis(dicarbollide) clusters with a linker to substituted ammonium group and obtained a set of compounds based on a lead formula [H(2)N-(8-(C(2)H(4)O)(2)-1,2-C(2)B(9)H(10))(1',2'-C(2)B(9)H(11))-3,3'-Co)(2)]Na. We explored inhibition properties of these compounds with various substitutions, determined the HIV PR:inhibitor crystal structure, and computationally explored the conformational space of the linker. Our results prove the capacity of linker-substituted dual-cage cobalt bis(dicarbollides) as lead compounds for design of more potent inhibitors of HIV PR.
- MeSH
- elektrony MeSH
- HIV-1 enzymologie účinky léků MeSH
- HIV-proteasa chemie metabolismus MeSH
- inhibitory HIV-proteasy farmakologie chemická syntéza chemie metabolismus MeSH
- kobalt chemie MeSH
- krystalografie rentgenová MeSH
- molekulární konformace MeSH
- molekulární modely MeSH
- racionální návrh léčiv MeSH
- sloučeniny boru chemická syntéza chemie farmakologie metabolismus MeSH
- uhlík chemie MeSH
- Publikační typ
- práce podpořená grantem MeSH
Metallacarborane moieties have been identified as promising pharmacophores. The pharmaceutical use of such compounds is, however, complicated by their low solubility and tendency to self-assemble in aqueous solution. In this work, we estimated the solubilities of a vast series of metallacarboranes [cobalt bis(dicarbollide) derivatives] in pure water, saline, and saline with human serum albumin as a model of blood plasma. In addition, we determined the octanol-water partition coefficients (Pow) as a lipophilicity descriptor. Pow weakly correlates with the water solubility of metallacarboranes, whereas the ability of HSA to increase the solubility of metallacarboranes correlates well with their Pow values. Because metallacarboranes are known inhibitors of HIV protease, the possible correlation between Pow and the ability to inhibit HIV protease was investigated. Results from this study indicate that interaction of metallacarborane inhibitors with HIV protease is driven by specific binding rather than by promiscuous lipophilic interactions. The most promising candidates for further drug development were identified by ligand lipophilicity efficiency analysis.
- MeSH
- inhibitory HIV-proteasy chemie farmakologie MeSH
- kobalt chemie farmakologie MeSH
- lidé MeSH
- ligandy MeSH
- lipidy chemie MeSH
- molekulární struktura MeSH
- objevování léků MeSH
- organokovové sloučeniny chemie farmakologie MeSH
- rozpustnost MeSH
- sérový albumin chemie MeSH
- sloučeniny boru chemie farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
HIV protease (PR) represents a prime target for rational drug design, and protease inhibitors (PI) are powerful antiviral drugs. Most of the current PIs are pseudopeptide compounds with limited bioavailability and stability, and their use is compromised by high costs, side effects, and development of resistant strains. In our search for novel PI structures, we have identified a group of inorganic compounds, icosahedral metallacarboranes, as candidates for a novel class of nonpeptidic PIs. Here, we report the potent, specific, and selective competitive inhibition of HIV PR by substituted metallacarboranes. The most active compound, sodium hydrogen butylimino bis-8,8-[5-(3-oxa-pentoxy)-3-cobalt bis(1,2-dicarbollide)]di-ate, exhibited a K(i) value of 2.2 nM and a submicromolar EC(50) in antiviral tests, showed no toxicity in tissue culture, weakly inhibited human cathepsin D and pepsin, and was inactive against trypsin, papain, and amylase. The structure of the parent cobalt bis(1,2-dicarbollide) in complex with HIV PR was determined at 2.15 A resolution by protein crystallography and represents the first carborane-protein complex structure determined. It shows the following mode of PR inhibition: two molecules of the parent compound bind to the hydrophobic pockets in the flap-proximal region of the S3 and S3' subsites of PR. We suggest, therefore, that these compounds block flap closure in addition to filling the corresponding binding pockets as conventional PIs. This type of binding and inhibition, chemical and biological stability, low toxicity, and the possibility to introduce various modifications make boron clusters attractive pharmacophores for potent and specific enzyme inhibition.
- MeSH
- aspartátové endopeptidasy chemie MeSH
- borany farmakologie chemická syntéza chemie MeSH
- financování organizované MeSH
- HIV-proteasa chemie MeSH
- inhibitory HIV-proteasy farmakologie chemická syntéza chemie MeSH
- krystalografie rentgenová MeSH
- kvantitativní vztahy mezi strukturou a aktivitou MeSH
- racionální návrh léčiv MeSH
Boron cluster compounds are extensively studied due to their possible use in medicinal chemistry, mainly in the boron neutron capture anticancer therapy and as new innovative pharmacophores. Concerning this research, the chiral separations of exceptionally stable anionic 7,8-dicarba-nido-undecaborate(1-) and metal bis(dicarbollide(1-) derivatives with asymmetric substitutions remain the unsolved challenge of the chiral chromatography nowadays. Although the successful enantioseparation of some anionic 7,8-dicarba-nido-undecaborate(1-) ion derivatives were achieved in CZE with native β-cyclodextrins, it has not been observed with HPLC, yet. This study aimed to systematically investigate the enantioseparation of selected compounds in HPLC using native β-cyclodextrin and brominated β-cyclodextrin. The findings revealed positively charged strong adsorption sites on a stationary phase, identified as the cationic metal impurities in the silica-gel backbone. All the anionic species under the study were at least partially enantioseparated when a chelating agent blocked these cationic sites. Consequently, the first-ever HPLC enantioseparations of the 7,8-dicarba-nido-undecaborates(1-) were achieved. The brominated β-cyclodextrin seemed to be a better chiral selector for separation of these species, whereas the native β-cyclodextrin separated the anionic cobalt bis(dicarbollide(1-). The results of this study bring new information concerning the chiral separation of anionic boron clusters and might be used in the chiral method development process on other chiral selectors. Furthermore, the possibility of chiral separation of these species could influence the ongoing research areas of anionic boron clusters.
