dicarbollide
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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
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
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
Anionic boron cluster compounds have recently made their way into many areas including medicinal chemistry and sensors due to favorable physical-chemical properties and their various biological activity. Notwithstanding the inherent chirality of these compounds, the exploration of the properties and activity of individual enantiomers remains uncharted territory. The permanent delocalized negative charge enables the electrophoretic mobility of these compounds. Thus, chiral electrophoresis, characterized by minimal consumption of chemicals and a sample, emerges as a promising candidate for a reliable quality control tool. The primary attempts in aqueous electrolytes showed some difficulties related to the limited solubility of these analytes. This study meticulously investigates the electrophoretic behavior and chiral separation of anionic [7,8-nido-C2B9H11]- and cobalt bis(dicarbollide)(1-) derivatives using a methanolic non-aqueous electrolyte with numerous derivatives of cyclodextrins. Randomly substituted hydroxypropyl-β-, methyl-β-, and hydroxypropyl-γ-cyclodextrins were identified as the most effective chiral selectors. The chiral separations delineated herein surpass previously published results in capillary electrophoresis in terms of resolution, peak shape, and the number of theoretical plates. Furthermore, the application of (2-hydroxy-3-N,N,N-trimethylamino)propylated β-cyclodextrin in non-aqueous environment resulted in the chiral separation of seven recently synthesized amino cobalt bis(dicarbollide)(1-) derivatives; thereby, reinforcing the extensive applicability of the developed methodology for different structural types of anionic cobalt bis(dicarbollides)(1-). These results qualify non-aqueous electrophoresis as a valuable tool for the enantiomeric purity control of anionic boron cluster compounds with respect to their further use in various areas.
- 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
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.
