The continuous expansion of research in the field of stable carboranes and their wide potential in the drug design require carrying out fundamental studies regarding their chiral separations. Although supercritical fluid chromatography (SFC) is a viable technique for fast enantioseparations, no investigation concerning boron cluster compounds has been done yet. We aimed at the development of a straightforward method enabling chiral separations of racemic mixtures of anionic cluster carboranes and metallacarboranes that represent an analytical challenge. The fast gradient screening testing nine polysaccharide-based columns was used. The key parameters affecting the selectivity were the type of chiral selector, the type of alcohol, and the base in cosolvent. Moreover, the addition of acetonitrile or water to the cosolvent was identified as an effective tool for decreasing the analysis time while preserving the resolution. After the optimization, the chiral separations of 19 out of 20 selected compounds were achieved in less than 10 min. These results demonstrate the clear advantage of SFC over chiral separations using HPLC in terms of both analysis time and structural variety of successfully separated compounds.
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.
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.
- Publikační typ
- časopisecké články MeSH
The development of 1,8-naphthalimide derivatives as DNA-targeting anticancer agents is a rapidly growing area and has resulted in several derivatives entering into clinical trials. One of original recent developments is the use of boron clusters: carboranes and metallacarboranes in the design of pharmacologically active molecules. In this direction several naphthalimide-carborane and metallacarborane conjugates were synthesized in the present study. Their effect on a cancer cell line - cytotoxicity, type of cell death, cell cycle, and ROS production were investigated. The tested conjugates revealed different activities than the leading members of the naphthalimides family, namely mitonafide and pinafide. These derivatives could induce G0/G1 arrest and promote mainly apoptosis in HepG2 cell line. Our investigations demonstrated that the most promising molecule is N-{[2-(3,3'-commo-bis(1,2-dicarba-3-cobalta(III)-closo-dodecaborate-1-yl)ethyl]-1'-aminoethyl)}-1,8-naphthalimide] (17). It was shown that 17 exhibited cytotoxicity against HepG2 cells, activated cell apoptosis, and caused cell cycle arrest in HepG2 cells. Further investigations in HepG2 cells revealed that compound 17 can also induce ROS generation, particularly mitochondrial ROS (mtROS), which was also proved by increased 8-oxo-dG level in DNA. Additionally to biological assays the interaction of the new compounds with ct-DNA was studied by CD spectra and melting temperature, thus demonstrating that these compounds were rather weak classical DNA intercalators.
- MeSH
- antitumorózní látky chemická syntéza chemie farmakologie MeSH
- borany chemie farmakologie MeSH
- buněčné linie MeSH
- buňky Hep G2 MeSH
- DNA nádorová účinky léků MeSH
- léky antitumorózní - screeningové testy MeSH
- lidé MeSH
- molekulární struktura MeSH
- naftalimidy chemie farmakologie MeSH
- organokovové sloučeniny chemická syntéza chemie farmakologie MeSH
- oxidační stres účinky léků MeSH
- proliferace buněk účinky léků MeSH
- vazebná místa MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem 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.
- MeSH
- antigeny nádorové genetika MeSH
- antitumorózní látky chemie farmakologie MeSH
- HEK293 buňky MeSH
- hydrofobní a hydrofilní interakce MeSH
- inhibitory karboanhydras chemie farmakologie MeSH
- karboanhydrasa IX antagonisté a inhibitory genetika MeSH
- katalytická doména MeSH
- krystalografie rentgenová MeSH
- léky antitumorózní - screeningové testy MeSH
- lidé MeSH
- sekvence aminokyselin MeSH
- sloučeniny boru chemie MeSH
- sulfonamidy chemie farmakologie MeSH
- vazba proteinů MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
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.
- MeSH
- antigeny nádorové metabolismus MeSH
- antitumorózní látky chemická syntéza chemie farmakologie MeSH
- experimentální nádory farmakoterapie metabolismus MeSH
- inhibitory karboanhydras chemická syntéza chemie farmakologie MeSH
- karboanhydrasa IX antagonisté a inhibitory metabolismus MeSH
- kultivované buňky MeSH
- léky antitumorózní - screeningové testy MeSH
- lidé MeSH
- molekulární struktura MeSH
- myši inbrední BALB C MeSH
- myši SCID MeSH
- myši MeSH
- nádory prsu farmakoterapie metabolismus MeSH
- proliferace buněk účinky léků MeSH
- psi MeSH
- rekombinantní proteiny metabolismus MeSH
- sulfonamidy chemická syntéza chemie farmakologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- psi MeSH
- zvířata MeSH
- 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.
Carbonic anhydrase IX (CAIX) is a transmembrane enzyme that regulates pH in hypoxic tumors and promotes tumor cell survival. Its expression is associated with the occurrence of metastases and poor prognosis. Here, we present nine derivatives of the cobalt bis(dicarbollide)(1-) anion substituted at the boron or carbon sites by alkysulfamide group(s) as highly specific and selective inhibitors of CAIX. Interactions of these compounds with the active site of CAIX were explored on the atomic level using protein crystallography. Two selected derivatives display subnanomolar or picomolar inhibition constants and high selectivity for the tumor-specific CAIX over cytosolic isoform CAII. Both derivatives had a time-dependent effect on the growth of multicellular spheroids of HT-29 and HCT116 colorectal cancer cells, facilitated penetration and/or accumulation of doxorubicin into spheroids, and displayed low toxicity and showed promising pharmacokinetics and a significant inhibitory effect on tumor growth in syngenic breast 4T1 and colorectal HT-29 cancer xenotransplants.
- MeSH
- amidy chemie MeSH
- biologický transport účinky léků MeSH
- borany chemie farmakologie MeSH
- doxorubicin metabolismus MeSH
- inhibitory karboanhydras chemie farmakologie MeSH
- karboanhydrasa IX chemie metabolismus MeSH
- katalytická doména MeSH
- lidé MeSH
- molekulární modely MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- racionální návrh léčiv MeSH
- synergismus léků MeSH
- xenogenní modely - testy antitumorózní aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem 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
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
