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
• HIV Protease Inhibitors chemistry   pharmacology   MeSH
• Cobalt chemistry   pharmacology   MeSH
• Humans MeSH
• Ligands MeSH
• Lipids chemistry   MeSH
• Molecular Structure MeSH
• Drug Discovery MeSH
• Organometallic Compounds chemistry   pharmacology   MeSH
• Solubility MeSH
• Serum Albumin chemistry   MeSH
• Boron Compounds chemistry   pharmacology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Two novel metallacarborane-based stationary phases for high performance liquid chromatography were synthesized and characterized utilizing linear solvation energy relationships concept. Interactions taking place between selected probes (45 analytes) and the stationary phases and the mobile phases consisting of a mixture of acetonitrile with buffer were described by the linear solvation energy relationship model in a broad range of acetonitrile/buffer ratios. The interaction properties of the metallacarborane phases were compared with plain silica, the starting material for the preparation of the metallacarborane phases, and with a typical silica-based reversed-phase sorbent. It was clearly demonstrated that the metallacarborane sorbents provide qualitatively and quantitatively different interactions with respect to both the plain silica and reversed-phase stationary phase. It was shown that these novel phases might have also a separation potential in the area of hydrophilic interaction liquid chromatography.

• MeSH
• Chromatography, Reverse-Phase instrumentation   methods   MeSH
• Hydrophobic and Hydrophilic Interactions MeSH
• Silicon Dioxide chemistry   MeSH
• Carbonates analysis   chemistry   MeSH
• Chromatography, High Pressure Liquid instrumentation   methods   MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

A new type of high performance liquid chromatography (HPLC) stationary phase was prepared, and its chromatographic properties were evaluated. The sorbent was composed of metallacarborane covalently bound to silica. Because of the chemical structure of the immobilized metallacarborane, the synthesized stationary phase was able to interact with nonpolar analytes via hydrophobic interactions. The chromatographic behavior of several low-molecular-weight hydrocarbons on the sorbent under typical reversed-phase conditions was compared with octadecyl-, sulfo phenyl- and aminopropyl-modified silica stationary phases. Moreover, as a consequence of the synthetic protocol employed, the immobilization of the metallacarborane led to the development of a zwitterionic chemically bonded phase, which demonstrated excellent resistance to "phase collapse" in a 100% aqueous environment. Finally, preliminary experiments indicated that the new stationary phase has the potential for utilization in hydrophilic interaction chromatography (HILIC) mode for the separation of polar compounds.

• MeSH
• Acetonitriles chemistry   MeSH
• Benzene Derivatives chemistry   MeSH
• Boranes chemistry   MeSH
• Chromatography, Reverse-Phase MeSH
• Hydrophobic and Hydrophilic Interactions MeSH
• Cobalt chemistry   MeSH
• Linear Models MeSH
• Silicon Dioxide chemistry   MeSH
• Spectrum Analysis, Raman MeSH
• Reproducibility of Results MeSH
• Chromatography, High Pressure Liquid instrumentation   methods   MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't 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
• Models, Chemical MeSH
• Cobalt chemistry   MeSH
• Humans MeSH
• Molecular Structure MeSH
• Organometallic Compounds chemical synthesis   pharmacology   MeSH
• Protein Isoforms MeSH
• Boron Compounds chemical synthesis   pharmacology   MeSH
• Nitric Oxide Synthase antagonists & inhibitors   metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural 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
• Antineoplastic Agents chemical synthesis   chemistry   pharmacology   MeSH
• Boranes chemistry   pharmacology   MeSH
• Cell Line MeSH
• Hep G2 Cells MeSH
• DNA, Neoplasm drug effects   MeSH
• Drug Screening Assays, Antitumor MeSH
• Humans MeSH
• Molecular Structure MeSH
• Naphthalimides chemistry   pharmacology   MeSH
• Organometallic Compounds chemical synthesis   chemistry   pharmacology   MeSH
• Oxidative Stress drug effects   MeSH
• Cell Proliferation drug effects   MeSH
• Binding Sites MeSH
• Dose-Response Relationship, Drug MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Deltahedral metallacarborane compounds have recently been discovered as potent, specific, stable, and nontoxic inhibitors of HIV-1 protease (PR), the major target for AIDS therapy. The 2.15 A-resolution X-ray structure has exhibited a nonsymmetrical binding of the parental compound [Co(3+)-(C2B9H11)2](-) (GB-18) into PR dimer and a symmetrical arrangement in the crystal of two PR dimer complexes into a tetramer. In order to explore structural and energetic details of the inhibitor binding, quantum mechanics coupled with molecular mechanics approach was utilized. Realizing the close positioning of anionic inhibitors in the active site cavity, the possibility of an exchange of structural water molecules Wat50 and Wat128 by Na+ counterions was studied. The energy profiles for the rotation of the GB-18 molecules along their longitudinal axes in complex with PR were calculated. The results show that two Na+ counterions are present in the active site cavity and provide energetically favorable and unfavorable positions for carbon atoms within the carborane cages. Eighty-one rotamer combinations of four molecules of GB-18 bound to PR out of 4 x 10(5) are predicted to be highly populated. These results lay ground for further calculations of interaction energies between GB-18 and amino acids of PR active site and will make it possible to interpret computationally the binding of similar metallacarborane molecules to PR as well as to resistant PR variants. Moreover, this computational tool will allow the design of new, more potent metallacarborane-based HIV-1 protease inhibitors.

• MeSH
• Financing, Organized MeSH
• HIV Protease chemistry   MeSH
• Catalytic Domain MeSH
• Crystallography, X-Ray MeSH
• Quantum Theory MeSH
• Ligands MeSH
• Molecular Structure MeSH
• Organometallic Compounds chemistry   MeSH
• Thermodynamics MeSH

HIV protease (PR) is a prime target for rational anti-HIV drug design. We have previously identified icosahedral metallacarboranes as a novel class of nonpeptidic protease inhibitors. Now we show that substituted metallacarboranes are potent and specific competitive inhibitors of drug-resistant HIV PRs prepared either by site-directed mutagenesis or cloned from HIV-positive patients. Molecular modeling explains the inhibition profile of metallacarboranes by their unconventional binding mode.

• MeSH
• Financing, Organized MeSH
• HIV-1 enzymology   drug effects   MeSH
• HIV Protease genetics   chemistry   metabolism   MeSH
• HIV Protease Inhibitors pharmacology   chemistry   MeSH
• Metals chemistry   MeSH
• Crystallography, X-Ray MeSH
• Models, Molecular MeSH
• Molecular Structure MeSH
• Mutation genetics   MeSH
• Boron Compounds pharmacology   chemistry   MeSH
• Drug Resistance, Viral drug effects   MeSH

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
• Amides chemistry   MeSH
• Biological Transport drug effects   MeSH
• Boranes chemistry   pharmacology   MeSH
• Doxorubicin metabolism   MeSH
• Carbonic Anhydrase Inhibitors chemistry   pharmacology   MeSH
• Carbonic Anhydrase IX chemistry   metabolism   MeSH
• Catalytic Domain MeSH
• Humans MeSH
• Models, Molecular MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Drug Design MeSH
• Drug Synergism MeSH
• Xenograft Model Antitumor Assays MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Metallacarboranes and their derivatives are the recently discovered inhibitors of HIV protease. The main goal of this work was to study the interaction of parent metallacarborane derivatives with cyclodextrins (CD) differing in the inner cavity size. This interaction can improve the drug solubility and its transport to the cells. For ?-, ß- and ?-CD, NMR titrations with sodium cobalt(III) bis(1,2-dicarbollide) were performed at various CD concentrations. It was found that the greatest change in the 1H NMR chemical shift is observed at position 3 of CD on the inner broader rim of the cone-shaped molecule of CD. For ?-CD, the NMR titration curves correspond to the 1:1 stoichiometry and to the stability constant ca. 900. For ß- CD, simultaneous formation of 1:1 and 2:1 complexes and higher stability constants at least by two orders of magnitude follow from the titration curves. For ?-CD, more than two types of complexes are present. It was shown for ß- CD that the increased temperature does not significantly influence the titration curves. The model, consisting of a high number of adjustable parameters, for the determination of stability constants of the complexes must be confirmed by independent analytical methods such as isothermal calorimetry and X-ray structure determination.

• MeSH
• Antiviral Agents MeSH
• Cyclodextrins chemical synthesis   chemistry   MeSH
• Research Support as Topic MeSH
• HIV Protease Inhibitors MeSH
• Magnetic Resonance Spectroscopy methods   MeSH
• Boron Compounds chemical synthesis   chemistry   MeSH
• Structure-Activity Relationship 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
• Electrons MeSH
• HIV-1 enzymology   drug effects   MeSH
• HIV Protease chemistry   metabolism   MeSH
• HIV Protease Inhibitors pharmacology   chemical synthesis   chemistry   metabolism   MeSH
• Cobalt chemistry   MeSH
• Crystallography, X-Ray MeSH
• Molecular Conformation MeSH
• Models, Molecular MeSH
• Drug Design MeSH
• Boron Compounds chemical synthesis   chemistry   pharmacology   metabolism   MeSH
• Carbon chemistry   MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH