Tetraphenylporphyrin-cobalt(III) bis(1,2-dicarbollide) conjugates: from the solution characteristics to inhibition of HIV protease

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.     

Aggregation behavior of nucleoside-boron cluster conjugates in aqueous solutions

We report the first evidence that boron-containing nucleoside conjugates have a tendency to associate in water solutions. The size, charge, and exoskeletal pattern of the boron cluster can strongly influence the aggregation. The aggregation of nucleosides with attached boron clusters was observed using light scattering and atomic force microscopy techniques. Although the species containing either the bulky amphiphilic [3-cobalt(III) bis(1,2-dicarbollide)]- anion or the electroneutral dicarba-closo-dodecaboranyl moiety tend to form stable nanoparticles in aqueous solutions, the compounds bearing the smaller, negatively charged dicarba-nido-undecaboranyl moiety as well as the unmodified nucleosides do not aggregate. The light scattering measurements also showed that the aggregated species can interact with nonionic surfactant Triton X-100 in solution. The partition coefficients P in the water-octanol system correlate fairly well with the aggregation tendency observed by light scattering measurements. This finding allows us to predict the association behavior of boron-cluster-containing nucleosides on a qualitative level. The observed phenomenon can contribute to a better understanding of biological properties of boronated nucleosides and the design of boronated nucleoside-based drugs such as boron carriers for boron neutron capture therapy of tumors (BNCT) and antiviral agents.     

Synthesis of 1,4-disubstituted 1,2,3-triazoles based on cobalt bis(1,2-dicarbollide)

An approach to the synthesis of new 1,4-disubstituted 1,2,3-triazoles, in which one or both substituents contain the cobalt bis(1,2-dicarbollide) fragment, was suggested based on the 1,3-dipolar cycloaddition of azides to alkynes catalyzed by copper(I) compounds. The reaction of cobalt bis(1,2-dicarbollide) azido derivatives with different terminal acetylenes led to 1,2,3-triazoles with the [((CH₂)₂X(CH₂)₂O-C₂B₉H₁₀)Co(C₂B₉H₁₁)] (X = O or CH₂) substituent at position 1 and the organic substituent at position 4. The [3+2] cycloaddition reaction of cobalt bis(1,2-dicarbollide) alkynyl derivatives with methyl azidoacetate furnished isomeric 1,4-disubstituted 1,2,3-triazoles with the metallacarborane fragment at position 4. 1,2,3-Triazole with metallacarborane substituents at positions 1 and 4 containing 36 boron atoms was also synthesized.     

Studies on nucleation from solution of some analytically important metal chelates

The combination of precipitation from homogeneous solution and Vonnegut's droplet technique is employed in the study of nucleation from solution of bis(1,2-cyclohexanedionedioxunato)Ni(II), bis(1,2-cycloheptanedionedioximato)Ni(II), bis(1,2-cyclohexanedionedioximato)Pd(II) and bis(1,2-cycloheptanedionedioximato)-Pd(II). Values of the kinetic constant, surface energy, critical radius and the number of molecules per critical nucleus are calculated and discussed in terms of the limitations of the classical theory of nucleation when applied to crystal nucleation from aqueous solutions of electrolytes.     

New B-substituted derivatives of m-carborane, p-carborane, and cobalt bis(1,2-dicarbollide) anion

The Pd-catalyzed cross-coupling reactions of B-I bond in m- and p-carboranes and cobalt bis(1,2-dicarbollide) anion with organomagnesium and organozinc compounds were studied. Carboranyl derivatives of furan, thiophene, indole, pyridine and quinoline were synthesized. 2-Pyridylethynyl and 3-quinolylethynyl derivatives of p-carborane were prepared by Pd-catalyzed cross-coupling reactions using corresponding alkynes or their magnesium derivatives.     

Molecular recognition studies on supramolecular systems. 32. Molecular recognition of dyes by organoselenium-bridged bis(beta-cyclodextrin)s.

A series of novel bis(beta-cyclodextrin)s tethered with organoselenium linkers, i.e., 6,6'-(o-phenylene-diseleno)-bridged bis(beta-cyclodextrin) (2), 6,6'-[2,2'-diselenobis(benzoyloxy)]-bridged bis(beta-cyclodextrin) (3), and 6,6'-[2,2'-diselenobis[2-(benzoylamino)ethylamino]]-bridged bis(beta-cyclodextrin) (4), were synthesized from beta-cyclodextrin (1). The inclusion complexation behavior of 1-4 with some dyes, such as 8-anilinonaphthalenesulfonate (ANS), Brilliant Green, Crystal Violet, Tropaeolin OO, Auramine O, and Methyl Orange, was investigated in aqueous phosphate buffer solution (pH 7.20) at 25 degrees C by UV-vis, fluorescence, and circular dichroism spectrometry, as well as fluorescence lifetime measurements. The complex stability constants (Ks) and Gibbs free energy changes (delta Go) for the stoichiometric 1:1 inclusion complexation of 1-4 with the dyes were obtained by the spectrophotometric or spectropolarimetric titrations. The bis(beta-cyclodextrin)s 2-4 showed much higher affinities toward these guest dyes than native beta-cyclodextrin 1 with fairly good molecular selectivities. The cooperative binding abilities of these bis(beta-cyclodextrin)s are discussed from the viewpoints of size/shape-fit interaction, induced-fit concept, and multiple recognition mechanism.     

Comparative study of pertechnetate reduction by thiourea using spectrophotometric,solvent extraction and ion-exchange methods

The results of a comparative study of pertechnetate reduction by thiourea in mineral acid (HCl, HNO₃, HClO₄, H₂SO₄) media using spectrophotometric, solvent extraction and ion-exchange chromatographic methods are presented. Changes of spectral characteristics of redox systems and distribution characteristics of reduced technetium (cationic) forms on extraction with bis(1,2-dicarbollide)cobaltic acid and on ion exchange on Dowex 50WX8 were established as a function of time and either aqueous or organic phase composition. Thiourea was tested as a reagent for reduction back-extraction of technetium from organic phases containing the amines Aliquat 336 and trilaurylmethylammonium as convenient extraction reagents for pertechnetate.     

Synthesis of new charge-compensated cobalt bis(1,2-dicarbollide) derivatives

New hetero-substituted charge-compensated cobalt bis(1,2-dicarbollide) derivatives were synthesized by the reaction of 8,8′-μ-iodo-3-commo-3-cobalta-bis(1,2-dicarba-closo-dodecaborane) [8,8′-μ-I-3,3′-Co(1,2-C₂B₉H₁₀)₂] with 1,4-thioxane, pyridine N-oxide, and tetrahydropyran. X-ray diffraction studies showed that the 8′-iodo-8-(pyridiniumoxy)eucosahydro-1,1′,2,2′-tetracarba-3-commo-cobalta-closo-tricosaborate molecule has the gauche-conformation (the substituents are turned with respect to each other by 69.2°). The positive charge is predominantly localized on the N(Py) atom.     

Studies on thermoplastic polyurethanes based on new diphenylethane-derivative diols. I. Synthesis and characterization of nonsegmented polyurethanes from HDI and MDI

New aliphatic–aromatic α,ω-diols containing sulfur in aliphatic chain: 4,4′-(ethane-1,2-diyl)bis(benzenethioethanol) [EBTE], 4,4′-(ethane-1,2-diyl)bis(benzenethiopropanol) [EBTP], 4,4′-(ethane-1,2-diyl)bis(benzenethiohexanol) [EBTH], 4,4′-(ethane-1,2-diyl)bis(benzenethiodecanol) [EBTD], and 4,4′-(ethane-1,2-diyl)bis(benzenethioundecanol) [EBTU] were prepared by the condensation reaction of 4,4′-(ethane-1,2-diyl)bis(benzenethiol) with suitable halogen alcohols in aqueous sodium hydroxide solution. Thermoplastic nonsegmented polyurethanes containing sulfide linkages were synthesized from these diols, and hexane-1,6-diyl diisocyanate (HDI) or 4,4′-methylenediphenyl diisocyanate (MDI) by solution and melt polymerization. The reaction was carried out at 1:1 or 1.05:1 molar ratios of isocyanate and hydroxy groups in the presence of dibutyltin dilaurate as a catalyst.The structures of the diols were determined by using elemental analysis, FTIR and ¹H NMR spectroscopy, and X-ray diffraction analysis. Thermal characteristics of the diols were determined by using differential scanning calorimetry (DSC). The polymers were studied to describe their structures and physicochemical, thermal (by DSC and thermogravimetric analysis) and tensile properties as well as Shore A/D hardness.All the polyurethanes possessed partially crystalline structures. Their melting temperatures were in the range of 94–179 °C (HDI) and 105–207 °C (MDI). The MDI-based polyurethanes showed higher tensile strengths, up to ∼50 MPa.     

Synthesis,cytotoxicity and antiviral activity studies of the conjugates of cobalt bis(1,2-dicarbollide)(-I) with 5-ethynyl-2′-deoxyuridine and its cyclic derivatives

A series of novel conjugates of cobalt bis(1,2-dicarbollide)(-I) with 5-ethynyl-2′-deoxyuridine and its cyclic derivatives were synthesized. Conjugates with 5-ethynyl-2-deoxyuridine were prepared by the direct Sonogashira coupling of a series of cobalt bis(1,2-dicarbollide)(-I) terminal alkynes and 5-iodo-2′-deoxyuridine. Their furo[2,3-d]pyrimidin-2(3H)-one isomers were obtained either by intermolecular cyclization of the above conjugates or by Sonogashira coupling using Pd/C as a catalyst. Action of ammonia on these furo[2,3-d]pyrimidin-2(3H)-one conjugates resulted in pyrrolo[2,3-d]pyrimidin-2(3H)-one conjugates. Most of the designed compounds have shown low cytotoxicity in several cell lines. Some 5-ethynyl-2-deoxyuridine and furo[2,3-d]pyrimidin-2(3H)-one conjugates have also presented antiviral activity.     

Phenyl-(3)-1,2-dicarbollylmercury anion

Conclusions The phenyl-(3)-1,2-dicarbollylmercury anion is formed by the action of phenylmercury chloride on disodium (3)-1,2-dicarbollide.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 11, pp. 2634–2636, November, 1970.     

The structure of aqueous pentaoxo silicon complexes with cis-1,2-dihydroxycyclopentane and furanoidic vicinal cis-diols

Addition of cis-1,2-dihydroxycyclopentane to aqueous alkaline silicate solutions results in the spontaneous formation of three organosilicate species, each with a 2:1 ligand to Si ratio and a pentacoordinated silicon centre. By using a mixture of both cis-1,2-dihydroxycyclopentane and 1,4-anhydroerythritol we show unambiguously that all three species are diastereomers of the monomeric bis(diolato)-hydroxo complex, [(L=)(2)SiOH](-)(where L represents the cis-diol ligand), thus clarifying the general assignment of (29)Si NMR spectra reported for silicate solutions containing furanoidic sugars with vicinal cis-diol functionality, such as ribose.     

New boron-containing 2′-deoxyadenosines

Conjugates of polyhedral boron hydrides with deoxyadenosine were synthesized by the opening of cyclic oxonium derivatives of closo-dodecaborate and cobalt bis(1,2-dicarbollide) with 2′-deoxyadenosine derivatives containing a nucleophilic group in the substituent at C(8). Biological studies of the derivatives obtained for cytotoxicity revealed that the derivatives based on closo-dodecaborate did not exhibit cytotoxicity. The conjugates obtained can be used in further biological trials as potential agents for boron neutron capture therapy of cancer.     

Reaction of 4,4-Dimethyl-1,3-dioxane with Dinitriles

The reaction of 4,4-dimethyl-1,3-dioxane with bis(2-cyano)diethyl ether or 1,2-di(beta-cyanoethoxy)ethane yields the corresponding bis[2-(4,4-dimethyl-5,6-dihydro-2-oxazinyl)]diethyl ether and 1,2-di{beta-[2-(4,4-dimethyl-5,6-dihydro-2-oxazinyl)]ethoxy}ethane which are readily hydrolyzed under the action of aqueous alkali to give 3-methyl-3-amino-1-butanol.     

Switching off electron transfer reactions in confined media: reduction of [Co(dipic)2]- and [Co(edta)]- by hexacyanoferrate(II)

The kinetics of reduction of two cobalt(III) complexes with similar redox potentials by hexacyanoferrate(II) were investigated in water and in reverse micelle (RM) microemulsions. The RMs were composed of water, surfactant [(sodium(bis(2-ethylhexylsulfosuccinate)), NaAOT], and isooctane. Compared to the reaction in water, the reduction rates of (ethylenediaminetetraacetato)cobaltate(III) by hexacyanoferrate(II) were dramatically suppressed in RM microemulsions whereas a slight rate increase was observed for reduction of bis-(2,6-dipicolinato)cobaltate(III). For example, the ferrocyanide reduction of [Co(dipic)(2)](-) increased from 55 M(-1) s(-1)in aqueous media to 85 M(-1) s(-1) in a w(o) = 20 RM. The one-dimensional (1-D) and two-dimensional (2-D) (1)H NMR and FT-IR studies are consistent with the reduction rate constants of these two complexes being affected by their location within the RM. Since reduction of [Co(edta)](-) is switched off, in contrast to [Co(dipic)(2)](-), these observations are attributed to the penetration of the [Co(edta)](-) into the interfacial region of the RM whereas [Co(dipic)(2)](-) is in a region highly accessible to the water pool and thus hexacyanoferrate(II). These results demonstrated that compartmentalization completely turns off a redox reaction in a dynamic microemulsion system by either reactant separation or alteration of the redox potentials of the reactants.     

Tuning of Thermoresponsivity of a Poly(2‐alkyl‐2‐oxazoline) Block Copolymer by Interaction with Surface‐Active and Chaotropic Metallacarborane Anion

Thermoresponsive nanoparticles based on the interaction of metallacarboranes, bulky chaotropic and surface‐active anions, and poly(2‐alkyl‐2‐oxazoline) block copolymers were prepared. Recently, the great potential of metallacarboranes have been recognized in biomedicine and many delivery nanosystems have been proposed. However, none of them are thermoresponsive. Therefore, a thermoresponsive block copolymer, poly(2‐methyl‐2‐oxazoline)‐block‐poly(2‐n‐propyl‐2‐oxazoline) (PMeOx–PPrOx), was synthesized to encapsulate metallacarboranes. Light scattering, NMR spectroscopy, isothermal titration calorimetry, and cryogenic TEM were used to characterize all solutions of the formed nanoparticles. The cloud‐point temperature (T_CP) of the block copolymer was observed at 30 °C and polymeric micelles formed above this temperature. Cobalt bis(dicarbollide) anion (COSAN) interacts with both polymeric segments. Depending on the COSAN concentration, this affinity influenced the phase transition of the thermoresponsive PPrOx block. The T_CP shifted to lower values at a lower COSAN content. At higher COSAN concentrations, the hybrid nanoparticles are fragmented into relatively small pieces. This system is also thermoresponsive, whereby an increase in temperature leads to higher polymer mobility and COSAN release.     

Mixed Micellization Behavior of 12-2-12 Gemini Surfactant with Some Alkyltrimetyl Ammonium Bromide Surfactants

Mixed micellization behavior of dimeric cationic surfactant ethanediyl-1,2-bis (dimethyldodecylammonium bromide) (12-2-12) with a series of monomeric cationic surfactants dodecyltrimethyl ammonium bromide (DTAB), tetradecyltrimethyl ammonium bromide (TTAB), and cetyltrimethyl ammonium bromide (CTAB) has been studied in aqueous and aqueous polyvinylpyrrolidone (PVP) solutions at 298.15, 308.15, and 318.15 K, respectively, using conductometric method. Various thermodynamic parameters like mixed micelle concentration (C_m), micelle mole fraction (X₁), interaction parameter (β), and free energy of mixing (ΔG_ex) of the mixed systems have been determined and analyzed using Rubingh's regular solution theory. The results indicate that in aqueous solutions the binary mixtures of 12-2-12 with DTAB/TTAB behave nonideally with mutual synergism whereas that with CTAB shows almost ideal behavior at 298.15 K. At 318.15 K, all these binary mixtures exhibit antagonistic behavior. The effect of variation in chain length of alkyltrimethyl ammonium bromide surfactants on the interactions with 12-2-12 have also been evaluated and discussed.     

The synthesis and characterisation of 4,1,2-MC2B10 metallacarboranes

Reduction of the tethered carborane 1,2-(CH2)3-1,2-closo-C2B10H10 followed by treatment with CoCl2/NaCp, [(p-cymene)RuCl2]2(p-cymene=C6H4MeiPr-1,4), (PMe2Ph)2PtCl2 or (dppe)NiCl2(dppe=Ph2PCH2CH2PPh2) affords reasonable yields of the new 13-vertex metallacarboranes 1,2-(CH2)3-4-Cp-4,1,2-closo-CoC2B10H10 (1), 1,2-(CH2)3-4-(p-cymene)-4,1,2-closo-RuC2B10H10 (2), 1,2-(CH2)3-4,4-(PMe2Ph)2-4,1,2-closo-PtC2B10H10 (3) and 1,2-(CH2)3-4,4-(dppe)-4,1,2-closo-NiC2B10H10 (4), respectively. All compounds were characterised spectroscopically and crystallographically. The cobalt and ruthenium species 1 and 2 have Cs symmetry in both solution and the solid state, having henicosahedral cage structures featuring a trapezoidal C1C2B9B5 face. The platinum and nickel compounds 3 and 4 have asymmetric docosahedral cage structures in the crystal (the more so for 4 than for 3) although both appear, by 11B and 31P NMR spectroscopy, to have Cs symmetry in solution. Low-temperature experiments on the more soluble platinacarborane could not freeze out the diamond-trapezium-diamond fluctional process that we assume is operating in solution, and we therefore conclude that this process has a relatively low activation barrier, probably <35 kJ mol-1.     

Boron-Containing Lipids and Liposomes: New Conjugates of Cholesterol with Polyhedral Boron Hydrides

A series of boron-containing lipids were prepared by reactions of cyclic oxonium derivatives of polyhedron boranes and metallacarboranes (closo-dodecaborate anion, cobalt and iron bis(dicarbollides)) with amine and carboxylic acids which are derived from cholesterol. Stable liposomal formulations, on the basis of synthesized boron-containing lipids, hydrogenated soybean l -α-phosphatidylcholine and (HSPC) 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG) as excipients, were prepared and then characterized by dynamic light scattering (DLS) that revealed the formation of particles to be smaller than 200 nm in diameter. The resulting liposomal formulations showed moderate to excellent loading and entrapment efficiency, thus justifying the design of the compounds to fit in the lipid bilayer and ensuring ease of in vivo use for future application. The liposomal formulations based on cobalt and iron bis(dicarbollide)-based lipids were found to be nontoxic against both human breast normal epithelial cells MCF-10A and human breast cancer cells MCF-7.     

Interaction of heteroboranes with biomolecules. Part 2. The effect of various metal vertices and exo-substitutions

Icosahedral heteroboranes and especially metallacarboranes, which have recently been shown to act as potent HIV-1 protease inhibitors, are a unique class of chemical compounds with unusual properties, one of which is the formation of dihydrogen bonds with biomolecules. In this study, we investigate the effect of various metal vertices and exo-substitutions on several series of heteroboranes, including 11-vertex carborane cages [nido-7,8-C2B9Hn]n-13(n= 11,12,13), closo-1-SB11H11, closo-1-NB11H12, metal bis(dicarbollides)[3,3'-M (1,2-C2B9H11)2]n(M/n=Fe/2-, Co/1-, Ni/0) and fluoro (F), amino (NH2) and hydroxo (OH) derivatives of the metal bis(dicarbollides). Besides the properties of isolated systems (geometries, electronic properties and hydration), we study their interactions with a tetrapeptide, which models their biomolecular partner. Calculations have confirmed that the extra hydrogen in [nido-7,8-C2B9H12]- forms a bridge, which fluctuates between two stationary states. Using RESP-derived charges, it was ascertained that the negative charge of heteroboranes is located mainly on boron-bound hydrogens. An increase of the negative total charge (from 0 to -1 or -2) of heteroboranes yields an increase in the stabilisation energies of heteroborane[dot dot dot]peptide complexes and also a substantial increase in the hydration free energies of heteroboranes. Compared to the substitutions of metal vertices, the exo-substitutions of metallacarboranes cause a larger increase in stabilisation energies and a smaller increase in desolvation penalties. These two terms, stabilisation energies and desolvation penalties, contribute in opposite directions to the total heteroborane-biomolecule binding energy and must both be taken into account when designing new HIV-1 protease inhibitors.