Inulin‐Based Hydrogel for Oral Delivery of Flutamide: Preparation,Characterization, and in vivo Release Studies

The ability of a hydrogel obtained by crosslinking INUDV and PEGBa to facilitate sustained release of flutamide is examined. The hydrogel is prepared in pH = 7.4 PBS and no toxic solvents or catalysts are used. It is recovered in microparticulate form and its size distribution is determined. Mucoadhesive properties are evaluated in vitro by reproducing gastrointestinal conditions. Flutamide is loaded into the hydrogel using a post‐fabrication encapsulation procedure that allows a drug loading comparable to that of market tablets. Drug‐loaded microparticles are orally administered to cross‐bred dogs and the in vivo study demonstrates their ability to prolong the half‐life of the principal active metabolite approximately threefold and to significantly increase its bioavailability.

     

Characterization of gas phase aggregates of bis(2‐ethylhexyl)sulfosuccinate (AOT) and divalent metal ions. Elimination of radical species in the decomposition pathways of even‐electron [AOTMIICl2]– anions

Structure and properties of even‐electron anionic species formed by bis(2‐ethylhexyl)sulfosuccinate (AOT) and divalent metal ions (M^II) with stoichiometry [AOTM^IICl₂]^– have been investigated by using electrospray ionization and different mass spectrometry techniques, such as high resolution, accurate mass measurements, collision‐induced dissociation (CID) multiple‐stage mass spectrometry. Owing to CID, eliminations of neutrals, mainly consisting in hydrochloric acid, 2‐ethyl‐1‐hexene and 2‐ethylhexanol, and an unexpected loss of an alkyl radical have been observed. The radical anions [C₄HO₆SM^IICl]^–? so produced have been characterized by MS³ experiments. Density functional theory calculations have been carried out for investigating structure and stability of the ionic species formed in the decomposition pathways. Copyright © 2012 John Wiley & Sons, Ltd.     

Powerful approach to heterocyclic skeletal diversity by sequential three-component reaction of amines, isothiocyanates, and 1,2-diaza-1,3-dienes

By highly efficient, one-pot, three-component reactions, combining one set of 1,2-diaza-1,3-dienes (DDs), primary amines, and isothiocyanates in a different sequential order of addition, heterocyclic skeletal diversity can be achieved. The key feature discriminating the different heterocyclic core formation is the availability of the N or S heteronucleophile to give the first Michael addition step affording regioselective substituted 2-thiohydantoins or 2-iminothiazolidinones. The hydrazone or enehydrazino side chain at the 5-position of both heterocycles represents a valuable functionality to reach novel 5-hydroxyethylidene derivatives difficult to obtain by other methods.     

Separating the basic logics of the basic recurrences

This paper shows that, even at the most basic level (namely, in combination with only ¬,∧,∨), the parallel, countable branching and uncountable branching recurrences of computability logic validate different principles.     

Planar tetracoordinated silicon in silicon carbonyl complexes: a DFT approach

Recently, some works have focused attention on the reactivity of the silicon atom with closed-shell molecules. With CO, silicon may form a few relatively stable compounds, i.e., Si(CO), Si(CO)(2), and Si[C(2)O(2)], while the existence of polycarbonyl (n > 2) silicon complexes has been rejected by current literature. In this paper, the reaction of silicon with carbonyl has been reinvestigated by density functional calculations. It has been found that the tetracoordinated planar Si(CO)(4) complex is thermodynamically stable. In Si(CO), silicon carbonyl, and Si(CO)(2), silicon dicarbonyl, the CO moieties are datively bonded to Si, and Si[C(2)O(2)], c-silicodiketone, is similar to the compounds formed by silicon and ethylene; Si(CO)(4), silicon tetracarbonyl, may be viewed as a resonance between the extreme configurations (CO)(2)Si + 2CO and 2CO + Si(CO)(2). A detailed orbital analysis has shown that the Si bonding with four CO is consistent with the use of sp(2)d-hybridized orbitals on silicon, giving rise to a planar structure about Si.     

Basicity and coordination properties of a new phenanthroline-based bis-macrocyclic receptor

The synthesis and characterisation of the new macrocyclic ligand 6-methyl-2,6,10-triaza-[11]-12,25-phenathrolinophane (L1), which contains a triamine aliphatic chain linking the 2,9 positions of 1,10-phenanthroline and of its derivative L2, composed by two L1 moieties connected by an ethylenic bridge, are reported. Their basicity and coordination properties toward Cu(II), Zn(II), Cd(II), Pb(II) and Hg(II) have been studied by means of potentiometric and spectroscopic (UV-Vis, fluorescence emission) measurements in aqueous solutions. L1 forms 1:1 metal complexes in aqueous solutions, while L2 can give both mono- and dinuclear complexes. In the mononuclear L2 complexes the metal is sandwiched between the two cyclic moieties. The metal complexes with L1 and L2 do not display fluorescence emission, due to the presence of amine groups not involved in metal coordination. These amine groups can quench the excited fluorophore through an electron transfer process. The ability of the Zn(II) complexes with L1 and L2 to cleave the phosphate ester bond in the presence has been investigated by using bis(p-nitrophenyl)phosphate (BNPP) as substrate. The dinuclear complex with L2 shows a remarkable hydrolytic activity, due to the simultaneous presence within this complex of two metals and two hydrophobic units. In fact, the two Zn(II) act cooperatively in substrate binding, probably through a bridging interaction of the phosphate ester; the interaction is further reinforced by pi-stacking pairing and hydrophobic interactions between the phenanthroline unit(s) and the p-nitrophenyl groups of BNPP.     

Ipso-chlorosulfonylation of calixarenes: a powerful tool for the selective functionalization of the large rim

In our quest for the elaboration of supramolecular models of metallo-enzyme active sites, we became interested in developing new methodologies for the selective functionalization of the large rim of calix[6]arenes. Here, we describe a novel reaction, i.e. the ipso-chlorosulfonylation of calixarene derivatives. The process has been found to be highly efficient, selective and versatile. The regioselectivity is controlled by the nature of the O-substituents at the small rim. Indeed, when O-alkylated by a protonable imidazole group, the aromatic rings are deactivated toward an electrophilic attack and the anisol units can be selectively ipso-chlorosulfonylated under mild conditions (rt). Performing the reaction at a higher temperature allowed the per-chlorosulfonylation to take place. Hence, the synthesis of various sulfonate and sulfonamide derivatives is reported. Finally, a combination of ipso-nitration and chlorosulfonylation allows the per-functionalization of the aromatic units at the large rim in selective alternate positions. Overall, this novel methodology opens new routes to a variety of calixarenes, allowing the tuning of their physical properties without drastically altering their hydrophobic conic cavities.     

Strong Kuhn–Tucker conditions and constraint qualifications in locally Lipschitz multiobjective optimization problems

We consider a Pareto multiobjective optimization problem with a feasible set defined by inequality and equality constraints and a set constraint, where the objective and inequality constraints are locally Lipschitz, and the equality constraints are Fréchet differentiable. We study several constraint qualifications in the line of Maeda (J. Optim. Theory Appl. 80: 483–500, 1994) and, under the weakest ones, we establish strong Kuhn–Tucker necessary optimality conditions in terms of Clarke subdifferentials so that the multipliers of the objective functions are all positive.     

Gas-phase doubly charged complexes of cyclic peptides with copper in +1, +2 and +3 formal oxidation states: formation, structures and electron capture dissociation

Copper complexes with a cyclic D-His-β-Ala-L-His-L-Lys and all-L-His-β-Ala-His-Lys peptides were generated by electrospray which were doubly charged ions that had different formal oxidation states of Cu(I), Cu(II) and Cu(III) and different protonation states of the peptide ligands. Electron capture dissociation showed no substantial differences between the D-His and L-His complexes. All complexes underwent peptide cross-ring cleavages upon electron capture. The modes of ring cleavage depended on the formal oxidation state of the Cu ion and peptide protonation. Density functional theory (DFT) calculations, using the B3LYP with an effective core potential at Cu and M06-2X functionals, identified several precursor ion structures in which the Cu ion was threecoordinated to pentacoordinated by the His and Lys side-chain groups and the peptide amide or enolimine groups. The electronic structure of the formally Cu(III) complexes pointed to an effective Cu(I) oxidation state with the other charge residing in the peptide ligand. The relative energies of isomeric complexes of the [Cu(c-HAHK + H)](2+) and [Cu(c-HAHK - H)](2+) type with closed electronic shells followed similar orders when treated by the B3LYP and M06-2X functionals. Large differences between relative energies calculated by these methods were obtained for open-shell complexes of the [Cu(c-HAHK)](2+) type. Charge reduction resulted in lowering the coordination numbers for some Cu complexes that depended on the singlet or triplet spin state being formed. For [Cu(c-HAHK - H)](2+) complexes, solution H/D exchange involved only the N-H protons, resulting in the exchange of up to seven protons, as established by ultra-high mass resolution measurements. Contrasting the experiments, DFT calculations found the lowest energy structures for the gas-phase ions that were deprotonated at the peptide C(α) positions.     

An Easy Access to Furan-Fused Polyheterocyclic Systems

Nitrostilbenes characterized by two different or differently substituted aryl moieties can be obtained from the initial ring-opening of 3-nitrobenzo[b]thiophene with amines. Such versatile building blocks couple the well-recognized double electrophilic reactivity of the nitrovinyl moiety (addition to the double bond, followed by, e.g., intramolecular replacement of the nitro group) with the possibility to exploit a conjugated system of double bonds within an electrocyclization process. Herein, nitrostilbenes are reacted with different aromatic enols provided by a double (carbon and oxygen) nucleophilicity, leading to novel, interesting naphthodihydrofurans. From these, as a viable application, aromatization and electrocyclization lead in turn to valuable polycondensed, fully aromatic O-heterocycles.