Reactions of Azovinylphosphonates with Nucleophilic Alkenes and Heterocycles: Synthesis of Tetrahydropyridazine-3-phosphonate and 2-Substituted-1-hydrazonoethylphosphonate Derivatives

Transient azovinylphosphonates, generated in situ by base induced dehydrohalogenation of the corresponding 2-bromo- and 2-chloro-acetylphosphonate- tertbutoxycarbonyl hydrazones are intercepted by electron rich alkenes and heterocycles in hetero Diels-Alder reactions, producing tetrahydopyridazine-3-phosphonates or open chain α-hydrazono phosphonates.     

A Triply [5]Helicene-Bridged (1,3,5)Cyclophane

A rigid propeller-shaped conjugated triple macrocycle consisting of two nearly perfectly stacked benzene rings and three linking [5]helicene moieties has been synthesized using a glyoxylic Perkin approach. Analysis of the electron delocalization in this atypical aromatic molecule revealed global aromaticity and a 78 π-electron circuit along the edge of its triple loop, to the detriment of the two 6 π-electron circuits in the two stacked benzene rings.     

Novel N-(4-Piperidinyl)benzamide antimalarials with mammalian protein farnesyltransferase inhibitory activity

Protein farnesyltransferase of Plasmodium falciparum is a potential target in the treatment of malaria for which increased drug resistance is observed. The design, synthesis and evaluation of a series of N-(4-piperidinyl)benzamides is reported. The most potent compounds showed in vitro activity against the parasite at submicromolar concentrations.     

Decompositions of para-complex vector bundles and para-complex affine immersions

In this work we study decompositions of para-complex and para-holomorphic vector-bundles endowed with a connection ? over a para-complex manifold. First we obtain results on the connections induced on the subbundles, their second fundamental forms and their curvature tensors. In particular we analyze para-holomorphic decompositions. Then we introduce the notion of para-complex affine immersions and apply the above results to obtain existence and uniqueness theorems for para-complex affine immersions. This is a generalization of the results obtained by Abe and Kurosu [AK] to para-complex geometry. Further we prove that any connection with vanishing (0, 2)-curvature, with respect to the grading defined by the para-complex structure, induces a unique para-holomorphic structure.     

Branch-and-Bound Algorithms for a Regional Water Authority Distribution Problem

A problem put forward recently by a Regional Water Authority differs from the well-known Capacitated Warehouse Location Problem only in that there are both weeks of normal demand levels and weeks of peak demand levels. We describe how Lagrangian relaxation based branch-and-bound algorithms have been adapted for the new problem. Computational results are given, enabling a comparison of the different approaches tried.     

Synthesis and biological evaluation of novel oxophenylarcyriaflavins as potential anticancer agents

We report the synthesis and biological evaluation of new oxophenylarcyriaflavins designed as potential anticancer agents. An efficient synthesis involving palladium-catalyzed Suzuki and Stille reactions is presented, without any indolic protective group. The central ring closure of the scaffold was performed through an electrophilic reaction on the position C-2 of the indole ring. The use of indole and 5-benzyloxyindole, along with substituted phenyl rings, generated three different scaffolds, which were successively exploited to modulate the structure. The cytotoxicity of the newly designed compounds on four cancer cell lines and activities against three kinases (CDK1, CDK5 and GSK3) were evaluated. Several compounds showed a marked cytotoxicity with IC(50) values in the sub-micromolar range, and induced important cell cycle perturbations, with a G2/M arrest. Some compounds revealed DNA binding properties and were found to inhibit topoisomerase-mediated DNA relaxation of supercoiled DNA, but these properties are not mandatory for a cytotoxic action. A novel lead compound () has been identified and warrants further investigations.     

Loading of praziquantel in the crystal lattice of solid lipid nanoparticles

Praziquantel (PZQ) is the drug of choice for oral treatment of schistosomiasis and other fluke infections that affect humans. Its low oral bioavailability demands the development of innovative strategies to overcome the first pass metabolism. In this article, solid lipid nanoparticles loaded with PZQ (PZQ-SLN) were prepared by a modified oil-in-water microemulsion method selecting stearic acid as lipid phase after solubility screening studies. The mean particle size (Z-Ave) and zeta potential (ZP) were 500 nm and −34.0 mV, respectively. Morphology and shape of PZQ-SLN were analysed by scanning electron microscopy revealing the presence of spherical particles with smooth surface. Differential scanning calorimetry suggested that SLN comprised a less ordered arrangement of crystals and the drug was molecularly dispersed in the lipid matrix. No supercooled melts were detected. The entrapment efficiency (EE) and loading capacity of PZQ, determined by high performance liquid chromatography, were 99.06 ± 0.3 and 17.48 ± 0.05, respectively. Effective incorporation of PZQ into the particles was confirmed by small angle X-ray scattering revealing the presence of a lipid lamellar structure. Stability parameters of PZQ-SLN stored at room temperature (25 °C) and at 4 °C were checked by analysing Z-Ave, ZP and the EE for a period of 60 days. Results showed a relatively long-term physical stability after storage at 4 °C, without drug expulsion.     

New multidentate potential ionophors of ether-amide type

The syntheses of acyclic compounds featuring ether-amide groups and different terminal substituents are presented. Three series of new multidentate potential ligands were obtained.

---

Neue mehrzähnige potentielle Ionophore des Ether-Amid-Typs

Zusammenfassung Es wird die Synthese acyclischer Verbindungen mit Ether-Amid-Gruppen und verschiedenen endständigen Substituenten beschrieben. Es wurden drei Verbindungsreihen erhalten, die neue potentielle mehrzähnige Liganden repräsentieren.

     

<Emphasis Type="Italic">N</Emphasis>-Arylamine derivatives of 3-hydroxy-4-pyridinones: solution studies and bioevaluation in view of Al-detoxification roles

A study of a series of bifunctional 3-hydroxy-4-pyridinone derivatives, containing side-chains with various alkyl-aryl-amine-amides as extra-functional groups, was conducted to assess the relevance of those groups to the Al-chelating affinity, the lipo–hydrophilic balance of the compounds, and ⁶⁷Ga biodistribution in mice, in view of their potential use as Al-decorporating agents; the results were compared with those for the drug Deferriprone. Their acid–base properties and Al-chelating affinity in aqueous solution were studied by potentiometric techniques. These ligands form very stable tris-chelated Al complexes and the non-chelating extra-groups are only responsible for small differences in the complex stability (pAl1.2). At physiological pH the major ligand/complex species have different charges, because of the different extent of protonation of the ligands. The introduction of the different groups induces a well-balanced stepwise-like lipo–hydrophilic character (–0.2<log D_oct./water<+1.1). The effect of each ligand on the biodistribution of ⁶⁷Ga in overloaded mice is rapid blood clearance for all of them, but with different biodistribution patterns, namely excretion pathways and brain uptake/clearance, thus suggesting potential different clinical use.