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• A set of naphthalene or oxazole-based compounds with positively charged groups was synthesized. • Their interaction with telomeric/oncogenic G-quadruplexes was studied by different biophysical techniques. • The oxazole-based derivatives proved to strongly and selectively recognize the target G-quadruplexes. • Molecular docking showed the preferential binding modes of the best ligands to the G-quadruplexes. • All oxazole-based ligands showed anticancer activity in the low micromolar range. New G-quadruplex-interactive and selective ligands are strongly required to evolve innovative, effective and minimally toxic anticancer agents. With this purpose, we have here synthesized and evaluated a mini-library of organic molecules featured by aromatic cores of different rigidity (naphthalene or bioxazole), decorated with pendant groups including positively charged moieties and/or H-bond donors/acceptors. By exploiting different biophysical techniques, we proved the ability of the bioxazole-based derivatives to strongly and selectively interact with telomeric and oncogenic G-quadruplexes, while the compound featured by a naphthalene core did not emerge as a good G-quadruplex ligand. Molecular docking studies demonstrated the ability of the bioxazole-based ligands to preferentially target the outer G-tetrads of both telomeric and oncogenic G-quadruplexes, by positioning their cores on the G-tetrads in a symmetrical or asymmetrical way respectively, with the pendant groups pointing towards or away from the grooves. All bioxazole-based ligands showed anticancer activity in the low micromolar range. Particularly, the bioxazole derivative bearing piperazine groups was the most active compound of the investigated series, whereas the derivatives bearing morpholine groups were the most selective ones on cancer cells, in full agreement with their ability to act as the strongest and most selective G-quadruplex ligands, respectively. [ABSTRACT FROM AUTHOR]

• Prepared ONO'O ligand analogous to known ONNO ligands. • Zr complex active in lactide polymerization. • Zr complex NOT active in ethene polymerization. • DFT results indicate highly flexible geometry. A synthetic protocol to access new aminophenolate-etherphenolate ONO'O ligands is presented. Zirconium iso -propoxide and benzyl complexes of a prototypical tert -butyl substituted ONO'O ligand can be synthesized in high yields as single conformational isomers. Combined NMR spectroscopy and single-crystal X-ray diffraction studies on (ONO'O)Zr(O i Pr) 2 show that the ligand binds to the metal center in a fac-fac coordination mode, like the well-known bis(aminophenolate) ONNO analogue. The iso -propoxide complex (ONO'O)Zr(O i Pr) 2 proved to be a competent catalyst for L - and rac -lactide polymerization, exhibiting a productivity similar to that of the benchmark (ONNO)Zr(O i Pr) 2 in solution and in neat monomer. The benzyl complex (ONO'O)ZrBn 2 is inactive in ethylene polymerization under the reaction conditions explored, unlike the benchmark (ONNO)ZrBn 2. DFT studies suggest that a larger range of geometries is accessible for cationic active species with ONO'O ligands compared to ONNO or OO'O'O ligands. [Display omitted] [ABSTRACT FROM AUTHOR]

Three symmetric ligands 7-methyl dipyrido-[3,2-a;2′,3′-c]phenazine (dppz-CH), 7-nitro dipyrido-[3,2-a;2′,3′-c]phenazine (dppz-NO) and benzo[i]dipyrido-[3,2-a;2′,3′-c]phenazine (dppn) and their ruthenium(II) complexes [Ru(en)(L)][ClO] (en= ethylenediamine), L= dppz-CH, dppz-NO and dppn have been synthesized and characterized by IR, H, C NMR and Mass spectra. The interactions of these complexes with calf thymus DNA have been investigated by spectrophotometric, spectrofluorimetric, circular dichroism, viscosity and thermal denaturation studies. As the planar extension of the intercalative ligand increases, the interaction of the complex with DNA increases, indicating that the size and shape of the intercalalative ligand has a marked effect on the strength of interaction. The plot of log K versus log [Na] yield a slope of -1.26, -1.53, -1.60 for the complexes 1, 2 and 3 respectively. These three complexes have been found to promote the cleavage of plasmid pBR 322 DNA upon irradiation. [ABSTRACT FROM AUTHOR]

In this paper, we show a strategy to modify salphen-type Schiff base ligands with naphtol (SYML1) and pyrocathecol (2,3-dihydroxyphenyl) groups (SYML2), or a combination of both (ASYML). Each of these ligands can be used to obtain polynuclear metal complexes following two different strategies. One relies on using metals that are either too large for the N2O2 cavity or not fond of coordination number 4 and the other one relies on forcing the polynuclear species by adding functional groups to the hydroxybenzaldehayde in order to have extra coordination sites in the ligand. We report and characterize the mononuclear complexes SYML1-Cu and SYML1-Ce, along with the dinuclear complex SYML1-Fe and the tetranuclear species SYML2-Mn. The asymmetric ligand ASYML routinely hydrolyzes into the symmetric ligands in the reaction mixtures. SYML1-Fe displays a nearly linear Fe-O-Fe bridge with very strong antiferromagnetic coupling between the Fe(III) ions. [ABSTRACT FROM AUTHOR]

Direct-acting antivirals (DAAs) form the current standard of care (SOC) against hepatitis C virus (HCV). These drugs selectively target the viral proteins, offering a unique mechanism to avoid toxicity, to increase their efficacy, and to evolve from decades of interferon- and ribavirin-based therapy. Among the promising HCV targets for DAAs is the NS5A protein, and daclatasvir (DCV) forms a first-in-class compound that selectively targets this protein. Despite the exceptional potency of DCV (∼picomolar IC 50 ) and although several DCV derivatives have been approved for human use or are close to approval, the exact mode of action of these drugs is still incomplete. This is simply due to the vast complexity of cocrystallizing DCV with NS5A in the absence of two amphipathic helices that are required for DCV binding. In this context, computational modeling provides a unique alternative to solve this problem. Here, we build upon our recent discovery of a completely symmetrical interaction between DCV and NS5A and investigate the mode of binding of six other structures similar to DCV. The selected compounds include both symmetric and asymmetric molecules. In addition, we show that our model correlates very well with mutations that can confer resistance to DCV. The current study enhances our understanding of the mode of action of this class of HCV inhibitors and helps in defining the origin of resistance to these drugs.

Guided by computational methods, a set of 1920 compounds were selected from the AstraZeneca corporate collection and screened for Kv1.5 activity. To facilitate rapid generation of structure-activity relationships, special attention was given to selecting subsets of structurally similar molecules by using a maximum common substructure similarity-based procedure. The focused screen hit rate was relatively high (12%). More importantly, a structural series featured by the symmetric 1,2-diphenylethane-1,2-diamine substructure was identified as potent Kv.1.5 blockers. The property profile for the series is shown to meet stringent lead-optimization criteria, providing a springboard for the development of a new and safe treatment for atrial fibrillation.