A new and efficient lactic acid polymerization by multimetallic cerium complexes: a poly(lactic acid) suitable for biomedical applications.

Among many, poly(lactic acid) (PLA) has received significant consideration. The striking price and accessibility of l-lactic acid, as a naturally occurring organic acid, are important reasons for poly-(l)-lactic acid (PLLA) improvement. PLLA is a compostable and biocompatible/bioresorbable polymer used for disposable products, for biomedical applications, for packaging film, in the automotive industry, for electronic device components, and for many other applications. Formerly, titanium and other metals have been used in different orthopaedic screws and plates, but they are not degradable and therefore remain in the body. So, the development of innovative and eco compatible catalysts for polyester synthesis is of great interest. In this study, an innovative and eco sustainable catalyst was employed for PLLA synthesis. The combined CeCl3·7H2O-NaI system has been demonstrated to be a very valuable and nontoxic catalyst toward PLLA synthesis, and it represents a further example of how to exploit the antibacterial properties of cerium ions in biomaterials engineering. A novel synthesis of poly-(l)-lactic acid was developed in high yields up to 95% conversion and with a truly valuable molecular weight ranging from 9000 to 145 000 g mol-1, testing different synthetic routes.

Natural Function and Structural Modification of Climacostol, a Ciliate Secondary Metabolite.

The review highlights the main results of two decades of research on climacostol (5-[(2Z)-non-2-en-1-yl]benzene-1,3-diol), the resorcinolic lipid produced and used by the ciliated protozoan Climacostomum virens for chemical defense against a wide range of predators, and to assist its carnivorous feeding. After the first studies on the physiological function of climacostol, the compound and some analogues were chemically synthesized, thus allowing us to explore both its effect on different prokaryotic and eukaryotic biological systems, and the role of its relevant structural traits. In particular, the results obtained in the last 10 years indicate climacostol is an effective antimicrobial and anticancer agent, bringing new clues to the attempt to design and synthesize additional novel analogues that can increase or optimize its pharmacological properties.

Multicomponent Reactions.

Multicomponent Reactions appear to be ideal for any form of synthesis, because of their numerous advantages in terms of sustainability and selectivity in building up complex molecular architectures, with high molecular diversity. This Special Issue collects seven contributions which expand our knowledge about Multicomponent Reactions, providing a good overview about innovative reactivities and applications.

Role of the NMDA Receptor in the Antitumor Activity of Chiral 1,4-Dioxane Ligands in MCF-7 and SKBR3 Breast Cancer Cells.

The potent N-methyl-d-aspartate (NMDA) receptor antagonists 1-3 have been demonstrated to show antiproliferative and cytotoxic effects in MCF-7 and SKBR3 breast cancer cell lines. To improve the knowledge about the role played by the NMDA receptor in the antitumor activity of these compounds, the enantiomers of 1 were prepared and evaluated for their affinity for the phencyclidine (PCP) site of the NMDA receptor and for their cytotoxic effect in MCF-7 and SKBR3 cell lines, both expressing the NMDA receptor. The (S)-1 enantiomer, showing negligible affinity for the PCP site, exhibited antiproliferative activity higher than that of (R)-1, which instead bound the PCP site. The downregulation of NMDA GluN1 expression resulted in a decreased (S)-1-induced cytotoxicity and apoptotic cell death, unequivocally demonstrating the involvement of the NMDA receptor in the antitumor effect of this compound. Due to its interesting biological profile, (S)-1 represents a lead compound to develop novel antitumor agents for breast cancer treatment.

Syntheses and biological studies of nitroimidazole conjugated heteroscorpionate ligands and related Cu(I) and Cu(II) complexes.

Copper(I) and copper(II) complexes of 5-nitroimidazole conjugated heteroscorpionate ligands have been synthesized. In particular, the new 2,2-bis(pyrazol-1-yl)-N-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)acetamide ligand (LHMN) was synthesized by direct coupling of preformed side chain acid with 5-nitroimidazole and its coordination chemistry was investigated towards Cu(I) and Cu(II) acceptors and compared with that of the related 2,2-bis(3,5-dimethyl-1-H-pyrazol-1-yl)-N-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)acetamide ligand (LMeMN). The copper(II) complexes {[(LMeMN)2Cu]Cl2} and {[(LHMN)2Cu]Cl2} were prepared by the reaction of CuCl2·2H2O with LHMN or LMeMN ligands in methanol solution. The water soluble copper(I) complexes {[(LMeMN)Cu(PTA)2]}(PF6) and {[(LHMN)Cu(PTA)2]}(PF6) were prepared by the reaction of Cu(CH3CN)4PF6 and 1,3,5-triaza-7-phosphaadamantane (PTA) with LHMN or LMeMN ligands in acetonitrile solution. The new Cu(I) and Cu(II) complexes as well as the corresponding uncoordinated ligands were evaluated for their cytotoxic activity against 2D monolayer cultures of multiple human cancer cell lines and 3D-cultured HCT-15 colon cancer spheroids. Morphological analysis by Transmission Electron Microscopy (TEM) revealed the induction of a massive cytoplasmic vacuolization consistent with a paraptotic-like cancer cell death.

Novel Potent N-Methyl-d-aspartate (NMDA) Receptor Antagonists or σ1 Receptor Ligands Based on Properly Substituted 1,4-Dioxane Ring.

Two series of 1,4-dioxanes (4-11 and 12-19) were rationally designed and prepared to interact either with the phencyclidine (PCP) binding site of the N-methyl-d-aspartate (NMDA) receptor or with σ1 receptors, respectively. The biological profiles of the novel compounds were assessed using radioligand binding assays, and the compounds with the highest affinities were investigated for their functional activity. The results were in line with the available pharmacophore models and highlighted that the 1,4-dioxane scaffold is compatible with potent antagonist activity at NMDA receptor or high affinity for σ1 receptors. The primary amines 6b and 7 bearing a cyclohexyl and a phenyl ring or two phenyl rings in position 6, respectively, were the most potent noncompetitive antagonists at the NMDA receptor with IC50 values similar to those of the dissociative anesthetic (S)-(+)-ketamine. The 5,5-diphenyl substitution associated with a benzylaminomethyl moiety in position 2, as in 18, favored the interaction with σ1 receptors.

An efficient one-pot two catalyst system in the construction of 2-substituted benzimidazoles: synthesis of benzimidazo[1,2-c]quinazolines.

The benzimidazole core is a common moiety in a large number of natural products and pharmacologically active small molecules. The synthesis of novel benzimidazole derivatives remains a main focus in medicinal research. In continuation of the efforts towards Ce(III) catalysts for organic transformations, we observed for the first time the activity of the iodide ion and copper cation in activating CeCl3·7H2O in the selective formation of prototypical 2-substituted benzimidazoles. The one-pot CeCl3·7H2O-CuI catalytic system procedure includes the cyclo-dehydrogenation of aniline Schiff's bases, generated in situ from the condensation of 1,2-phenylenediamine and aldehydes, followed by the oxidation with iodine, which works as a hydrogen sponge. Mild reaction conditions, good to excellent yields, and clean reactions make the procedure a useful contribution to the synthesis of biologically active fused heterocycles containing benzimidazoquinazolines.

Borane-mediated asymmetric reduction of acetophenone by enantiopure aminonaphthols and aminoalcohols as catalytic source.

Practical, cheap, and stereoselective synthetic methods were applied to the preparation of novel 1-(aminoalkyl)naphthol and gamma-aminoalcohol tridentate ligands. The ligands obtained were conveniently applied with good results as catalytic sources in the borane-mediated enantioselective reduction of acetophenone with borane dimethylsulfide. Conformational analysis through molecular modeling allows the rationalization of observed stereochemical outcomes.

Synthesis of enantiopure 2-(aminoalkyl)phenol derivatives and their application as catalysts in stereoselective reactions.

Enantiopure 2-(aminoalkyl)phenol derivatives are an interesting class of compounds widely used in homogeneous ligand accelerated catalysis. A series of practical and convenient methods available for their preparation are revised, together with the methodologies for the determination of their configuration. The uses of these compounds in metal catalysed asymmetric reactions in the addition of dialkyl zinc reagents to aldehydes and in the reduction of ketones with borane are described. Moreover 2-(aminoalkyl)phenol derivatives have found use also as chiral shift reagents for carboxylic acids.

Stereoselective alkylation of chiral 2-imidoylphenols with organolithium reagents: synthesis of enantiopure 2-aminoalkylphenols.

In this paper the addition of organolithium reagents to chiral imidoylphenols to prepare enantiopure phenolic Mannich-type bases is described. The experimental data show that this kind of imine is surprisingly reactive toward organolithium reagents, differently from classical imines, and does not need any Lewis acid or base activation. Moreover, interesting results have been obtained with aldimines but more unusually with ketimines. This reaction results in high yields and diastereoselectivities and allows the preparation of aminophenols quaternary at the C-1 carbon atom, which cannot be prepared with the methods available till now. The sense of asymmetric induction has been explained and confirmed in agreement with the results previously obtained by hydride reduction of the same substrates. In some cases this procedure is complementary to the reductive one, allowing the preparation of the diastereomers less abundant in the reduction. The reaction allows the synthesis of one or the other of the two diastereomers, choosing the opportune starting imidoylphenol and the organolithium reagent.