Zinc(II) Triflate‐Catalyzed Divergent Synthesis of Polyfunctionalized Pyrroles

The zinc(II) triflate‐catalyzed synthesis of highly functionalized pyrroles is described. The sequence involves the preliminary preparation of α‐aminohydrazones by Michael addition of primary amines to 1,2‐diaza‐1,3‐dienes. The treatment of these intermediates with dialkyl acetylenedicarboxylates produces α‐(N‐enamino)‐hydrazones that are converted into the corresponding pyrroles. The substituents on the carbon in position four of 1,2‐diaza‐1,3‐dienes drive the regioselectivity of the ring closure process. Starting from 4‐aminocarbonyl‐1,2‐diaza‐1,3‐dienes only dialkyl 1‐substituted 5‐aminocarbonyl‐1H‐pyrrole‐2,3‐dicarboxylates are achieved by Lewis acid‐catalyzed ring closure. A screening of several Lewis/Brønsted acid catalysts is performed. Zinc(II) triflate is the most efficient catalyst. Under similar reaction conditions, employing 4‐alkoxycarbonyl‐1,2‐diaza‐1,3‐dienes, only 4‐hydroxy‐1H‐pyrrole‐2,3‐dicarboxylates are synthesized. These latter reactions can be accomplished regioselectively also in one pot. Using 4‐aminocarbonyl‐1,2‐diaza‐1,3‐dienes, diamines and dialkyl acetylenedicarboxylates the sequence provides the corresponding α,ω‐di(N‐pyrrolyl)alkanes.     

Anticancer Ruthenium(III) Complex KP1019 Interferes with ATP‐Dependent Ca2+ Translocation by Sarco‐Endoplasmic Reticulum Ca2+‐ATPase (SERCA)

Sarco‐endoplasmic reticulum Ca²⁺‐ATPase (SERCA), a P‐type ATPase that sustains Ca²⁺ transport and plays a major role in intracellular Ca²⁺ homeostasis, represents a therapeutic target for cancer therapy. Here, we investigated whether ruthenium‐based anticancer drugs, namely KP1019 (indazolium [trans‐tetrachlorobis(1H‐indazole)ruthenate(III)]), NAMI‐A (imidazolium [trans‐tetrachloro(1H‐imidazole)(S‐dimethylsulfoxide)ruthenate(III)]) and RAPTA‐C ([Ru(η⁶‐p‐cymene)dichloro(1,3,5‐triaza‐7‐phosphaadamantane)]), and cisplatin (cis‐diammineplatinum(II) dichloride) might act as inhibitors of SERCA. Charge displacement by SERCA adsorbed on a solid‐supported membrane was measured after ATP or Ca²⁺ concentration jumps. Our results show that KP1019, in contrast to the other metal compounds, is able to interfere with ATP‐dependent translocation of Ca²⁺ ions. An IC₅₀ value of 1 μM was determined for inhibition of calcium translocation by KP1019. Conversely, it appears that KP1019 does not significantly affect Ca²⁺ binding to the ATPase from the cytoplasmic side. Inhibition of SERCA at pharmacologically relevant concentrations may represent a crucial aspect in the overall pharmacological and toxicological profile of KP1019.     

The Effect of Electrospun Gelatin Fibers Alignment on Schwann Cell and Axon Behavior and Organization in the Perspective of Artificial Nerve Design

Electrospun fibrous substrates mimicking extracellular matrices can be prepared by electrospinning, yielding aligned fibrous matrices as internal fillers to manufacture artificial nerves. Gelatin aligned nano-fibers were prepared by electrospinning after tuning the collector rotation speed. The effect of alignment on cell adhesion and proliferation was tested in vitro using primary cultures, the Schwann cell line, RT4-D6P2T, and the sensory neuron-like cell line, 50B11. Cell adhesion and proliferation were assessed by quantifying at several time-points. Aligned nano-fibers reduced adhesion and proliferation rate compared with random fibers. Schwann cell morphology and organization were investigated by immunostaining of the cytoskeleton. Cells were elongated with their longitudinal body parallel to the aligned fibers. B5011 neuron-like cells were aligned and had parallel axon growth when cultured on the aligned gelatin fibers. The data show that the alignment of electrospun gelatin fibers can modulate Schwann cells and axon organization in vitro, suggesting that this substrate shows promise as an internal filler for the design of artificial nerves for peripheral nerve reconstruction.     

Molecularly imprinted polymers by phase inversion technique for the selective recognition of saccharides of biomedical interest in aqueous solutions

The purpose of this work was the preparation and characterization of polymeric membranes for the selective recognition of saccharides using molecular imprinting technology associated with phase inversion. A system able to bind saccharides with high selectivity is particularly important in the pharmaceutical sector, since some of these compounds are constituents of molecules which can exert serious toxic effects even at very low concentrations. Two polymeric matrices were prepared using poly(ethylene‐co‐vinyl alcohol) copolymers, with an ethylene molar content of 32% and 44%, and were imprinted with two different saccharide molecules: maltose and 2‐keto‐3‐deoxy‐d ‐manno‐octulosonate (KDO). Matrices imprinted against maltose and KDO showed an easy template extraction, high binding capability and satisfactory selectivity, particularly for the matrix with an ethylene molar content of 44%. © 2017 Society of Chemical Industry     

Ceria‐coated diesel particulate filters for continuous regeneration

The potential of diesel particulate filters wash‐coated with highly dispersed nano‐metric ceria particles for continuous regeneration has been investigated. To this end, catalytic filters were prepared, soot‐loaded (avoiding the formation of the cake layer), and regenerated—under isothermal conditions—at temperature ranging from 200–600°C. Results have shown that catalytic oxidation of soot starts from 300°C and, at all temperatures, the selectivity to CO₂ is higher than 99%. 475°C is the minimum temperature at which the filter is regenerated via catalytic path. At this temperature, the catalytic filter maintains substantially the same performance over repeated cycles of soot loading and regeneration, indicating that the thermal stability of ceria is preserved. This has been further confirmed by comparison between the outcomes obtained from characterization (X‐ray powder diffraction, N₂ adsorption at 77 K, Hg intrusion porosimetry, and scanning electron microscope/energy dispersive X‐ray analysis) of fresh filter and filter subjected to repeated regeneration tests. © 2017 American Institute of Chemical Engineers AIChE J, 63: 3442–3449, 2017     

Selective Oxidation of Alcohols to Carbonyl Compounds Mediated by Fluorous‐Tagged TEMPO Radicals

Oxidation of primary, benzylic and secondary alcohols into their corresponding aldehydes and ketones with safe, inexpensive oxidants was achieved in good yields under mild conditions in the presence of catalytic amounts of 2,2,6,6‐tetramethylpiperidine‐1‐oxyl (TEMPO) radicals bearing perfluoroalkyl substituents. These “fluorous‐tagged” TEMPOs were readily isolated from the reaction products by liquid‐liquid or solid‐phase extraction, considerably simplifying the purification step. Their recyclability was strongly influenced by the nature of the oxidizing system. The best results were obtained using either [bis(acetoxy)iodo]benzene (BAIB) or aqueous NaOCl as the primary oxidants. Fluorous TEMPO 10 could be reused up to six times in the BAIB oxidation of 1‐octanol with only minor loss of catalytic activity.     

Overcoming Multidrug Resistance (MDR): Design,Biological Evaluation and Molecular Modelling Studies of 2,4-Substituted Quinazoline Derivatives

Some 2,4-disubstituted quinazolines were synthesized and studied as multidrug resistance (MDR) reversers. The new derivatives carried the quinazoline-4-amine scaffold found in modulators of the ABC transporters involved in MDR, as the TKIs gefitinib and erlotinib. Their behaviour on the three ABC transporters, P-gp, MRP1 and BCRP, was investigated. Almost all compounds inhibited the P-gp activity in MDCK-MDR1 cells overexpressing P-gp, showing EC₅₀ values in the nanomolar range ( 1 d , 1 e , 2 a , 2 c , 2 e ). Some compounds were active also towards MRP1 and/or BCRP. Docking results obtained by in silico studies on the P-gp crystal structure highlighted common features for the most potent compounds. The P-gp selective compound 1 e was able to increase the doxorubicin uptake in HT29/DX cells and to restore its antineoplastic activity in resistant cancer cells in the same extent of sensitive cells. Compound 2 a displayed a dual inhibitory effect showing good activities towards both P-gp and BCRP.     

PDGF/PDGFR: A Possible Molecular Target in Scleroderma Fibrosis

Systemic sclerosis (SSc) is a clinically heterogeneous disorder of the connective tissue characterized by vascular alterations, immune/inflammatory manifestations, and organ fibrosis. SSc pathogenesis is complex and still poorly understood. Therefore, effective therapies are lacking and remain nonspecific and limited to disease symptoms. In the last few years, many molecular and cellular mediators of SSc fibrosis have been described, providing new potential options for targeted therapies. In this review: (i) we focused on the PDGF/PDGFR pathway as key signaling molecules in the development of tissue fibrosis; (ii) we highlighted the possible role of stimulatory anti-PDGFRα autoantibodies in the pathogenesis of SSc; (iii) we reported the most promising PDGF/PDGFR targeting therapies.     

Impact of fluorinated vinylene units on supramolecular organization and optical properties of poly(p-phenylenedifluorovinylene) thin films as a class of blue band gap conjugated polymers

This study is an investigation on the interplay between supramolecular organization and optical properties of thin films of conjugated polymers with fluorinated vinylene units such as poly[2-(2-ethylhexyloxy)-5-methoxy]-1,4-phenylenedifluorovinylene (MEH-PPDFV) and poly(2-methoxy-5-propyloxysulfonatephenylenedifluorovinylene) (MPS-PPDFV), which are both PPV polymers with fluorinated double bonds with alkoxy chains in the 2 and 5 positions. MEH-PPDFV is the fluorinated version of the widely investigated MEH-PPV, and MPS-PPDFV is characterized by the presence of ionic alkoxy side chains. This interplay is elucidated exploiting atomic force microscopy, spectroscopic ellipsometry and photoluminescence to obtain complementary information. It is demonstrated that the presence of F-atoms in the vinylene units of the MEH-PPDFV yields a blue optical band gap with the maximum of the fundamental HOMO-LUMO transition and of the room temperature photoluminescence at 3.74 eV (331 nm) and at 2.71 eV (458 nm), respectively. The blue-absorption and emission in the thin films are ascribed to the fact that fluorine atoms on the vinylene units prevent π-stacking of polymeric chains. Furthermore, the dependence of morphology, anisotropy in optical properties and photoluminescence properties of films on deposition methodology is also discussed. MEH-PPDFV also emits homogeneous blue-greenish electroluminescence at 2.46 eV (504 nm).     

In Silico Logical Modelling to Uncover Cooperative Interactions in Cancer

The multistep development of cancer involves the cooperation between multiple molecular lesions, as well as complex interactions between cancer cells and the surrounding tumour microenvironment. The search for these synergistic interactions using experimental models made tremendous contributions to our understanding of oncogenesis. Yet, these approaches remain labour-intensive and challenging. To tackle such a hurdle, an integrative, multidisciplinary effort is required. In this article, we highlight the use of logical computational models, combined with experimental validations, as an effective approach to identify cooperative mechanisms and therapeutic strategies in the context of cancer biology. In silico models overcome limitations of reductionist approaches by capturing tumour complexity and by generating powerful testable hypotheses. We review representative examples of logical models reported in the literature and their validation. We then provide further analyses of our logical model of Epithelium to Mesenchymal Transition (EMT), searching for additional cooperative interactions involving inputs from the tumour microenvironment and gain of function mutations in NOTCH.