Synthesis, biological and in silico evaluation of pure nucleobase-containing spiro (Indane-Isoxazolidine) derivatives as potential inhibitors of MDM2-p53 interaction

Nucleobase-containing isoxazolidines spiro-bonded to an indane core have been synthesized in very good yields by regio- and diastereoselective 1, 3-dipolar cycloaddition starting from indanyl nitrones and N-vinylnucleobases by using environmentally benign microwave technology. The contemporary presence of various structural groups that are individually active scaffolds of different typology of drugs, has directed us to speculate that these compounds may act as inhibitors of MDM2-p53 interaction. Therefore, both computational calculations and antiproliferative screening against A549 human lung adenocarcinoma cells and human SH-SY5Y neuroblastoma cells were carried out to support this hypothesis

Novel Regioselective Synthesis of 1,3,4,5-Tetrasubstituted Pyrazoles and Biochemical Valuation on F1FO-ATPase and Mitochondrial Permeability Transition Pore Formation

An efficient, eco-compatible, and very cheap method for the construction of fully substituted pyrazoles (Pzs) via eliminative nitrilimine-alkene 1,3-dipolar cycloaddition (ENAC) reaction was developed in excellent yield and high regioselectivity. Enaminones and nitrilimines generated in situ were selected as dipolarophiles and dipoles, respectively. A deep screening of the employed base, solvent, and temperature was carried out to optimize reaction conditions. Recycling tests of ionic liquid were performed, furnishing efficient performance until six cycles. Finally, a plausible mechanism of cycloaddition was proposed. Then, the effect of three different structures of Pzs was evaluated on the F1FO-ATPase activity and mitochondrial permeability transition pore (mPTP) opening. The Pz derivatives’ titration curves of 6a, 6h, and 6o on the F1FO-ATPase showed a reduced activity of 86%, 35%, and 31%, respectively. Enzyme inhibition analysis depicted an uncompetitive mechanism with the typical formation of the tertiary complex enzyme-substrate-inhibitor (ESI). The dissociation constant of the ESI complex (Ki’) in the presence of the 6a had a lower order of magnitude than other Pzs. The pyrazole core might set the specific mechanism of inhibition with the F1FO-ATPase, whereas specific functional groups of Pzs might modulate the binding affinity. The mPTP opening decreased in Pz-treated mitochondria and the Pzs’ inhibitory effect on the mPTP was concentration-dependent with 6a and 6o. Indeed, the mPTP was more efficiently blocked with 0.1 mM 6a than with 1 mM 6a. On the contrary, 1 mM 6o had stronger desensitization of mPTP formation than 0.1 mM 6o. The F1FO-ATPase is a target of Pzs blocking mPTP formation

Le Basi della Chimica Organica

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A Mild Oxidative Conversion of Nitroalkanes into Carbonyl Compounds in Ionic Liquids.

Basic hydrogen peroxide and sodium perborate were found to be cheap and efficient alternatives for the conversion of primary and secondary nitro to carbonyl compounds (Nef reaction) in ionic liquid

A sustainable procedure for highly enantioselective organocatalyzed Diels-Alder cyclo-additions in homogeneous ionic liquid/water phase

The MacMillan iminium catalyst was investigated for asymmetric Diels–Alder cycloadditions in ionic liquid/H2O homogeneous phase. Superior selectivity, product yield, and shorter reaction times were observed in comparison with classical organic solvents. Additional advantages are the easy synthetic procedure, the excellent recovery of products, and the recyclability of the whole system

Dissolution of nitrones in alkylphosphates: A structural study

Nitrones are chemical compounds with well-established anti-oxidant and spin-trapping properties. Their low solubility in water for many of them limits their applications, so opportune solvents must be found. In this study, two recently synthetized oxindole nitrones with proven antiproliferative and antioxidant activity have been dissolved in several liquid amphiphiles, chosen as model solvents. The effect of the polar head nature and the alkyl chain length/type have been investigated by a combined experimental (solubility, UV–vis spectroscopy) / computational (molecular dynamics) approach. The different chemical structures of the various solvents offer different chemical environments to the nitrones. The intermolecular interactions involved in the nitrone stabilization in the considered solvents have been highlighted, furnishing precious information for the ad-hoc design of specific carrier for nitrones delivery