Cosimo G. Fortuna

Design and synthesis of trans 2-(furan-2-yl)vinyl heteroaromatic iodides with antitumour activity

A new molecular modelling approach based on physico-chemical and pharmacokinetic properties, called Volsurf plus, was used to design new heterocyclic compounds with antiproliferative activity. The synthesis and in vitro antitumour tests on a breast carcinoma cell line (MCF7) confirmed VOLSURF predicted activity values.

Intramolecular Charge Transfer of Push–Pull Pyridinium Salts in the Singlet Manifold

The solvent effect on the photophysical and photochemical properties of the iodides of three trans (E) isomers of 2-D-vinyl,1-methylpyridinium, where D is a donor group (4-dimethylaminophenyl, 3,4,5-trimethoxyphenyl and 1-pyrenyl), was studied by stationary and transient absorption techniques. The results obtained allowed the negative solvatochromism and relaxation pathways of the excited states in the singlet manifold to be reasonably interpreted. Resorting to ultrafast absorption techniques and DFT calculations allowed information on the excited state dynamics and the role of the solvent-controlled intramolecular charge transfer (ICT) processes to be obtained. The structure-dependent excited state dynamics in nonpolar solvents, where the ICT is slower than solvent rearrangement, and in polar solvents, where an opposite situation is operative, was thus explained. The push-pull character of the three compounds, particularly the anilino-derivative, suggests their potential application in optoelectronics.

New linezolid-like 1,2,4-oxadiazoles active against Gram-positive multiresistant pathogens.

The synthesis and the in vitro antibacterial activity of novel linezolid-like oxadiazoles are reported. Replacement of the linezolid morpholine C-ring with 1,2,4-oxadiazole results in an antibacterial activity against Staphylococcus aureus both methicillin-susceptible and methicillin-resistant comparable or even superior to that of linezolid. While acetamidomethyl or thioacetoamidomethyl moieties in the C(5) side-chain are required, fluorination of the phenyl B ring exhibits a slight effect on an antibacterial activity but its presence seems to reduce the compounds cytotoxicity. Molecular modeling performed using two different approaches - FLAP and Amber software - shows that in the binding pose of the newly synthesized compounds as compared with the crystallographic pose of linezolid, the 1,2,4-oxadiazole moiety seems to perfectly mimic the function of the morpholinic ring, since the H-bond interaction with U2585 is retained.

Exposition and reactivity optimization to predict sites of metabolism in chemicals

Chemical modifications of drugs induced by phase I biotransformations significantly affect their pharmacokinetic properties. Because the metabolites produced can themselves have a pharmacological effect and an intrinsic toxicity, medicinal chemists need to accurately predict the sites of metabolism (SoM) of drugs as early as possible. However, site of metabolism prediction is rarely accompanied by a prediction of the relative abundance of the various metabolites. Such a prediction would be a great help in the study of drug– drug interactions and in the process of reducing the toxicity of potential drug candidates. The aim of this paper is to present recent developments in the prediction of xenobiotic metabolism and to use concrete examples to explain the computational mechanism employed.

Design, synthesis and biological evaluation of trans 2-(thiophen-2-yl)vinyl heteroaromatic iodides

A modeling approach based on physico-chemical and pharmacokinetic properties, called Volsurf+, was used to design new trans 2-(thiophen-2-yl)vinyl heteroaromatic iodides with antiproliferative activity. The synthesis and in vitro antitumor tests on two cell lines (MCF-7 and LNCap) confirmed Volsurf predicted activity values. An Almond model, derived to have an overall structural insight on the above compounds, supported the validity of Volsurf and provided guidelines for the synthesis of new compounds.

In vitro antitumor activities of 2,6-di-[2-(heteroaryl)vinyl]pyridines and pyridiniums.

The in vitro antitumor activities of 2,6-di-[2-(heteroaryl)vinyl]pyridines versus the standard National Cancer Institute 60 cell lines panel and of 2,6-di-[2-(heteroaryl)vinyl] pyridinium cations versus MCF7 (human mammary carcinoma) and LNCap (prostate carcinoma) cell lines are reported. Antiproliferative effects in both series are particularly evident for MCF7 mammary adenocarcinoma cells. Multivariate analysis of DNA microarray data for responsive tumor cell lines suggest a mechanistic pathway involving polyamine biosynthesis and prolactin signal transduction.

Efficient Excited‐State Symmetry Breaking in a Cationic Quadrupolar System Bearing Diphenylamino Donors

We report a joint experimental and theoretical investigation of a quadrupolar D-π-A(+) -π-D system, the electron donors being diphenylamino groups and the electron acceptor being a methylpyridinium, in comparison with the dipolar D-π-A(+) system. The emission spectra of the two compounds overlap in all the investigated solvents. This finding could be rationalized by TD-DFT calculations: the LUMO-HOMO molecular orbitals involved in the emission transition are localized on the same branch of the quadrupolar structure that becomes the fluorescent portion, corresponding to that of the single-arm compound. Excited-state symmetry breaking has been rarely observed for quadrupolar systems showing negative solvatochromism and is here surprisingly revealed, even in low polarity solvents. Femtosecond transient absorption measurements revealed that an efficient photoinduced intramolecular charge transfer takes place in the quadrupolar chromophore, more efficient than in its dipolar analogue. This result is promising in view of the application of these compounds as novel two-photon absorbing materials.

An ultrafast spectroscopic and quantum mechanical investigation of multiple emissions in push-pull pyridinium derivatives bearing different electron donors.

A joint experimental and theoretical approach, involving state-of-the-art femtosecond fluorescence up-conversion measurements and quantum mechanical computations including vibronic effects, was employed to get a deep insight into the excited state dynamics of two cationic dipolar chromophores (Donor-π-Acceptor(+)) where the electron deficient portion is a N-methyl pyridinium and the electron donor a trimethoxyphenyl or a pyrene, respectively. The ultrafast spectroscopic investigation, and the time resolved area normalised emission spectra in particular, revealed a peculiar multiple emissive behaviour and allowed the distinct emitting states to be remarkably distinguished from solvation dynamics, occurring in water in a similar timescale. The two and three emissions experimentally detected for the trimethoxyphenyl and pyrene derivatives, respectively, were associated with specific local emissive minima in the potential energy surface of S1 on the ground of quantum-mechanical calculations. A low polar and planar Locally Excited (LE) state together with a highly polar and Twisted Intramolecular Charge Transfer (TICT) state is identified to be responsible for the dual emission of the trimethoxyphenyl compound. Interestingly, the more complex photobehaviour of the pyrenyl derivative was explained considering the contribution to the fluorescence coming not only from the LE and TICT states but also from a nearly Planar Intramolecular Charge Transfer (PICT) state, with both the TICT and the PICT generated from LE by progressive torsion around the quasi-single bond between the methylpyridinium and the ethene bridge. These findings point to an interconversion between rotamers for the pyrene compound taking place in its excited state against the Non-equilibrated Excited Rotamers (NEER) principle.

General role of the amino and methylsulfamoyl groups in selective cyclooxygenase(COX)-1 inhibition by 1,4-diaryl-1,2,3-triazoles and validation of a predictive pharmacometric PLS model.

A novel set of 1,4-diaryl-1,2,3-triazoles were projected as a tool to study the effect of both the heteroaromatic triazole as a core ring and a variety of chemical groups with different electronic features, size and shape on the catalytic activity of the two COX isoenzymes. The new triazoles were synthesized in fair to good yields and then evaluated for their inhibitory activity towards COXs arachidonic acid conversion catalysis. Their COXs selectivity was also measured. A predictive pharmacometric Volsurf plus model, experimentally confirmed by the percentage (%) of COXs inhibition at the concentration of 50 μM and IC50 values of the tested compounds, was built by using a number of isoxazoles of known COXs inhibitory activity as a training set. It was found that two compounds {4-(5-methyl-4-phenyl-1H-1,2,3-triazol-1-yl)benzenamine (18) and 4-[1-(4-methoxyphenyl)-5-methyl-1H-1,2,3-triazole-4-yl]benzenamine (19)} bearing an amino group (NH2) are potent and selective COX-1 inhibitors (IC50 = 15 and 3 μM, respectively) and that the presence of a methylsulfamoyl group (SO2CH3) is not a rule to have a Coxib. In fact, 4-(4-methoxyphenyl)-5-methyl-1-[4-(methylsulfonyl)phenyl]-1H-1,2,3-triazole (23) has COX-1 IC50 = 23 μM and was found inactive towards COX-2.

Modeling, design and synthesis of new heteroaryl ethylenes active against the MCF-7 breast cancer cell-line

A dataset of 50 compounds was used to generate a QSAR model and to design 9 new heteroaryl ethylenes. These compounds were synthesized, tested in vitro and a significant agreement with in silico predictions observed. Studies using Laser Scanning Confocal Microscopy pointed out that the compounds may act by different mechanisms.