Tet. Lett. in press 2018

DOI:110.1016/j.tetlet.2018.06.040

O. Dada, G. Sánchez-Sanz, M.Tacke, X. Zhu,

Synthesis and anticancer activity of novel NHC-gold(I)-sugar complexes

Gold(I) complexes containing stabilising ligands such as phosphines or N-heterocyclic carbenes (NHCs) are known to be inhibitors of the enzyme thioredoxin reductase (TrxR) and therefore act as potential apoptosis-inducing anticancer drug candidates. The conjugation of biomolecules overexpressed in cancer cells to the gold complexes makes them semi-targeted metabolites. Auranofin, an anti-arthritis agent, encompasses this property and exhibits anti-tumour activities. The synthesis, characterization and biological evaluation of four novel N-heterocyclic carbene-gold(I)-thiosugar complexes derived from glucose, lactose and galactose is reported. The reactions of 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene gold(I) chloride (NHC∗-Au-Cl) with pre-synthesized glycosyl thiols under mildly basic conditions gave the desired NHC-Au-thiosugar complexes in high to excellent yields (79–91%). The complexes retain the strong and redox-active Au-S bond contained in Auranofin. All complexes showed good solubility in biological media and were tested against the NCI 60 cancer cell panel for cytotoxicity. The synthesized NHC∗-Au derivatives showed good activity in the medium to low micromolar region, while complex 2 showed activity in the low micromolar to nanomolar region against the tested cell lines. To provide a theoretical structure of 4, computational calculations were carried out based on the crystal structures of NHC-Au-SCN and NHC-Au-S-C6H4OMe.

Org. Lett. 20, 2948, 2018

 DOI:10.1021/acs.orglett.8b00996

R. McCourt, F. Denes, G. Sánchez-Sanz, E. Scanlan

Rapid Access to Thiolactone Derivatives Through Radical-Mediated Acyl-Thiol-Ene and Acyl-Thiol-Yne Cyclisation

A new synthetic approach to thiolactones that employs an efficient acyl thiol–ene (ATE) or acyl thiol–yne (ATY) cyclization to convert unsaturated thiocarboxylic acid derivatives into thiolactones under very mild conditions is described. The high overall yields, fast kinetics, high diastereoselectivity, excellent regiocontrol, and broad substrate scope of these reaction processes render this a very useful approach for diversity-oriented synthesis and drug discovery efforts. A detailed computational rationale is provided for the observed regiocontrol.

Biophys. Chem. 238, 16, 2018

DOI:10.1016/j.bpc.2018.04.002

G. Sánchez-Sanz, D. Crowe, A. Nicholson, A. Fleming, E. Carey, F. Kelleher

Conformational studies of Gram-negative bacterial quorum sensing acyl homoserine lactone (AHL) molecules: the importance of the n→pi* interaction

A 1H NMR study shows the presence of intermolecular hydrogen bonds for AHLs in CDCl3 solution. A detailed computational study of the structure of AHLs and the relative stability between the extended conformations (X) and those showing n→p* interactions (np) have been carried out by means of DFT calculations. Solvent effects have been shown to be very important when stabilising np conformations, particularly with polar solvents. This was shown by the shortening of C···O intramolecular distances and the increase in the relative energies favouring the np conformation with the dielectric constant of the solvent. The charge transfer between the O donor and the acceptor carbonyl group, assessed by second order perturbation energies, E(2), also shows an increase in the E(2) values with the dielectric constant of the solvent.

J. Phys. Chem. A,122, 1369, 2018

DOI:10.1021/acs.jpca.7b10920

G. Sánchez-Sanz, C. Trujillo

Improvement of Anion Transport Systems by Modulation of Chalcogen Interactions: The influence of solvent

A series of potential anion transporters, dithieno[3,2-b;2′,3′-d]thiophenes (DTT), involving anion-chalcogen interactions have been studied analysing the interaction energy, geometry and charge transfer. It was found that gas phase calculations show very negative interaction energies with short anion-chalcogen distances, but when solvent effects are considered the interaction energy values decreased drastically concomitantly with an elongation on the interatomic distances. In order to enhance the chalcogen interaction between the DTT derivatives and the anion, increasing the anion transporter capacity, bisisothioazole moiety was considered, i. e. the s-hole of the chalcogen atom was modulated by substitution of the adjacent carbon by a nitrogen atom in the S-C axis, increasing the depth of the s-hole and therefore the interaction between the chalcogen and anion. Finally, different anions were analysed within the complexes finding that F and NO3would be the best candidate to form complexes and possibly displace other anions such as Clor Br.

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