J. Phys. Chem. A, 121, 8995, 2017


G. Sánchez-Sanz, C. Trujillo, I. Alkorta and J. Elguero

Enhancing Intramolecular Chalcogen Interactions in 1-Hydroxy-8-YH-Naphthalenes Derivatives

Forty-two peri-substituted naphthalenes presenting chalcogen weak interactions have been studied. They correspond to O···Y interactions, Y being O, S and Se. While the O atom bear H or CH3 substituents (OH and OCH3 groups), the Y atom is substituted by H, F and CN in order to explore the effect of these electron-donating and electron-withdrawing substituents on the chalcogen bond strength. The effect of F and CH3 substituents on positions ortho/para (2,4,5,7 of the naphthalene ring) was also studied. Optimizations were carried out at the MP2/augl-cc-pVDZ and binding energies at the MP2/aug-cc-pVTZ followed by an MP2/CBS estimation. The main properties studied were geometries, energies (Eb, Eiso and Edef), the Molecular Electrostatic Potential (MEP), Electron density shifts and NBO E(2) energies and the relationship between these properties.

Phys. Chem. Chem. Phys.,19, 20647, 2017


G. Sánchez-Sanz, C. Trujillo, I. Alkorta and J. Elguero

Modulation of in:out and out:out conformations in [X.X'.X"] Phosphatranes by Lewis Acids

A theoretical study of the [X.X'.X"]phosphatrane:Lewis acid complexes has been carried out in order to analyze how the in:out and out:out conformations can be modulated by the interaction with Lewis acids. It has been found that in:out structures are more stable in larger systems i.e. in [4.4.3]:X and [4.4.4]:X than in [3.3.3]:X and [4.3.3]:X. The results obtained for the relative energies in conjunction with electron density properties showed that upon complexation, in:out conformers become more stable with the increasing acidity of the corresponding Lewis acid. In fact, the binding energies found for in:out complexes are larger than those obtained for out:out complexes. The complexes with the largest relative energy favoring the in:out structure correspond to those with charged Lewis acids, followed by the complexes with ClF. In all cases, the complexes are cooperative, reaching a maximum value of 168.5 kJ·mol–1 for the [4.3.3]:F+ complex.

Bioorg. Med. Chem., 25, 4285, 2017


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

Conformational studies of Gram-negative bacterial quorum sensing 3-oxo N-acyl homoserine lactone molecules

In their 1H NMR spectra in CDCl3 3-oxo-N-acyl homoserine lactones (OHLs) show significant downfield chemical shifts of the amide Nsingle bondH proton when compared to the parent N-acyl homoserine lactones (AHLs). NMR spectroscopic and DFT calculation studies have shown that this is most likely due to the presence of a stabilising intramolecular H-bond from the Nsingle bondH to the 3-oxo group. The 1H NMR spectra also show evidence for the enol tautomers and that the amount of enol present for a range of OHLs is 4.1–4.5% in CDCl3 and 6.5–7.2% in CD3CN. In contrast, DFT calculations show that the lowest energy enol tautomer and the keto tautomer are of equal energy in the gas phase, but that the keto tautomer is more stable in chloroform, acetonitrile and water solution. The calculations also show that there is no evidence for any n → π∗ or C5H-bonding interactions being present in either the lowest energy keto or enol tautomer of the OHLs in solution or the gas phase, which is in contrast to the reported solid-state structure.

Eur. J. Med. Chem.,138, 38, 2017.


A. Flood, C. Trujillo, G. Sánchez-Sanz, B. Kelly, B. Twamley, C. Muguruza, L. F. Callado, and I. Rozas

Thiophene/Thiazole-Benzene Replacement on Guanidine Derivatives Targeting α2 -Adrenoceptors

Searching for improved antagonists of α2-adrenoceptors, a thorough theoretical study comparing the aromaticity of phenyl-, pyridinyl-, thiophenyl- and thiazolylguanidinium derivatives has been carried out [at M06-2X/6–311++G(p,d) computational level] confirming that thiophene and thiazole will be good ‘ring equivalents’ to benzene in these guanidinium systems. Based on these results, a small but chemically diverse library of guanidine derivatives (15 thiophenes and 2 thiazoles) were synthesised to explore the effect that the bioisosteric change has on affinity and activity at α2-adrenoceptors in comparison with our previously studied phenyl derivatives. All compounds were tested for their α2-adrenoceptor affinity and unsubstituted guanidinothiophenes displayed the strongest affinities in the same range as the phenyl analogues. In the case of cycloakyl systems, thiophenes with 6-membered rings showed the largest affinities, while for the thiazoles the 5-membered analogue presented the strongest affinity. From all the compounds tested for noradrenergic activity, only one compound exhibited agonistic activity, while two compounds showed very promising antagonism of α2-adrenoceptors.

Molecules, 22, 227, 2017


G. Sánchez-Sanz, I. Akorta, J. Elguero

Theoretical study of intramolecular interactions in peri-substituted naphthalenes: chalcogen and hydrogen bonds  

A theoretical study of the peri interactions, both intramolecular hydrogen (HB) and chalcogen bonds (YB), in 1-hydroxy-8YH-naphthalene, 1,4-dihydroxy-5,8-di-YH-naphthalene and 1,5-dihydroxy-4,8-di-YH-naphthalene, with Y = O, S and Se has been carried out. The systems with a OH:Y hydrogen bond are the most stable ones followed by those with a chalcogen O:Y interaction, being those with a YH:O hydrogen bond (Y = S and Se) the least stable ones. The electron density values at the hydrogen bond critical points indicate that they have partial covalent character. The Natural Bond Orbital (NBO) analysis shows stabilization due to charge transfer between lone pair orbitals towards empty Y-H that correlate with the interatomic distances. The electron density shift maps and non-covalent indexes in the different systems are consistent with the relative strength of the interactions. The structures found on the CSD have been used to compare the experimental and calculated results.

J. Phys. Chem. A., 121, 1362, 2017


Janet E. Del Bene, I. Akorta, J. Elguero, G. Sánchez-Sanz

Lone-Pair Hole on P: P···N Pnicogen Bonds Assisted by Halogen Bonds 

Ab initio MP2/aug’-cc-pVTZ calculations have been performed on the binary complexes XY:PH3 for XY = ClCl, FCl, and FBr; and PH3:N-base for N-base = NCH, NH3, NCF, NCCN, and N2; and the corresponding ternary complexes XY:PH3:N-base, to investigate P…N pnicogen bond formation through the lone-pair hole at P in the binary complexes, and P…N pnicogen-bond formation assisted by P…Y halogen bond formation through the σ-hole at Y.  Although the binary complexes PH3:N-base which form through the lone-pair hole have very small binding energies, they are not equilibrium structures on their potential surfaces. The presence of the P…Y halogen bond makes PH3 a better electron-pair acceptor through its lone-pair hole, leading to stable ternary complexes XY:PH3:N-base. The halogen bonds in ClCl:PH3 and ClCl:PH3:NCCN are traditional halogen bonds, but in the remaining binary and ternary complexes they are chlorine- or bromine-shared halogen bonds.  For a given nitrogen base, the P...N pnicogen bond in the ternary complex FCl:PH3:N-base appears to be stronger than that bond in FBr:PH3:N-base, which is stronger than the P…N bond in the corresponding ClCl:PH3:N-base complex.  EOM-CCSD spin-spin coupling constants for the binary and ternary complexes with ClCl and FCl are also consistent with the changing nature of the halogen bonds in these complexes. At long P-Cl distances, the coupling constant 1xJ(P-Cl) increases with decreasing distance, but then decreases as the P-Cl distance continues to decrease, and the halogen bonds become chlorine-shared bonds.  At the shorter distances, 1xJ(P-Cl) approaches the value of 1J(P-Cl) for the cation +(Cl-PH3). The coupling constants 1pJ(P-N) are small and with one exception, are greater in ClCl:PH3:N-base complexes compared to FCl:PH3:N-base, despite the shorter P-N distances in the latter.

Struct. Chem., 28, 345, 2017


C. Trujillo, G. Sánchez-Sanz, I. Akorta, J. Elguero

An insight on the aromatic changes in closed shell icosagen, tetrel and pnictogen phenalenyl derivatives 

A computational study of the aromatic and antiaromatic characteristics of charged phenalenyl (PLY+1 andPLY-1) upon replacement of the central carbon atom by icosagen (B, Al and Ga), tetrel (Si and Ge) and pnictogen (N, P and As) atoms comprising systems in which the icosagen and pnictogen derivatives considered are neutral while the tetrel ones are anions or cations, has been carried out at the B3LYP/6-311++G(d,p) computational level. By substitution, two different kinds of structures have been obtained, one planar (N and B) and another one bowl-shaped depending on the size of the central atom. In terms of aromaticity, the substitution of the central C atom causes a loss of the aromatic character in all cases as indicated by NICS (Nucleus-Independent Chemical Shifts) profiles and NICS values on the 0.001 a.u. isosurface. Regarding the charge, PLY+1 present larger electron delocalisation than PLY–1, phenomenon associated with aromaticity. Furthermore, the current density maps for those planar systems corroborate NICS findings, showing anticlockwise currents in PLY+1 (like in benzene) but clockwise in PLY-N0 and PLY-B0, indicating aromatic and antiaromatic behaviour respectively.

Lett. Drug Des. Discov., 14, 125, 2017


W. Walther, O. Dada, C. O’Beirne, I. Ott, G. Sánchez-Sanz, C. Schmidt, C.Werner, X.Zhu and M.Tacke

In Vitro and In Vivo Investigations into the Carbene Gold Chloride and Thioglucoside Anticancer Drug Candidates NHC-AuCl and NHC-AuSR

The anticancer drug candidate 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene gold(I) chloride (NHC-AuCl) and its 2',3',4',6'-tetra-O-acetyl-β-D-glucopyranosyl-1’-thiolate derivative (NHC-AuSR), which is a potential ligand for glucose transporters, were tested on the NCI 60 cancer cell panel in vitro. NHC-AuCl and NHC-AuSR showed very good activity against a wide range of human cancer cell lines inclusive renal cell cancer with similar average GI50 values of 1.78 and 1.95 μM, respectively. This encouraged maximum tolerable dose (MTD) experiments in mice, where MTD values of 10 mg/kg for NHC-AuCl and 7.5 mg/kg for NHC-AuSR were determined with single injections to groups of 2 mice. In the following tumor xenograft experiment NHC-AuCl and NHC-AuSR were given at MTD in 6 injections to two cohorts of 6 CAKI-1 tumor-bearing NMRI:nu/nu mice, while a control cohort of 6 mice was treated with solvent only. NHC-AuCl at the dose of 10 mg/kg and NHC-AuSR at the lower dose of 7.5 mg/kg induced both low toxicities in the form of abdominal swelling but no significant body weight loss was seen in both groups. The tumor volume growth reduction was significant and almost identical; optimal T/C values of 0.47 were observed on day 19 for NHC-AuCl and on day 29 for NHC-AuSR. Immunohistochemistry for the proliferation marker Ki-67 and the angiogenesis marker CD31 did not show significant changes due to NHC-AuCl or NHC-AuSR treatment in the animals. However, thioredoxin reductase (TrxR) inhibition with IC50 values of 1.5 μM for NHC-AuCl and 3.1 μM for NHC-AuSR seem to indicate that apoptosis induction through elevated oxidative stress is the main mechanism for the two gold compounds.

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