Structural and thermodynamic characterization of allosteric transitions in human serum albumin with metadynamics simulations.

Human serum albumin (HSA) is the most prominent protein in blood plasma, responsible for the maintenance of blood viscosity and transport of endogenous and exogenous molecules. Fatty acids (FA) are the most common ligands of HSA and their binding can modify the protein's structure. The protein can assume two well-defined conformations, referred to as 'Neutral' and 'Basic'. The Neutral (N) state occurs at pH close to 7.0 and in the absence of bound FA. The Basic (B) state occurs at pH higher than 8.0 or when the protein is bound to long-chain FA. HSA's allosteric behaviour is dependent on the number on FA bound to the structure. However, the mechanism of this allosteric regulation is not clear. To understand how albumin changes its conformation, we compared a series of HSA structures deposited in the protein data bank to identify the minimum amount of FA bound to albumin, which is enough to drive the allosteric transition. Thereafter, non-biased molecular dynamics (MD) simulations were used to track protein's dynamics. Surprisingly, running an ensemble of relatively short MD simulations, we observed rapid transition from the B to the N state. These simulations revealed differences in the mobilities of the protein's subdomains, with one domain unable to fully complete its transition. To track the transition dynamics in full, we used these results to choose good geometrical collective variables for running metadynamics simulations. The metadynamics calculations showed that there was a low energy barrier for the transition from the B to the N state, while a higher energy barrier was observed for the N to the B transition. These calculations also offered valuable insights into the transition process.

One-pot synthesis of γ-lactams from ketoaziridines.

The remarkable biological activities of γ-lactams have stimulated the search for efficient synthetic methods to achieve these scaffolds. In this work, we have developed a simple one-pot diastereoselective synthesis of new γ-lactams from ketoaziridines with moderate to good yields via the Horner-Wadsworth-Emmons reaction, followed by an intramolecular ester-aziridine cyclization and its opening in situ. Preliminary efforts towards an enantioselective version of this method are also reported.

Copper-Mediated Intramolecular Interrupted CuAAC Selanylation.

We, herein, describe a copper-mediated domino CuAAC intramolecular selanylation for the synthesis of unprecedented fused benzo[4,5][1,3]selenazolo[3,2-c][1,2,3]triazoles from 1,2-bis(2-azidoaryl)diselenides and terminal alkynes under microwave irradiation. This is the seminal method for the synthesis of these fused heterocycles, and it proceeds under mild conditions, tolerates several functional groups, and can be carried out using environmentally benign solvents such as dimethyl carbonate. This transformation has been successfully extended to TMS-protected alkynes and to bioactive alkynes. A plausible reaction mechanism is proposed based on several control experiments and previous reports.

Rh(III)-Catalyzed C-2 Alkylation of Indoles followed by a Post-Synthetic Modification via the Ugi Reaction.

Indole derivatives substituted at the C-2 position have shown important biological activities. Due to these properties, several methods have been described for the preparation of structurally diverse indoles. In this work, we have synthesized highly functionalized indole derivatives via Rh(III)-catalyzed C-2 alkylation with nitroolefins. Under the optimized condition, 23 examples were prepared with 39-80 % yield. Moreover, the nitro compounds were reduced and submitted to the Ugi four-component reaction, furnishing a series of new indole-peptidomimetics in moderate to good overall yields.

Resistance to a tyrosine kinase inhibitor mediated by changes to the conformation space of the kinase.

Gilteritinib is a highly selective and effective inhibitor of the FLT3/ITD mutated protein, and is used successfully in treating acute myeloid leukaemia (AML). Unfortunately, tumour cells gradually develop resistance to gilteritinib due to mutations in the molecular drug target. The atomistic details behind this observed resistance are not clear, since the protein structure of the complex is only available in the inactive state, while the drug binds better to the active state. To overcome this limitation, we used a computer-aided approach where we docked gilteritinib to the active site of FLT3/ITD and calculated the Gibbs free energy difference between the binding energies of the parental and mutant enzymes. These calculations agreed with experimental estimations for one mutation (F691L) but not the other (D698N). To further understand how these mutations operate, we used metadynamics simulations to study the conformational landscape of the activation process. Both mutants show a lower activation energy barrier which suggests that they are more likely to adopt an active state until inhibited, making the mutant enzymes more active. This suggests that a higher efficiency of tyrosine kinases contributes to resistance not only against type 2 but also against type 1 kinase inhibitors.

Methyl 3-[(1-benzyl-4-phenyl-1H-1,2,3-triazol-5-yl)formamido]-propano-ate: crystal structure, Hirshfeld surface analysis and computational chemistry.

The title compound, C20H20N4O3, is constructed about a tri-substituted 1,2,3-triazole ring, with the substituent at one C atom flanked by the C and N atoms being a substituted amide group, and with the adjacent C and N atoms bearing phenyl and benzyl groups, respectively; the dihedral angle between the pendant phenyl rings is 81.17 (12)°, indicative of an almost orthogonal disposition. In the crystal, pairwise amide-N-H⋯O(carbon-yl) hydrogen bonds lead to a centrosymmetric dimer incorporating methyl-ene-C-H⋯π(benzene) inter-actions. The dimers are linked into a supra-molecular layer in the ab plane via methyl-ene-C-H⋯N(azo) and benzene-C-H⋯O(amide) inter-actions; the layers stack along the c-axis direction without directional inter-actions between them. The above-mentioned inter-molecular contacts are apparent in the analysis of the calculated Hirshfeld surface, which also provides evidence for short inter-layer H⋯C contacts with a significant dispersion energy contribution.

4-Nitro-benzyl 3,4-bis-(acet-yloxy)-2-(4-meth-oxy-phen-yl)pyrrolidine-1-carboxyl-ate: crystal structure, Hirshfeld surface analysis and computational chemistry.

The title compound, C23H24N2O9, is a tetra-substituted pyrrolidine derivative with a twisted conformation, with the twist evident in the C-C bond bearing the adjacent acet-yloxy substituents. These are flanked on one side by a C-bound 4-meth-oxy-phen-yl group and on the other by a methyl-ene group. The almost sp 2-N atom [sum of angles = 357°] bears a 4-nitro-benzyl-oxycarbonyl substituent. In the crystal, ring-methyl-ene-C-H⋯O(acet-yloxy-carbon-yl) and methyl-ene-C-H⋯O(carbon-yl) inter-actions lead to supra-molecular layers lying parallel to (01); the layers stack without directional inter-actions between them. The analysis of the calculated Hirshfeld surfaces indicates the combined importance of H⋯H (42.3%), H⋯O/O⋯H (37.3%) and H⋯C/C⋯H (14.9%) surface contacts. Further, the inter-action energies, largely dominated by the dispersive term, point to the stabilizing influence of H⋯H and O⋯O contacts in the inter-layer region.

1-Ethyl 2-methyl 3,4-bis-(acet-yloxy)pyrrolidine-1,2-di-carboxyl-ate: crystal structure, Hirshfeld surface analysis and computational chemistry.

The title compound, C13H19NO8, is based on a tetra-substituted pyrrolidine ring, which has a twisted conformation about the central C-C bond; the Cm-Ca-Ca-Cme torsion angle is 38.26 (15)° [m = methyl-carboxyl-ate, a = acet-yloxy and me = methyl-ene]. While the N-bound ethyl-carboxyl-ate group occupies an equatorial position, the remaining substituents occupy axial positions. In the crystal, supra-molecular double-layers are formed by weak methyl- and methyl-ene-C-H⋯O(carbon-yl) inter-actions involving all four carbonyl-O atoms. The two-dimensional arrays stack along the c axis without directional inter-actions between them. The Hirshfeld surface is dominated by H⋯H (55.7%) and H⋯C/C⋯H (37.0%) contacts; H⋯H contacts are noted in the inter-double-layer region. The inter-action energy calculations point to the importance of the dispersion energy term in the stabilization of the crystal.

Is breaking of a hydrogen bond enough to lead to drug resistance?

Drug resistance is a serious problem in cancer, viral, bacterial, fungal and parasitic diseases. Examination of crystal structures of protein-drug complexes is often not enough to explain why a certain mutation leads to drug resistance. As an example, the crystal structure of the kinase inhibitor dasatinib bound to the Abl1 kinase shows a hydrogen bond between the drug and residue Thr315 and very few contacts between the drug and residues Val299 and Phe317, yet mutations in those residues lead to drug resistance. In the first case, it is tempting to suggest that the loss of a hydrogen bond leads to drug resistance, whereas in the other two cases it is not known why mutations lead to drug resistance in the first place. We carried out extensive molecular dynamics (MD) simulations and free energy calculations to explain drug resistance to dasatinib from a molecular point of view and show that resistance is due to a multitude of subtle effects. Importantly, our calculations could reproduce the experimental values for the binding energies upon mutations in all three cases and shed light on their origin.

Ethyl 3,4-bis-(acet-yloxy)-2-(4-meth-oxy-phen-yl)pyrrol-idine-1-carboxyl-ate.

The title pyrrolidine compound, C18H23NO7, is a tetra-substituted species in which the five-membered ring has a twisted conformation with the twist occurring in the C-C bond bearing the adjacent acet-yloxy substituents; the Cm-Ca-Ca-Cp torsion angle is -40.76 (18)° [m = methyl-ene, a = acet-yloxy and p = phen-yl]. The N atom, which is sp 2-hybridized [sum of bond angles = 359.4°], bears an ethyl-carboxyl-ate substitutent and is connected to a methyl-ene-C atom on one side and a carbon atom bearing a 4-meth-oxy-phenyl group on the other side. Minor disorder is noted in the ethyl-carboxyl-ate substituent as well as in one of the acet-yloxy groups; the major components of the disorder have site occupancies of 0.729 (9) and 0.62 (3), respectively. The most notable feature of the mol-ecular packing is the formation of helical, supra-molecular chains aligned along the b-axis direction whereby the carbonyl-O atom not involved in a disordered residue accepts C-H⋯O inter-actions from methyl-ene-H and two-C atom separated methine-H atoms to form a six-membered {⋯HCCCH⋯O} synthon.

Stereo- and regioselective cu-catalyzed hydroboration of alkynyl chalcogenoethers

A mild stereo- and regioselective Cu-catalyzed hydroboration method for the synthesis of (Z)-seleno-alkenyl boronates and (Z)-thio-alkenylboronates from internal alkynes in the presence of commercially available B2pin2 is presented. This highly selective transformation relies on the use of N-heterocyclic carbene (NHC) complex IPrCuCl as the active catalytic species. We also explore the functionalization of the alkenylboronates obtained via oxidation to give a -chalcogeno ketones, useful building blocks for the synthesis of more complex chalcogen-containing molecules.

Stereo- and regioselective cu-catalyzed hydroboration of alkynyl chalcogenoethers

A mild stereo- and regioselective Cu-catalyzed hydroboration method for the synthesis of (Z)-seleno-alkenyl boronates and (Z)-thio-alkenylboronates from internal alkynes in the presence of commercially available B2pin2 is presented. This highly selective transformation relies on the use of N-heterocyclic carbene (NHC) complex IPrCuCl as the active catalytic species. We also explore the functionalization of the alkenylboronates obtained via oxidation to give a -chalcogeno ketones, useful building blocks for the synthesis of more complex chalcogen-containing molecules.

2-Methyl-4-(4-nitro-phen-yl)but-3-yn-2-ol: crystal structure, Hirshfeld surface analysis and computational chemistry study.

The di-substituted acetyl-ene residue in the title compound, C11H11NO3, is capped at either end by di-methyl-hydroxy and 4-nitro-benzene groups; the nitro substituent is close to co-planar with the ring to which it is attached [dihedral angle = 9.4 (3)°]. The most prominent feature of the mol-ecular packing is the formation, via hy-droxy-O-H⋯O(hy-droxy) hydrogen bonds, of hexa-meric clusters about a site of symmetry . The aggregates are sustained by 12-membered {⋯OH}6 synthons and have the shape of a flattened chair. The clusters are connected into a three-dimensional architecture by benzene-C-H⋯O(nitro) inter-actions, involving both nitro-O atoms. The aforementioned inter-actions are readily identified in the calculated Hirshfeld surface. Computational chemistry indicates there is a significant energy, primarily electrostatic in nature, associated with the hy-droxy-O-H⋯O(hy-droxy) hydrogen bonds. Dispersion forces are more important in the other identified but, weaker inter-molecular contacts.

2-[(4-Bromo-phen-yl)sulfan-yl]-2-meth-oxy-1-phenyl-ethan-1-one: crystal structure, Hirshfeld surface analysis and computational chemistry.

The title compound, C15H13BrO2S, comprises three different substituents bound to a central (and chiral) methine-C atom, i.e. (4-bromo-phen-yl)sulfanyl, benzaldehyde and meth-oxy residues: crystal symmetry generates a racemic mixture. A twist in the mol-ecule is evident about the methine-C-C(carbon-yl) bond as evidenced by the O-C-C-O torsion angle of -20.8 (7)°. The dihedral angle between the bromo-benzene and phenyl rings is 43.2 (2)°, with the former disposed to lie over the oxygen atoms. The most prominent feature of the packing is the formation of helical supra-molecular chains as a result of methyl- and methine-C-H⋯O(carbon-yl) inter-actions. The chains assemble into a three-dimensional architecture without directional inter-actions between them. The nature of the weak points of contacts has been probed by a combination of Hirshfeld surface analysis, non-covalent inter-action plots and inter-action energy calculations. These point to the importance of weaker H⋯H and C-H⋯C inter-actions in the consolidation of the structure.

Ion-Pair Complexes of Pyrylium and Tetraarylborate as New Host-Guest Dyes: Photoinduced Electron Transfer Promoting Radical Polymerization.

Ultrafast transient absorption spectroscopy, NOESY-NMR, and EPR spectroscopy shed light on how π-π stacking interactions combined with electrostatic interactions can be used to form stable ion-pair complexes between pyrylium and tetraarylborate ions in which the interaction of the π-delocalized clouds promotes the observation of new radiative processes and also electron transfer processes excitation using visible light. The results exhibit a striking combination of properties, chemical stability and photophysical and photochemical events, that make these ion-pair complexes as a step toward the realization of chromophore/luminescent materials and also their use as a new monophotoinitiator system in radical polymerization reactions.

Synthesis of (Z)-ß-halo α,ß-unsaturated carbonyl systems via the combination of halotrimethylsilane and tetrafluoroboric acid.

A convenient and broadly applicable method for the hydrohalogenation of ynones is described, by the combination of halotrimethylsilanes and tetrafluoroboric acid. Practically, one equivalent of HX (Brønsted acid) and BF3 (Lewis acid) is smoothly generated, which activates the carbonyl compounds. Through this protocol, 42 examples of (Z)-ß-halovinyl carbonyl compounds (Cl, Br and I) were obtained, in good yields and high stereoselectivity having 2-MeTHF as a solvent.

Spectroscopic and theoretical studies of some 2­(methoxy)­2­[(4­substituted)­phenylsulfanyl]­(4'­substituted) acetophenones.

The conformational analysis of some 2­(methoxy)­2­[(4­substituted)­phenylsulfanyl]­(4'­substituted) acetophenones was performed through infrared (IR) spectroscopic analysis of the carbonyl stretching band (νCO), supported by B3LYP/6-31+G(d,p) calculations and X-ray diffraction. Five (1-5) of the seven studied compounds (1-7) presented Fermi resonance (FR) on the νCO fundamental transition band. Deuteration of these compounds (1a-5a) precluded the occurrence of FR, revealing a νCO doublet for all compounds in all solvents used. The computational results indicated the existence of three conformers (c1, c2 and c3) for the whole series whose relative abundances varied with solvent permittivity. The higher νCO frequency c1 conformer was assigned to the higher frequency component of the carbonyl doublet, while both c2 and c3 were assigned to the lower frequency one. Anharmonic vibrational frequencies and Potential Energy Distribution (PED) calculations of compound 3 indicated that the combination band (cb) between the methyne δCH and one skeletal mode couples with the νCO mode giving rise to the FR on the c2 conformer in vacuum and on the c1 one in non-polar solvents. The experimental data indicated a progressive increase in c1 conformer stability with the increase of the solvent dielectric constant, which is in good agreement with the polarizable continuum model (PCM) calculations. The higher νCO frequency and the stronger solvation of the c1 conformer is a consequence of the repulsive field effect (RFE) originated by the alignment and closeness of the Cδ+Oδ- and Cδ+Oδ- dipoles. Finally, the balance between orbital and electrostatic interactions dictates the conformational preferences. X-ray single crystal analysis for compound 6 revealed the c1 geometry in the solid state and its stabilization by CH…O hydrogen bonds.

Stereoselective oxa-Michael addition of tyrosine to propargyl aldehyde/esters: formation of benzofurans and flavones

The steroselective oxa-Michael addition of the phenol moiety present in tyrosine and 3-iodotyrosine to different propargyl aldehydes delivered products with predominantly Z stereochemistry, as evidenced by X-ray crystallography analysis. When ethyl ropiolate was used as the propargyl ester source, the products were achieved with exclusively E stereochemistry with yields ranging from 17% to 91%. The oxa-Michael addition compounds served as substrates in the synthesis of 5- and 6-membered heterocyclic compounds. The atmosphere applied to the reaction medium directly influenced the formation of the products. When an inert atmosphere of nitrogen was applied, a 2-aryl-3-formyl-5-alanylbenzofuran core was selectively obtained via a Heck intramolecular reaction, while the reactions carried out under a carbon monoxide atmosphere led exclusively to 6-alanyl-2-arylflavone derivatives via reductive intramolecular acylation.

Iron (III)-promoted synthesis of substituted 4H-Chalcogenochromenes and chemoselective functionalization

The iron(III)-promoted synthesis of densely-substituted 4H-chalcogenchromene from organochalcogen propargylamines in the presence of diaryl dichalcogenides is reported. Subsequent C2-functionalization with electrophiles and potassium trifluoroborate salts via Suzuki-Miyaura coupling reaction are also presented. A plausible mechanism based on HRMS experiments is proposed and discussed.