Julia Revuelta

A DFT study on the 1,3-dipolar cycloaddition reactions of C-(methoxycarbonyl)-N-methyl nitrone with methyl acrylate and vinyl acetate

In the 1,3-dipolar cycloaddition of glyoxylic nitrones with electron-poor and electron-rich alkenes, the configurational instability of the nitrone leads to parallel models when regio- and stereoselectivities are rationalized. The energetics of the cycloaddition reactions have been investigated through molecular orbital calculations at the B3LYP/6-31-G(d) theory level. By studying different reaction channels and reagent conformations, leading to a total of sixteen transition structures for each dipolarophile, the regio- and stereochemical preferences of the reaction are discussed.

A comparative study of the stereoselective addition of trimethylsilyl cyanide and diethylaluminum cyanide to chiral cyclic nitrones

The mild cyanating agent trimethylsilyl cyanide adds with total stereoselectivity to α-alkoxy cyclic nitrones to afford the corresponding trans-hydroxyaminonitriles. The addition of Lewis acids to precomplexing the nitrones does not affect the stereoselectivity of these additions significantly. In all of the cases examined, excellent yields of diastereomerically homogeneous products were obtained. On the other hand, the use of diethylaluminum cyanide as cyanating agent leads to low diastereoselectivities. Both NMR studies and theoretical calculations show that whereas the addition of trimethylsilyl cyanide takes place through a concerted mechanism, in the addition of diethylaluminum cyanide, a complex is formed prior to the intramolecular delivery of the cyanide ion.

Role of Aromatic Rings in the Molecular Recognition of Aminoglycoside Antibiotics: Implications for Drug Design

Aminoglycoside antibiotics participate in a large variety of binding processes involving both RNA and proteins. The description, in recent years, of several clinically relevant aminoglycoside/receptor complexes has greatly stimulated the structural-based design of new bioactive derivatives. Unfortunately, design efforts have frequently met with limited success, reflecting our incomplete understanding of the molecular determinants for the antibiotic recognition. Intriguingly, aromatic rings of the protein/RNA receptors seem to be key actors in this process. Indeed, close inspection of the structural information available reveals that they are frequently involved in CH/pi stacking interactions with sugar/aminocyclitol rings of the antibiotic. While the interaction between neutral carbohydrates and aromatic rings has been studied in detail during past decade, little is known about these contacts when they involve densely charged glycosides. Herein we report a detailed experimental and theoretical analysis of the role played by CH/pi stacking interactions in the molecular recognition of aminoglycosides. Our study aims to determine the influence that the antibiotic polycationic character has on the stability, preferred geometry, and dynamics of these particular contacts. With this purpose, different aminoglycoside/aromatic complexes have been selected as model systems. They varied from simple bimolecular interactions to the more stable intramolecular CH/pi contacts present in designed derivatives. The obtained results highlight the key role played by electrostatic forces and the desolvation of charged groups in the molecular recognition of polycationic glycosides and have clear implications for the design of improved antibiotics.

Experimental and theoretical study of the 1,3-dipolar cycloaddition between d-glyceraldehyde nitrones and acrylates. Diastereoselective approach to 4-hydroxy pyroglutamic acid derivatives

Abstract The 1,3-dipolar cycloaddition reactions of five d -glyceraldehyde nitrones with alkyl acrylates and Oppolzers sultam acrylamide have been studied in detail, the study including double chiral induction experiments. A complete theoretical study of the reaction has also been carried out using density functional methods (B3LYP/6-31G*) in which both ortho and meta channels leading to 3,5- and 3,4-disubstituted isoxazolidines, respectively, were considered. The adducts obtained from the cycloaddition reactions have been further used for the stereoselective synthesis of protected 4-hydroxy pyroglutamic acids, particularly the (2S,4S)-isomer, which is prepared from the major adducts of the cycloaddition reactions.

Enantioselective synthesis of 4-hydroxy-d-pyroglutamic acid derivatives by an asymmetric 1,3-dipolar cycloaddition

Abstract The 1,3-dipolar cycloaddition of a chiral nitrone derived from glyoxylic acid and protected d -ribosyl hydroxylamine with the acrylamide of Oppolzers sultam provides a perfectly stereoselective approach to protected (2 R ,4 R )-4-hydroxy- d -pyroglutamic acid.

Synthesis, structure, theoretical and experimental in vitro antioxidant/pharmacological properties of α-aryl, N-alkyl nitrones, as potential agents for the treatment of cerebral ischemia

The synthesis, structure, theoretical and experimental in vitro antioxidant properties using the DPPH, ORAC, and benzoic acid, as well as preliminary in vitro pharmacological activities of (Z)-α-aryl and heteroaryl N-alkyl-nitrones 6-15, 18, 19, 21, and 23, is reported. In the in vitro antioxidant activity, for the DPPH radical test, only nitrones bearing free phenol groups gave the best RSA (%) values, nitrones 13 and 14 showing the highest values in this assay. In the ORAC analysis, the most potent radical scavenger was nitrone indole 21, followed by the N-benzyl benzene-type nitrones 10 and 15. Interestingly enough, the archetypal nitrone 7 (PBN) gave a low RSA value (1.4%) in the DPPH test, or was inactive in the ORAC assay. Concerning the ability to scavenge the hydroxyl radical, all the nitrones studied proved active in this experiment, showing high values in the 94-97% range, the most potent being nitrone 14. The theoretical calculations for the prediction of the antioxidant power, and the potential of ionization confirm that nitrones 9 and 10 are among the best compounds in electron transfer processes, a result that is also in good agreement with the experimental values in the DPPH assay. The calculated energy values for the reaction of ROS (hydroxyl, peroxyl) with the nitrones predict that the most favourable adduct-spin will take place between nitrones 9, 10, and 21, a fact that would be in agreement with their experimentally observed scavenger ability. The in vitro pharmacological analysis showed that the neuroprotective profile of the target molecules was in general low, with values ranging from 0% to 18.7%, in human neuroblastoma cells stressed with a mixture of rotenone/oligomycin-A, being nitrones 18, and 6-8 the most potent, as they show values in the range 24-18.4%.

A simple NMR analysis of the protonation equilibrium that accompanies aminoglycoside recognition: Dramatic alterations in the neomycin-B protonation state upon binding to a 23-mer RNA aptamer

A complete characterisation of the protonation equilibrium that accompanies the molecular recognition of neomycin-B by a specific RNA receptor has been achieved by employing simple NMR measurements.

A General Method for the Vinylation of Nitrones. Synthesis of Allyl Hydroxylamines and Allyl Amines

Abstract An examination of the vinylation of several nitrones is presented. Whereas a complete diastereofacial discrimination was observed upon the addition of vinyl organometallic reagents to α-alkoxy nitrones, the same reaction with α-amino nitrones gave syn adducts in all cases, with the only exception of a L-serine-derived α-amino monoprotected nitrone. The obtained allyl hydroxylamines were easily transformed into synthetically valuable allyl amines.

Role of conserved salt bridges in homeodomain stability and DNA binding.

The sequence information available for homeodomains reveals that salt bridges connecting pairs 19/30, 31/42, and 17/52 are frequent, whereas aliphatic residues at these sites are rare and mainly restricted to proteins from homeotherms. We have analyzed the influence of salt and hydrophobic bridges at these sites on the stability and DNA binding properties of human Hesx-1 homeodomain. Regarding the protein stability, our analysis shows that hydrophobic side chains are clearly preferred at positions 19/30 and 31/42. This stabilizing influence results from the more favorable packing of the aliphatic side chains with the protein core, as illustrated by the three-dimensional solution structure of a thermostable variant, herein reported. In contrast only polar side chains seem to be tolerated at positions 17/52. Interestingly, despite the significant influence of pairs 19/30 and 31/42 on the stability of the homeodomain, their effect on DNA binding ranges from modest to negligible. The observed lack of correlation between binding strength and conformational stability in the analyzed variants suggests that salt/hydrophobic bridges at these specific positions might have been employed by evolution to independently modulate both properties.

Structure‐Based Design of Highly Crowded Ribostamycin/Kanamycin Hybrids as a New Family of Antibiotics

Aminoglycoside antibiotics are highly potent, wide-spectrum bactericidals. These drugs bind to the aminoacyl-tRNA site (A-site) in the ribosome decoding region inducing codon misreading and inhibiting translocation, which eventually results in cell death. Unfortunately, their use in clinical practice has been seriously limited as a result of their toxicity and susceptibility to enzymatic inactivation prompting the search for new active derivatives. Most aminoglycosides incorporate an aminocyclitol unit called 2-deoxystreptamine (2-DOS) that can exhibit two alternative glycosidation patterns, giving rise to the so-called 4,5-DOS and 4,6-DOS subfamilies (Scheme 1). The relevance of the different sugar units for biological activity has been firmly established from structural and functional studies. Thus, the pseudodisaccharide fragment I/II (see Scheme 1), with slightly different patterns of OH/NH2 distribution in unit I, is present in most aminoglycosides and has been shown to be essential for specific complex formation with the prokaryotic 16S RNA. Despite their secondary importance, sugar units at the 5or 6-positions in the 2-DOS ring provide additional contacts with the lower and upper stems, respectively, of the RNA receptor as shown by detailed NMR and crystallographic studies carried out in recent years (represented in Scheme 1 and Figure 1).