Bioorganic Chemistry Research Group
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Welcome to the Biological and Computational Chemistry Research Group

The Biological and Computational Chemistry group focus its activity on pursuing new insights in to our understanding of health related biological processes. With a wide experience on asymmetric organic synthesis the group is interested in the design and synthesis of small molecules for therapeutic application or their use in the elucidation of biological functions. By combining a series of multidisciplinary tools and techniques including in-house developed synthetic methodologies, computer-based molecular modelling (QM calculations, docking and Molecular Dynamics) and advanced spectroscopic techniques (i.e. STD-NMR), the main activity of the group concerns identification of small molecules as key modulators and/or inhibitors of target enzymes associated to specific biological functions. This approach provides target validation as well as starting points for further drug discovery.

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Currently, the group is dedicating major efforts in the clmputational study of diverse mechanisms of enzymatic reactions using QM/MM methods. We are also interested in organic reaction mechanisms, with special dedication to organocatalytic and metal-catalyzed reactions.


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Group Announcements on Recent Research Achievements   News & Events

SE OFRECEN DOS CONTRATOS para Graduados en Quimica, Botecnologia o Farmacia.

El trabajo realizado podrá presentarse como Trabajo Fin de máster

Published book
Chemical Biology of Neurodegeneration (P. Merino), Wiley-VCH 2020
Inside Cover
in Org. Biomol. Chem.
Review on Reactivity
See Cover and read
Cover Picture (Hot paper)
in Chem. Eur. J.
Congratulations Vero!
See Cover and read Cover Profile
Cover Picture (Editor`s choice) in
Chem. Biol. Drug Design
Congratulations Eduardo!
Ongoing work ...  

Currently we are working on several enzymatic mechanisms using QM/MM techniques and various organic reactions mechanism using classical QM but also less used MD simulatons with explicit solvents

Figure. Left: A transition structure of a glycosylation reaction. iddle Left: An organic reacion embedded in a box of THF molecules and a transition structure. Middle Right: A NCI analysis of non-covalent ineractions in a transition structure.Right. QM/MD of a bifurcation reaction.

Acyl Migration in Carbohydrates. Experimental and computational studies  
Published in Chem. Eur. J. 2022,  

Full mechanistic model, based on computations, demonstrates that the acyl migration proceeds through an anionic stepwise mechanism with linear dependence on the [OH- ] and the pKa of the hydroxyl group toward which the acyl group is migrating.

Molecular Dynamics simulations of Glucocerebrosidase (GCase) Inhibitors  
Published in J. Org. Chem. 2021,86, 12745-12761.  

Stable complexes of piperidine ligands bearing alkyl chains were reached after 10 ns of simulation and continued to be stable for 250 ns 462 (all MD simulations were replicated four times). The complexes showed the ligand in the binding site establishing different interactions with key residues Asp128, Trp180, Asn235, Glu236, Tyr314, and Glu341 and with the correct orientation of the piperidine ring. The ligands showed a complete stability of chair conformations and tend to arrange the aliphatic chains toward the external part, exposed to the solvent, in order to keep interactions of the hydroxyl groups of the piperidine ring.

Atropoisomerism in Asymmetric Catalysis  
Published in Chem. Sci. 2021, 12, 15291-15297.  

A copper-catalyzed asymmetric intramolecular reductive cyclization for the synthesis of dibenzo[b,d]azepines is described. Use of 2'-vinyl-biaryl-2-imines as substrates and in situ formed [CuI/(Ph-BPE)] as the catalyst enables the synthesis of 7-membered bridged biarylamines containing both central and axial stereogenic elements in high yields (up to 98%) and with excellent diastereo- and enantioselectivities (>20:1 dr, up to 99% ee).

Quantitative NCI in Anion-Binding Enantioselective Organocatalysis  
Published in Angew. Chem. Int. Ed. 2021, 60, 5096-5101.  

A highly enantio- and diastereoselective thioureacatalyzed dearomatization of isoquinolines employing N-tert-butyl hydrazones as neutral α-azo carbanion and masked acyl anion equivalents has been developed. Experimental and computational data supports the generation of highly ordered complexes wherein the chloride behaves as a template for the catalyst, the hydrazone reagent and the isoquinolinium cation, providing an excellent stereocontrol in the formation of two contiguous stereogenic centers. Ensuing selective and high-yielding transformations provide appealing dihydroisoquinoline derivatives.

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The Essential Role of Anomeric-β-Triflates in Glycosylation Reactions.  
Posted September, 2020  

Glycosylations promoted by triflate-generating reagents are widespread synthetic methods for the construction
of glycosidic scaffolds and glycoconjugates of biological and chemical interest. These processes are thought to proceed with the participation of a plethora of activated high energy intermediates such as the α- and β-glycosyl triflates, or even increasingly unstable glycosyl oxocarbenium-like species, among which only α-glycosyl triflates have been well characterized under representative reaction conditions. Interestingly, the remaining less accessible intermediates, yet to be experimentally described, seem to be particularly relevant in α-selective processes, involving weak acceptors. A detailed analysis of several paradigmatic and illustrative examples of such reactions, employing a combination of chemical, NMR, kinetic and theoretical approaches, culminating in the unprecedented detection and quantification of the true β-glycosyl triflate intermediates within activated donor mixtures conclusively show that, even for highly dissociative reactions involving β-close ion pair
(β-CIP) species, the formation of the α-glycoside is necessarily preceded by a bimolecular α → β triflate interconversion, which under certain circumstances becomes the rate-limiting step. Overall, our results rule out the prevalence of the Curtin−Hammett fastexchange assumption for most glycosylations and highlight the distinct reactivity properties of α- and β-glycosyl triflates against neutral and anionic acceptors.


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Open-to-Closed Motion in Mannosyltransferase PimA.  
Posted May, 2020  

The phosphatidyl-myo-inositol mannosyltransferase A (PimA) is an essential peripheral membrane glycosyltransferase that initiates the biosynthetic pathway of phosphatidyl-myo-inositol mannosides (PIMs), key structural elements and virulence factors of Mycobacterium tuberculosis. PimA undergoes functionally important conformational changes, including (i) α-helix-to-β-strand and β-strand-to-α-helix transitions and (ii) an “open-toclosed” motion between the two Rossmann-fold domains, a conformational change that is necessary to generate a catalytically competent active site. The nucleotide moiety of GDPMan, and not the sugar ring, facilitates the “open-to-closed” motion, with the β-phosphate group providing the high-affinity binding to PimA. Altogether, the experimental data contribute to a better understanding of the structural determinants involved in the “opento-closed” motion not only observed in PimA but also visualized and/or predicted in other glycosyltransfeases.

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DFT Studies on the Ennatioselective Organocatalytic Synthesis of Tropanols.  
Posted March, 2020  

The enantioselective synthesis of tropanols has been accomplished through chiral phosphoric acid catalyzed pseudotransannular ring opening of 1-aminocyclohept-4-enederived epoxides. The reaction proceeds together with the desymmetrization of the starting material and leads to the direct formation of the 8-azabicyclo[3.2.1]octane scaffold with excellent stereoselectivity. The synthetic applicability of the reaction was demonstrated by the enantioselective synthesis of the two natural products ()-a-tropanol and (+)-ferruginine.

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Concerted albeit not Pericyclic Cycloadditions.  
Posted December, 2019  

The mechanism of (4+3) cycloaddition reactions of nitrones with 1,2-diaza-1,3-dienes has been studied by using density functional theory (DFT) methods. The cycloaddition reaction takes place through an asynchronous concerted transition state that reflects a two-stage process in which the formation of the first bond occurs close to the transition state, while the second bond forms well after the transition state.

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Antineoplastic Activity of 1-Azaspiro derivatives on Drug- Resistant Leukemias.  
Posted December, 2019  

The addition of 2-bromobenzylmagnesium bromide to chiral N-tert-butanesulfinyl imines provided sulfinamide derivatives that were transformed into dibenzoazaspiro compounds after a palladiumcatalyzed
intramolecular N-arylation. DFT calculations have been performed to rationalize the stereochemical course of the reaction. NCI topological calculations have also been used to evidence crucial noncovalent interactions.The azaspiro compounds reduced the viability of chronic myeloid leukemia cells in the micromolar


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UDP-GlcNAc Analogs as Inhibitors of O-GlcNAc Transferase (OGT).  
Posted March, 2018  

A series of glycomimetics of UDP-GlcNAc in which the β-phosphate has been replaced by either an alkyl chain or a triazolyl ring and the sugar moiety has been replaced by a pyrrolidine ring counterbalance with the presence of hydrophobic groups the lack of beta-phosphate. Two of the glycomimetics prepared reach inhibition in the micromolar scale.


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Inhibitors against Fungal Cell Wall-remodelling Enzymes.  
Posted February, 2018  

Fungal beta-1,3-glucan glucanosyltransferases are glucan-remodeling enzymes that play important roles in cell wall integrity, and are essential for the viability of pathogenic fungi/yeasts. A structure-guided design using a highly conserved transglycosylase from Sacharomyces cerevisiae led to carbohydrate derivatives with high affinity for Aspergillus fumigatus Gel4. Topological anayses seerved to identify main interactions.


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A small molecule inhibitis GalNAc-T2.  
Posted December, 2017  

A fruitful collaboration led to discover that small molecules are capable of inhibiting glycosyltransferases in sch a efficient way like complex bisubstrates. This study study provides a base of structure and kinetics for further optimization to develop more potent and specific selective inhibitor of ppGalNAc-T to explore site-specific O-GalNAc glycosylation and a new perspective for exploring the molecular mechanism of luteolin.

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A New Perspective to Study Organic Reactivity  
Posted April 2, 2017  
The reactivity of nitrones in cycloadditions and related reactions is revisited by introducing a topological perspective.

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Organocatalytic Oxa-Michael Reactions  
Posted March 3, 2017  
A collaboration with Prof. Vicario's research group at the University of Basque Country (Bilbao, Spain) showed that 2-hydroxydihydropyran-5-ones behave as excellent polyfunctional reagents able to react with enals through oxa-Michael/Michael process cascade under the combination of iminium and enamine catalysis.
Read more .... (Open Access)  
Inhibitors of Isoprenoid Biosynthesis  
Posted February 10, 2017  
A review. approaches currently employed to synthesize new inhibitors of isoprenoid biosynthesis.

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Highly Enantioselective Organocatalytic Reactions with Nitrone Ylides.  
Posted February 10, 2017  
A new publication from Vero's Ph.D. Thesis. Congratulations Vero!. The work made in collaboration with Prof. Vicario's research group at the University of Basque Country (Bilbao, Spain) established that reaction of nitrones with enals under iminium activation can be modulated by using cooperative H-bonding catalysis to induce the participation of a nitrone ylide (C-N-C) instead of the classical C-N-O dipole
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Evidences of Carbocation Intermediates in Thionation of Alcohols  
Posted February 10, 2017  
Evidences that carbocations are involved in the mechanism of the thionation of alcohols with Lawesson's reagent have been found. The mechanism is completely different to that recently established for thionation of carbonyls. The presence of a phenyl ring at the alcoholic carbon exerts a pivotal role in the stability of the carbocation, enabling an S-π interaction which is crucial for favoring thionation instead undesired elimination. The study is in a complete agreement with the different behavior observed experimentally for primary, secondary and tertiary alcohols (bearing a phenyl ring or not) and predict the best conditions for minimizing undesired elimination.
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