Synthesis and N-functionalization of isoxazolidines: a new approach to nucleoside analogues

A straightforward synthetic approach for the preparation of non N-functionalized isoxazolidines from BF₃-catalyzed 1,3-cycloaddition reactions between methyl glyoxylate oxime and alkenes is described. Subsequently, isoxazolidines were N-functionalized with three chemically active groups (2-chloroethyl, cyanomethyl and 2-acetoxyethyl), thus allowing the preparation of a wide array of N-functionalized isoxazolidines. The compounds were characterized by means of ¹H and ¹³C NMR spectroscopy and mass spectrometry. X-ray analysis was used for stereochemical elucidation.     

X-Ray Crystallography and Free Energy Calculations Reveal the Binding Mechanism of A2A Adenosine Receptor Antagonists

We present a robust protocol based on iterations of free energy perturbation (FEP) calculations, chemical synthesis, biophysical mapping and X-ray crystallography to reveal the binding mode of an antagonist series to the A_2A adenosine receptor (AR). Eight A_2AAR binding site mutations from biophysical mapping experiments were initially analyzed with sidechain FEP simulations, performed on alternate binding modes. The results distinctively supported one binding mode, which was subsequently used to design new chromone derivatives. Their affinities for the A_2AAR were experimentally determined and investigated through a cycle of ligand-FEP calculations, validating the binding orientation of the different chemical substituents proposed. Subsequent X-ray crystallography of the A_2AAR with a low and a high affinity chromone derivative confirmed the predicted binding orientation. The new molecules and structures here reported were driven by free energy calculations, and provide new insights on antagonist binding to the A_2AAR, an emerging target in immuno-oncology.     

Synthesis of methyl (±)-3,5-bis(substitutedmethyl)pyrrolidine-2-carboxylates: a convenient approach to proline-mimetics

Starting from readily available N-benzyl protected methyl 3,5-bis(hydroxymethyl)pirrolidinecarboxylate a number of racemic methyl t-3,t-5-disubstitutedprolinates have been synthesised, thus opening a practical way towards the preparation of a variety of putative proline-mimetics. In this context, N-Boc protected derivatives proved to be better intermediates than their N-benzyl counterparts in terms of cleanness and overall yield of the synthetic procedure.     

Highly diastereoselective synthesis of 2-azabicyclo[2.2.1]hept-5-ene derivatives: Bronsted acid catalyzed aza-Diels-Alder reaction between cyclopentadiene and imino-acetates with two chiral auxiliaries

The cycloaddition between protonated glyoxylate imines possessing two chiral auxiliaries, N-(S)- or N-(R)-1-phenylethyl and (−)-8-phenylmenthyl or (+)-8-phenylneomenthyl, and cyclopentadiene is described. The absolute configuration of all adducts formed was unequivocally assigned through NMR, specific optical rotation, and X-ray data of appropriated derivatives. Experimental results confirm the highly exo-selectivity for these aza-Diels-Alder reactions, single adducts being obtained from combinations of (8PM)-(R-PEA) and (8PNM)-(S-PEA).     

Aza‐Diels–Alder reaction between cyclopentadiene and protonated N‐phenylethyliminoacetates of 8‐phenylmenthol and 8‐phenylneomenthol: a density functional theory study

The cycloaddition between glyoxylate imines possessing two chiral auxiliaries, N‐(R)‐ or N‐(S)‐1‐phenylethyl and 8‐phenylmenthyl or 8‐phenylneomenthyl, and cyclopentadiene is described. Computational calculations using density functional theory with the Becke, three‐parameter, Lee–Yang–Parr functional and the 6‐31G(d) basis set were performed to better understand the highly diastereoselective mechanism and the exo‐selectivity observed experimentally for these ionic aza‐Diels–Alder reactions. Copyright © 2011 John Wiley & Sons, Ltd.     

Theoretical study of GSK−3<Emphasis Type="Italic">α</Emphasis>: neural networks QSAR studies for the design of new inhibitors using 2D descriptors

Glycogen synthase kinase-3 (GSK-3) targets encompass proteins implicated in AD and neurological disorders. The functions of GSK-3 and its implication in various human diseases have triggered an active search for potent and selective GSK-3 inhibitors. In this sense, QSAR could play an important role in studying these GSK-3 inhibitors. For this reason, we developed QSAR models for GSK−3α, linear discriminant analysis (LDA), and artificial neural networks (ANNs) from nearly 50,000 cases with more than 700 different GSK−3α inhibitors obtained from ChEMBL database server; in total we used more than 20,000 different molecules to develop the QSAR models. The model correctly classified 237 out of 275 active compounds (86.2%) and 14,870 out of 15,970 non-active compounds (93.2%) in the training series. The overall training performance was 93.0%. Validation of the model was carried out using an external predicting series. In these series, the model classified correctly 458 out of 549 (83.4%) compounds and 29,637 out of 31,927 non-active compounds (83.4%). The overall predictability performance was 92.7%. In this study, we propose three types of non-linear ANN as alternative to already existing models, such as LDA. Linear neural network: LNN: 236:236-1-1:1 which had an overall training performance of 96% proved to be the best model. In addition, we did a study of the different fragments of the molecules of the database to see which fragments had more influence in the activity. This can help design new inhibitors of GSK−3α. This study reports the attempts to calculate, within a unified framework probabilities of GSK−3α inhibitors against different molecules found in the literature.     

X‐Ray Crystallography and Free Energy Calculations Reveal the Binding Mechanism of A2A Adenosine Receptor Antagonists

We present a robust protocol based on iterations of free energy perturbation (FEP) calculations, chemical synthesis, biophysical mapping and X‐ray crystallography to reveal the binding mode of an antagonist series to the A_2A adenosine receptor (AR). Eight A_2AAR binding site mutations from biophysical mapping experiments were initially analyzed with sidechain FEP simulations, performed on alternate binding modes. The results distinctively supported one binding mode, which was subsequently used to design new chromone derivatives. Their affinities for the A_2AAR were experimentally determined and investigated through a cycle of ligand‐FEP calculations, validating the binding orientation of the different chemical substituents proposed. Subsequent X‐ray crystallography of the A_2AAR with a low and a high affinity chromone derivative confirmed the predicted binding orientation. The new molecules and structures here reported were driven by free energy calculations, and provide new insights on antagonist binding to the A_2AAR, an emerging target in immuno‐oncology.     

Synthesis of novel purinyl-1'-homocarbanucleosides based on a cyclopenta[b]pyrazine system

cis-2,3-Diphenyl-6,7-dihydro-5H-cyclopenta[b]pyrazine-5,7-dimethanol, prepared by Diels-Alder reaction from cyclopentadiene and appropriately protected 2-imidazolone--followed by dihydroxylation, glycol protection, diamine deprotection, condensation with benzyl, glycol deprotection, oxidative cleavage and reduction--, was used to synthesize (+/-)-cis-([7-(6-chloro-9H-purin-9-yl)methyl]-2,3-diphenyl-6,7-dihydro-5H-cyclopenta[b]pyrazin-5-yl)methanol, a key intermediate for novel 1'-homocarbanucleosides based on a cyclopenta[b]pyrazine scaffold as shown by its conversion into several 6-substituted purinyl derivatives.     

1,3- versus 1,4-[π4+π2] Cycloadditions between methyl glyoxylate oxime and cyclopentadiene or cyclopentene

The acid catalyzed cycloaddition reaction of methyl glyoxylate oxime with cyclopentadiene (CPD) afforded the corresponding aza-Diels–Alder adducts, the endo and exo isomers of (±)-methyl 2-hydroxy-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylates, and as the major product a 1,3-cycloadduct, methyl (1RS,4RS,5RS)-(2-oxa-3-azabicyclo[3.3.0]oct-7-ene)-4-carboxylate. The similar reaction using cyclopentene (CP) provided only the 1,3-cycloadduct methyl (1SR,4RS,5SR)-(2-oxa-3-azabicyclo[3.3.0]octane)-4-carboxylate. The influence of various parameters on the reaction outcome was studied and, based on the results obtained, a mechanism for the formation of both 1,3- and 1,4-cycloadducts is proposed. The structure of all adducts was confirmed by NMR spectroscopic data and/or by X-ray crystallography.     

Structural analysis of three methyl N-phosphorylated 5,6-dihydroxy-2-azabicyclo[2.2.1]heptane-3-carboxylates

Both exo and endo isomers of (±)-methyl N-diphenylphosphoryl-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate and (±)-methyl N-diphenylphosphoryloxy-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate were dihydroxylated with OsO₄. The unexpected formation of (±)-methyl 5,6-dihydroxy-N-diphenylphosphoryl-2-azabicyclo[2.2.1]heptane-3-endo-carboxylate from (±)-methyl N-diphenylphosphoryloxy-2-azabicyclo[2.2.1]hept-5-ene-3-endo-carboxylate is discussed based on NMR analyses and experimental observations. The two N-diphenylphosphoryl dihydroxybicycles are analyzed in terms of their crystalline structure by X-ray crystallography.