Isohexide-Based Tunable Chiral Platforms as Amide- and Thiourea-Chiral Solvating Agents for the NMR Enantiodiscrimination of Derivatized Amino Acids.

New arylamide- and arylthiourea-based chiral solvating agents (CSAs) were synthesized starting from commercially available isomannide and isosorbide. The two natural isohexides were transformed into the three amino derivatives, having isomannide, isosorbide, and isoidide stereochemistry, then the amino groups were derivatized with 3,5-dimethoxybenzoyl chloride or 3,5-bis(trifluoromethyl)phenyl isothiocyanate to obtain the CSAs. Bis-thiourea derivative containing the 3,5-bis(trifluoromethyl)phenyl moiety with exo-exo stereochemistry was remarkably efficient in the differentiation of NMR signals (NH and acetyl) of enantiomers of N-acetyl (N-Ac) amino acids in the presence of 1,4-diazabicyclo[2,2,2]octane (DABCO). Nonequivalences in the ranges of 0.104-0.343 ppm and 0.042-0.107 ppm for NH and acetyl groups, respectively, allowed for very accurate enantiomeric excess determination, and a reliable correlation was found between the relative positions of signals of enantiomers and their absolute configuration. Therefore, a complete stereochemical characterization could be performed. Dipolar interactions detected in the ternary mixture CSA/N-Ac-valine/DABCO led to the identification of a different interaction model for the two enantiomers, involving the formation of a one-to-one substrate/CSA complex for (S)-N-Ac-valine and a one-to-two complex for (R)-N-Ac-valine, as suggested by the complexation stoichiometry.

Site-Selective Functionalized PD-1 Mutant for a Modular Immunological Activity against Cancer Cells.

Targeting immune checkpoints is a well-established strategy in cancer therapy, and antibodies blocking PD-1/PD-L1 interactions to restore the immunological activity against cancer cells have been clinically validated. High-affinity mutants of the PD-1 ectodomain have recently been proposed as an alternative to antibodies to target PD-L1 on cancer cells, shedding new light on this research area. In this dynamic scenario, the PD-1 mutant, here reported, largely expands the chemical space of nonantibody and nonsmall-molecule inhibitor therapeutics that can be used to target cancer cells overexpressing PD-L1 receptors. The polyethylene glycol moieties and the immune response-stimulating carbohydrates, used as site-selective tags, represent the proof of concept for future applications.

Tunable Excimer Circularly Polarized Luminescence in Isohexide Derivatives from Renewable Resources.

Organic compounds showing circularly polarized luminescence (CPL) are at the forefront of novel applications and technologies. Here we show the synthesis and chiroptical properties of pyrene and perylene derivatives of inexpensive chiral scaffolds: isomannide and isosorbide. Low-intensity ECD spectra were obtained, suggesting the absence of chromophore interaction in the ground state, except in the case of isomannide bis-perylenecarboxylate, whose ECD spectrum showed a positive exciton couplet. All isomannide derivatives, with the only exception of the one containing a pyrenecarboxylate and a perylenecarboxylate, exhibited excimer CPL spectra, whereas isosorbide derivatives did not show any CPL. Isomannide derivatives bearing two pyrenecarboxylate or two pyrenylacetate groups showed positive CPL emission with dissymmetry factors up to 10-2 , which depends on the conformational freedom of the appended units. The CPL sign, Stokes shift and order of magnitude of dissymmetry factor were reproduced by excited-state calculations on a representative compound. Interestingly, the mixed derivative containing pyrenic units with different spacing from the isomannide scaffold showed an oppositely signed excimer band with respect to the homo-substituted derivatives.

Renewable Resources for Enantiodiscrimination: Chiral Solvating Agents for NMR Spectroscopy from Isomannide and Isosorbide.

A new family of chiral selectors was synthesized in a single synthetic step with yields up to 84% starting from isomannide and isosorbide. Mono- or disubstituted carbamate derivatives were obtained by reacting the isohexides with electron-donating arylisocyanate (3,5-dimethylphenyl- or 3,5-dimethoxyphenyl-) and electron-withdrawing arylisocyanate (3,5-bis(trifluoromethyl)phenyl-) groups to test opposite electronic effects on enantiodifferentiation. Deeper chiral pockets and derivatives with more acidic protons were obtained by derivatization with 1-naphthylisocyanate and p-toluenesulfonylisocyanate, respectively. All compounds were tested as chiral solvating agents (CSAs) in 1H NMR experiments with rac-N-3,5-dinitrobenzoylphenylglycine methyl ester in order to determine the influence of different structural features on the enantiodiscrimination capabilities. Some selected compounds were tested with other racemic analytes, still leading to enantiodiscrimination. The enantiodiscrimination conditions were then optimized for the best CSA/analyte couple. Finally, a 2D- and 1D-NMR study was performed employing the best performing CSA with the two enantiomers of the selected analyte, aiming to determine the enantiodiscrimination mechanism, the stoichiometry of interaction, and the complexation constant.

Targeting osteoarthritis-associated galectins and an induced effector class by a ditopic bifunctional reagent: Impact of its glycan part on binding measured in the tissue context.

Pairing glycans with tissue lectins controls multiple effector pathways in (patho)physiology. A clinically relevant example is the prodegradative activity of galectins-1 and -3 (Gal-1 and -3) in the progression of osteoarthritis (OA) via matrix metalloproteinases (MMPs), especially MMP-13. The design of heterobifunctional inhibitors that can block galectin binding and MMPs both directly and by preventing their galectin-dependent induction selectively offers a perspective to dissect the roles of lectins and proteolytic enzymes. We describe the synthesis of such a reagent with a bivalent galectin ligand connected to an MMP inhibitor and of two tetravalent glycoclusters with a subtle change in headgroup presentation for further elucidation of influence on ligand binding. Testing was performed on clinical material with mixtures of galectins as occurring in vivo, using sections of fixed tissue. Two-colour fluorescence microscopy monitored binding to the cellular glycome after optimization of experimental parameters. In the presence of the inhibitor, galectin binding to OA specimens was significantly reduced. These results open the perspective to examine the inhibitory capacity of custom-made ditopic compounds on binding of lectins in mixtures using sections of clinical material with known impact of galectins and MMPs on disease progression.

Sugar-Based Ionic Liquids: Multifaceted Challenges and Intriguing Potential.

Carbohydrates represent a promising option in transitioning from oil-based chemical resources to renewable ones, with the goal of developing chemistries for a sustainable future. Cellulose, hemicellulose, and largely available monosaccharides already provide useful chemical building blocks, so-called platform chemicals, such as levulinic acid and hydroxymethyl furfural, as well as solvents like cyrene or gamma-valerolactone. Therefore, there is great anticipation for novel applications involving materials and chemicals derived from sugars. In the field of ionic liquids (ILs), sugar-based ILs have been overlooked for a long time, mainly on account of their multistep demanding preparation. However, exploring new strategies for accessing sugar-based ILs, their study, and their exploitation, are attracting increasing interest. This is due to the growing concerns about the negative (eco)toxicity profile of most ILs in conjunction with their non-sustainable nature. In the present review, a literature survey concerning the development of sugar-based ILs since 2011 is presented. Their preparation strategies and thermal behavior analyses, sorted by sugar type, make up the first two sections with the intention to provide the reader with a useful guide. A final overview of the potential applications of sugar-based ILs and their future perspectives complement the present analysis.

Predicting retrosynthetic pathways using transformer-based models and a hyper-graph exploration strategy.

We present an extension of our Molecular Transformer model combined with a hyper-graph exploration strategy for automatic retrosynthesis route planning without human intervention. The single-step retrosynthetic model sets a new state of the art for predicting reactants as well as reagents, solvents and catalysts for each retrosynthetic step. We introduce four metrics (coverage, class diversity, round-trip accuracy and Jensen-Shannon divergence) to evaluate the single-step retrosynthetic models, using the forward prediction and a reaction classification model always based on the transformer architecture. The hypergraph is constructed on the fly, and the nodes are filtered and further expanded based on a Bayesian-like probability. We critically assessed the end-to-end framework with several retrosynthesis examples from literature and academic exams. Overall, the frameworks have an excellent performance with few weaknesses related to the training data. The use of the introduced metrics opens up the possibility to optimize entire retrosynthetic frameworks by focusing on the performance of the single-step model only.

On the Absolute Stereochemistry of Tolterodine: A Circular Dichroism Study.

Tolterodine (1) is a potent muscarinic receptor antagonist used in the treatment of overactive urinary bladder (OAB) syndrome. Tolterodine is chiral and it was patented, and is currently marketed, as the l-tartrate salt of the (R)-enantiomer. However, the existing literature does not offer an ultimate proof of a stereoselective mode of action of 1. A second open stereochemical issue concerns the absolute configuration (AC) of 1. Neither the original patents nor subsequent studies have established the AC of 1 in an unambiguous way, although the AC of the l-tartrate salt of 1 was assigned by X-ray diffractometry. Finally, neither electronic nor vibrational circular dichroism (ECD and VCD) spectra of 1 are reported so far. We performed a thorough ECD/VCD study of 1 in different solvents and at variable temperatures. Solvent and temperature dependence highlighted the existence of moderate flexibility which was confirmed by molecular modelling. ECD calculations with time-dependent density functional theory (TDDFT) accurately reproduced the experimental spectra and allowed us to confirm the AC of 1 in an independent way.