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During the last two decades, disulfide-based dynamic combinatorial chemistry has been extensively used in the field of molecular recognition to deliver artificial receptors for molecules of biological interest. Commonly, the nature of library members and their relative amounts are provided from HPLC-MS analysis of the libraries, allowing the identification of potential binders for a target (bio)molecule. By re-investigating dynamic combinatorial libraries generated from a simple 2,5-dicarboxy-1,4-dithiophenol building block in water, we herein demonstrated that multiple analytical tools were actually necessary in order to comprehensively describe the libraries in terms of size, stereochemistry, affinity, selectivity, and finally to get a true grasp on the different phenomena at work within dynamic combinatorial systems., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Glycoconjugates and their applications as lectin ligands in biology have been thoroughly investigated in the past decades. Meanwhile, the intrinsic properties of such multivalent molecules were limited essentially to their ability to bind to their receptors with high selectivity and/or avidity. The present review will focus on multivalent glycoconjugates displaying an additional capability such as fluorescence properties not only for applications toward imaging of cancer cells and detection of proteins or pathogens but also for drug delivery systems toward targeted cancer therapy. This review is a collection of research articles discussed in the context of the structural features of fluorescent glycoconjugates organized according to their fluorescent core scaffold and with their representative applications.

Tetraphenylethylene (TPE) is fluorescent through aggregation induced emission (AIE) in water. Herein, TPE was used as the core of glycoclusters that target the bacterial lectins LecA and LecB of Pseudomonas aeruginosa. Synthesis of these TPE-based glycoclusters was accomplished by using azide-alkyne "click" chemistry. The AIE properties of the resulting glycoclusters could be readily verified, but imaging could not be pursued due to the overlap of the fluorescence signals from cells and bacteria. Nonetheless, the glycoclusters displayed nanomolar affinities toward LecA and LecB. Further evaluation in a cell-based anti-adhesive assay highlighted a limited decrease in adhesion (20%) for the fucosylated glycocluster. This confirmed that these TPE-based glycoclusters are indeed LecA and LecB high-affinity ligands. Nevertheless, the hypotheses involving their application in imaging or anti-adhesive therapy could not be verified.

By using a combination of readily accessible experimental and computational experiments in water, we explored the factors governing the association between polyanionic dyn[4]arene and a series of α,ω-alkyldiammonium ions of increasing chain length. We found that the lock-and-key concept based on the best match between the apolar and polar regions of the molecular partners failed to explain the observed selectivities. Instead, the dissection of the energetic and structural contributions demonstrated that the binding events were actually guided by two crucial solvent-related phenomena as the chain length of the guest increases: the expected decrease of the enthalpic cost of guest desolvation and the unexpected increase of the favourable enthalpy of complex solvation. By bringing to light the decisive enthalpic impact of complex solvation during the binding of polyelectrolytes by inclusion, this study may provide a missing piece to a puzzle that one day could display the global picture of molecular recognition in water.

The extension of the family of dyn[ n]arenes toward a three-membered macrocycle is reported. Through a templated approach, a single diastereoisomer of a dyn[3]arene that bears six carboxyl groups could be isolated by precipitation in 59-63% yield and excellent purity (≥95%). A combination of experimental and computational experiments in water at physiological pH revealed that the macrocycle could bind parent biogenic polyamines with a unique diversity of surface-binding modes. Whereas no binding event could be accurately measured with 1,3-diaminopropane, spermidine formed a classical stoichiometric complex with the dyn[3]arene in the millimolar concentration range. On the other hand, the data obtained for spermine could only be attributed to a more complex binding event with the formation of a 2:1 complex at high [host]/[guest] ratios and redistribution toward a 1:1 complex upon further addition of guest.

The synthesis of eight perylenediimide-based glycoclusters was readily performed from hexa- and tetra-propargylated cores through azide-alkyne "click" conjugation. Variations in the carbohydrate epitope (Glc, Gal, Man, Fuc) and the linker arm provided molecular diversity. Interactions with LecA and LecB, two proteins involved in the adhesion of Pseudomonas aeruginosa to host tissues, were evaluated by microcalorimetry (ITC). In both cases high affinities were obtained with K d values in the nanomolar range. Further evaluation of their anti-adhesive properties using cultured epithelial cells demonstrated their potent anti-adhesive activities against Pseudomonas aeruginosa with only 30-40% residual adhesion observed. The fluorescence properties of the PDI core were then investigated by confocal microscopy on cell-bacteria cultures. However, the red fluorescence signal of the PDI-based glycocluster was too weak to provide significant data. The present study provides another type of anti-adhesive glycocluster against bacterial infection with a large aromatic PDI core.

A series of novel benzamide-derived compounds was designed, synthesized and pharmacologically evaluated. Among all 37 synthesized compounds, two series were developed with the modulation of the nature, the position of atoms or groups on the benzamide scaffold, but also the nature of the amine group separated from the benzamide with 2, 3 or 4 methylene groups. In vitro competition binding assays against sigma proteins (sigma-1 S1R and sigma-2 S2R) revealed that most of them conferred S2R/S1R selectivity toward without cytotoxic effects on SY5Y cells, especially with the first series with compounds 7a-z. Some selected compounds were also evaluated for their agonist and antagonist activities on a panel of 40 receptors. Results showed the importance of the nature and the position with halogeno atom on the benzamide scaffold, the length chain but also the contribution of the hydrophobic part on the amine group. Among them, compounds 7i, w, y with Cl, CN or NO 2 groups at the 4-position of the benzamide scaffold showed excellent affinity for S1R (Ki = 1.2-3.6 nM), selectivity for S2R (Ki up to 1400 nM) and high selectivity index (IC 50(SY5Y) /Ki (S1R) ratio from 28 000 to 83 000). Futhermore, these compounds presented an excellent safety profile over 40 other receptors. These derivatives will be selected for further biological investigations., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

The asymmetric deformation of a dyn[4]arene upon the binding of various lysine derivatives leads to distinct induced circular dichroism outputs in buffered water, which can be exploited not only for the determination of their enantiomeric excesses, but also for their classification by linear discriminant analysis.

Introduction: Control of glycemia is crucial in the treatment of type 2 diabetes complications. Glycogen phosphorylase (GP) releases glucose from the liver into the blood stream. Design of potent GP inhibitors is a therapeutic strategy in the context of type 2 diabetes., Areas Covered: Glucose-based inhibitors have found potential applications since they now reach low nanomolar Ki values. Another set of patents disclose cholic acid/7-aza-indole conjugates for targeted drug delivery to the liver. A series of benzazepinones have also been reported as potent GP inhibitors. In vitro data are reported for GP inhibition but the in vivo biological data at the cellular or animal levels are often missing, even though the literature reported for these molecules is also discussed., Expert Opinion: A structural analogy between glucose-based GP inhibitors and C-glucosides targeting sodium glucose co-transporter 2 (SGLT2) is intriguing. Cholic acid/7-aza-indole conjugates are promising in vivo drug delivery systems to the liver. Benzazepinones were very recently described and no associated literature is available, making it very difficult to comment at present. While industry has slowed down on GP inhibitors design, academic groups are pursuing investigations and have provided potential drug candidates which will resuscitate the interest for GP, including its potential for targeting cancer.

Glycogen phosporylase (GP) is a promising target for the control of glycaemia. The design of inhibitors binding at the catalytic site has been accomplished through various families of glucose-based derivatives such as oxadiazoles. Further elaboration of the oxadiazole aromatic aglycon moiety is now reported with 3-glucosyl-5-amino-1,2,4-oxadiazoles synthesized by condensation of a C-glucosyl amidoxime with N,N'-dialkylcarbodiimides or Vilsmeier salts. The 5-amino group introduced on the oxadiazole scaffold was expected to provide better inhibition of GP through potential additional interactions with the enzyme's catalytic site; however, no inhibition was observed at 625 µM.

The σ1 proteins are considered to be a new class of target structures for several central nervous system disorders, including depression, anxiety, psychosis, and Parkinson's and Alzheimer's diseases. Recently, the involvement of these receptors in neuropathic pain and cancer has also been observed. So far, only a few ligands are in clinical trials. In a continuation of our previous studies on the development of σ1 ligands, a new series of benzannulated heterocycles was designed and synthesised. In vitro competition binding assays showed that many of them possessed high σ1 receptor affinity (Ki = 0.6-10.3 nM), and good σ2/σ1 subtype selectivity, without cytotoxic effects on SY5Y cells (human neuroblastoma cell line)., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Sigma 1 receptors are associated with neurodegenerative and psychiatric disorders. These receptors, via their chaperoning functions that counteract endoplasmic reticulum stress and block neurodegeneration, may serve as a target for a new generation of antidepressants or neuroprotective agents. The involvement of these receptors has also been observed in neuropathic pain and cancer. Only a few ligands, such as Igmesine and Anavex 2-73, have been involved in clinical trials. Thus the development of sigma 1 ligands is of interest to a new generation of drugs. Previous work in our lab underlined the potency of benzannulated bicyclic compounds as interesting ligands. Herein the work was extended to a series of novel tricyclic compounds. Carboline- and phenothiazine-derivated compounds were designed and synthesized. In vitro competition binding assays for sigma 1 and 2 receptors showed that most of them have high affinity for sigma 1 receptor (Ki = 2.5-18 nM), and selectivity toward sigma 2 receptor, without cytotoxic effects on SY5Y cells., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)