Juan Xie

Sugars to Control Ligand Shape in Metal Complexes: Conformationally Constrained Glycoligands with a Predetermination of Stereochemistry and a Structural Control

In coordination chemistry, ligand shape can be used to tune properties, such as metal selectivity, coordination number, electronic structure, redox potential, and metal center stereochemistry including coordination helicates formation, and also to generate cavities for encapsulation. The results presented in this article indicate that two epimeric glycoligands (3 and 4) based on the conformationally restrained xylo- and ribo-1,2-O-isopropylidenefurano scaffolds are preorganized in water through pi-pi stacking due to hydrophobic interactions, as evidenced from excimer observation. The structure obtained in the solid state for one of the Cu(II) complexes (5) is chiral, with an original helical chirality arising from the coiling of the two ligands around the Cu-Cu axis. It shows an unusual double-deck type structure, with pi-pi interaction between two triazoyl-pyridyl rings and with a small cavity between the two Cu(II) ions able to host a bridging water molecule, as suggested by electron paramagnetic resonance. The Cu(II) complex from the epimeric ligand (6) shows similar properties with a mirror-image CD spectrum in the d-d region of the Cu(II). There is a predetermination of chirality at the metal center by the glycoligand induced by the C3 configuration, 6 and 5 being pseudoenantiomers. Interestingly, the stereochemistry at the metal center is here controlled by the combination of pi-stacking and chiral backbone.

Synthesis of glucoconjugates of oleanolic acid as inhibitors of glycogen phosphorylase

Synthesis and biological evaluation of glucoconjugates of oleanolic acid, linked by either a triazole moiety or an ester function, as novel inhibitors of glycogen phosphorylase have been described. Several triterpene-glycoside conjugates exhibited moderate-to-good inhibitory activity against rabbit muscle GPa. Compound 12 showed the best inhibition with an IC(50) value of 1.14 microM. Structure-activity relationship (SAR) analysis of these inhibitors is also discussed. Possible binding modes of compound 12 were explored by molecular docking simulations.

CuAAC Click Chemistry Accelerates the Discovery of Novel Chemical Scaffolds as Promising Protein Tyrosine Phosphatases Inhibitors

Protein tyrosine phosphatases (PTPs) are crucial regulators for numerous biological processes in nature. The dysfunction and overexpression of many PTP members have been demonstrated to cause fatal human diseases such as cancers, diabetes, obesity, neurodegenerative diseases and autoimmune disorders. In the past decade, considerable efforts have been devoted to the production of PTPs inhibitors by both academia and the pharmaceutical industry. However, there are only limited drug candidates in clinical trials and no commercial drugs have been approved, implying that further efficient discovery of novel chemical entities competent for inhibition of the specific PTP target in vivo remains yet a challenge. In light of the click-chemistry paradigm which advocates the utilization of concise and selective carbon-heteroatom ligation reactions for the modular construction of useful compound libraries, the Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition reaction (CuAAC) has fueled enormous energy into the modern drug discovery. Recently, this ingenious chemical ligation tool has also revealed efficacious and expeditious in establishing large combinatorial libraries for the acquisition of novel PTPs inhibitors with promising pharmacological profiles. We thus offer here a comprehensive review highlighting the development of PTPs inhibitors accelerated by the CuAAC click chemistry.

Fluorescent glycoprobes: a sweet addition for improved sensing

The development of small-molecule fluorescent probes for the detection of ions and biomacromolecules and for cellular and in vivo imaging has been a very active research area. Nevertheless, many problems exist for traditional probes including their poor water solubility, toxicity and the inability to target specific tissues. Because of the enhanced water solubility, biocompatibility and targeting ability for specific cells, there has been an emerging movement to use carbohydrates as either the backbone or as a warhead to decorate conventional fluorescent probes, producing glycoprobes with enhanced properties. This feature article provides an overview of recently developed glycoprobes for ion and protein detection as well as targeted (receptor targeting) cellular imaging and theranostics. Here, we summarise the tactics for preparing small molecular glycoprobes and their supramolecular 2D material composites.

Preparation of triazole-linked glycosylated α-ketocarboxylic acid derivatives as new PTP1B inhibitors.

The synthesis of triazole-linked glycosyl acetophenone, benzoic acid, and α-ketocarboxylic acid derivatives was readily achieved via Cu(I)-catalyzed azide-alkyne cycloaddition (click reaction) in excellent yields of 93-97%. Among the synthesized glycoconjugates, the triazolyl α-ketocarboxylic acids were identified as the most potent protein tyrosine phosphatase 1B (PTP1B) inhibitors with micromole-ranged IC(50) values and moderate-to-good selectivity over a panel of homologous PTPs including TCPTP (4.6-fold), LAR (>30-fold), SHP-1 (>30-fold) and SHP-2 (>30-fold). Moreover, a docking simulation was conducted to propose a plausible binding mode of the glucosyl α-ketocarboxylic acid triazole with the enzymatic target.

Synthesis of Oleanolic Acid Dimers as Inhibitors of Glycogen Phosphorylase

Recently, oleanolic acid was found to be an inhibitor of glycogen phosphorylase. For further structural modification, we have synthesized several dimers of oleanolic acid by using amide, ester, or triazole linkage with click chemistry. The click chemistry was shown to be the most efficient method for the dimer synthesis. Nearly quantitative yield of triazole‐linked dimers was obtained. Biological evaluation of the synthesized dimers as inhibitors of glycogen phosphorylase has been described. Four of six dimers exhibited inhibitory activity against rabbit muscle glycogen phosphorylase a (RMGPa), with compounds 2 and 7 as the most potent inhibitors, which displayed an IC50 value (ca. 3u2005μM) lower than that of oleanolic acid (IC50=14u2005μM).

Synthesis of triazole-linked beta-C-glycosyl dimers as inhibitors of PTP1B.

Protein tyrosine phosphatase 1B (PTP1B) has emerged as a promising target for type 2 diabetes. We have successfully synthesized dimeric acetylated and benzoylated beta-C-d-glucosyl and beta-C-D-galactosyl 1,4-dimethoxy benzenes or naphthalenes by click chemistry. These compounds were further transformed into the corresponding beta-C-D-glycosyl-1,4-quinone derivatives by CAN oxidation. The in vitro inhibition test showed that dimeric benzoylated beta-C-D-glycosyl 1,4-dimethoxybenzenes or 1,4-benzoquinones were good inhibitors of PTP1B (IC(50): 0.62-0.88 miroM), with no significant difference between gluco and galacto derivatives.

Microwave-assisted construction of triazole-linked amino acid–glucoside conjugates as novel PTP1B inhibitors

There has been increasing interest in the development of protein tyrosine phosphatase 1B (PTP1B) inhibitors for the treatment of type 2 diabetes, obesity and breast cancer. We report here the identification of a series of mono- and bis-phenylalaninyl and tyrosinyl glucoside derivatives as novel PTP1B inhibitors. The designed compounds bearing one or two phenylalanine or tyrosine derivatives on the 6-, 2,3-, 2,6-, 3,4- and 4,6-positions of the glucosyl scaffolds were efficiently constructed via the microwave-assisted Cu(I)-catalyzed azide–alkyne cycloaddition in moderate-to-excellent yields. Successive biological assays identified these compounds as novel PTP1B inhibitors, with the 4,6-disubstituted tyrosinyl glucoside being the most potent. A kinetic study established that both mono- and bis-triazole-linked glycosyl acids act as typical competitive inhibitors whereas the bis-triazolyl ester that also exhibited inhibitory activity on PTP1B displayed a mixed-type inhibition pattern. Furthermore, docking simulation plausibly proposed the diverse binding modes of these compounds with the enzymatic target.

A unique and rapid approach toward the efficient development of novel protein tyrosine phosphatase (PTP) inhibitors based on ‘clicked’ pseudo-glycopeptides

There has been considerable interest in the development of protein tyrosine phosphatase (PTP) inhibitors since many of the PTP members are tightly associated with major human diseases including autoimmune disorders, diabetes and cancer. We report here a unique and rapid approach toward the development of novel PTP inhibitor entities based on triazolyl pseudo-glycopeptides. By employing microwave-accelerated Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC or click reaction), a series of triazole-linked serinyl, threoninyl, phenylalaninyl and tyrosinyl 1-O-gluco- or galactosides have been efficiently synthesized in high yields within only ~30 min. Successive biological assay identified these glycopeptidotriazoles as favorable PTP1B and CDC25B inhibitors with selectivity over TCPTP, LAR, SHP-1 and SHP-2. Both the structural diversity of the amino acid (Ser, Thr, Phe and Tyr) introduced and the epimeric identity (Glc or Gal) on monosaccharide scaffold were determined to impact the corresponding inhibitory activity and selectivity. In addition, the benzylated sugar scaffold was demonstrated to act as a crucial role for enhancing the binding affinity of the inhibitors with the targeted PTP. Docking simulation was eventually conducted to propose plausible binding modes of this compound series with PTP1B and CDC25B. Our approach readily realized from naturally abundant raw materials (sugar and amino acid) and via facile, regioselective and expeditious synthetic method (microwave-assisted click reaction) might provide new insights toward the click fabrication of structurally diverse PTP inhibitors.

Facile fabrication of promising protein tyrosine phosphatase (PTP) inhibitor entities based on 'clicked' serine/threonine-monosaccharide hybrids

Protein tyrosine phosphatases (PTPs) are well-validated therapeutic targets for many human major diseases. The development of their potent inhibitors has therefore become a main focus of both academia and the pharmaceutical industry. We report herein a facile strategy toward the fabrication of new and competent PTP inhibitor entities by simply clicking alkynyl amino acids onto diverse azido sugar templates. Triazolyl glucosyl, galactosyl, and mannosyl serine and threonine derivatives were efficiently synthesized via click reaction, which were then identified as potent CDC25B and PTP1B inhibitors selective over a panel of homologous PTPs tested. Their inhibitory activity and selectivity were found to largely lie on the structurally and configurationally diversified monosaccharide moieties whereon serinyl and threoninyl residues were introduced. In addition, MTT assay revealed the triazole-connected sugar-amino acid hybrids may also inhibit the growth of several human cancer cell lines including A549, Hela, and especially HCT-116. On the basis of such compelling evidence, we consider that this compound series could furnish promising chemical entities serving as new CDC25B and PTP1B inhibitors with potential cellular activity. Furthermore, the click strategy starting from easily accessible and biocompatible amino acids and sugar templates would allow the modular fabrication of a rich library of new PTP inhibitors efficaciously and productively.