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For the purpose of seeking new antibiotics, researchers usually modify the already-existing ones. However, this strategy has been extensively used and is close to its limits, especially in the case of aminoglycosides, and it is difficult to find a proper aminoglycoside antibiotic for novel modification. In this paper, we reported the design, synthesis, and evaluation of a series of 5-epi-neamine derivatives based on the structural information of bacterial 16S RNA A-site binding with aminoglycosides. Bioassay results showed that our design strategy was feasible. Our study offers a new way to search for structurally novel aminoglycosides. Meanwhile, our study provides valuable structure-activity relationship information, which will lead to better understanding and exploitation of the drug target, and improved development of new aminoglycoside antibiotics.

Bergenin, which is isolated from Bergenia species, exhibits various pharmacological properties. In the search for new types of immunosuppressants, a series of bergenin derivatives were designed and synthesized, and their immunosuppressive effects were evaluated by the CCK-8 assay. The experimental data demonstrated that compounds 7 and 13 showed the strongest inhibition effects on mouse splenocyte proliferation (IC(50) = 3.52 and 5.39 μM, respectively). Further studies revealed that the inhibitory effect may come from the suppression of both IFN-γ and IL-4 cytokines. Alkylated derivatives of bergenin with n-hexyl and n-heptyl on the two phenolic hydroxyl groups showed better inhibitory activities. The hydrophobicity of bergenin derivatives, the configuration of the 4-OH in bergenin, and the ability to form hydrogen bonds of the substituents on the C-4 position are important to the immunosuppressive activity. This work proved that the modifications of bergenin may represent a new route to the discovery of a new class of immunosuppressive agents.

O-Linked N-acetylglucosamine (O-GlcNAc) is an abundant posttranslationalmonosaccaride-modification found on Ser or Thr residues of intracellular proteins in most eukaryotes. The dynamic nature of O-GlcNAc has enabled researchers to modulate the stoichiometry of O-GlcNAc on proteins in order to investigate its function. Cell permeable small moleculars have proven invaluable tools to increase O-GlcNAc levels. Herein, using in vitro substrate screening, we identified GlcNAcF3 as an OGT-accepted but OGA-resistant sugar mimic. Cellular experiments with cell-permeable peracetylated-GlcNAcF3 (Ac4GlcNAcF3) displayed that Ac4GlcNAcF3 was a potent tool to increase O-GlcNAc levels in several cell lines. Further, NIH3T3 cells interfered with OGT (siOGT) showed significant decreasing of O-GlcNAc levels with Ac4GlcNAcF3 treatment, indicating O-GlcNAcF3 was an OGT-dependent modification. In addition, cellular toxic assay confirmed O-GlcNAcF3 production has no significant effect on cell proliferation or viability. Thus, Ac4GlcNAcF3 represents a safe and dual regulator for both OGT and OGA, which will benefit the study of O-GlcNAc.

It is important to find more effective and safer immunosuppressants, because clinically used immunosuppressive agents have significant side effects. A series of N-substituted iminosugar derivatives were designed and synthesized, and their immunosuppressive effects were evaluated by the CCK-8 assay. The results revealed that iminosugars 10 e and 10 i, that is, (3R,4S)-1-(4-heptyloxylphenylethyl)pyrrolidine-3,4-diol and (3R,4S)-1-[2-(2-chloro-4-(p-tolylthio)-phenyl-1-yl)ethyl]pyrrolidine-3,4-diol, respectively, exhibited the strongest inhibitory effects on mouse splenocyte proliferation (IC50 =2.16 and 2.48 μm, respectively), whereas the iminosugars containing an amide group near the hydrophilic head (compounds 10 j-n) exhibited no inhibitory effects. Further studies revealed that the inhibitory effects on splenocyte proliferation may have come from the suppression of both IFN-γ and IL-4 cytokines. Our results suggest that synthetic iminosugars, especially compounds 10 e and 10 i, hold potential as immunosuppressive agents.

A general approach to the synthesis of diverse heteroaryl-C-Δ1,2-glycosides has been developed by employing the Pd(OAc)2/CuI cocatalyzed direct cross-coupling of five-membered nitrogen heterocycles with 1-iodoglycals in a C–H activation manner. Using this method, 27 examples of heteroaryl-C-Δ1,2-glycosides, containing indoles, thiazoles, benzothiazoles, imidazoles, benzimidazoles, and benzoxazoles as aglycones were obtained in 43–99% yield.

A general and efficient approach to the synthesis of various C-acyl glycosides has been developed via Pd2(dba)3/CuTC co-catalyzed cross-coupling reaction of glycosyl carbothioates with arylboronic acids. The reaction showed a broad substrate scope and 25 examples were exhibited in 61%–97% isolated yields. Furthermore, this reaction was applied to the gram-scale preparation of C-acyl glycosides. The coupled products can be further transformed into diverse biologically useful compounds, as exemplified by the synthesis of protected sergliflozin-A mimics.

Since the immunosuppressive agents currently used in clinics have significant side effects, it is very important to search for new effective and safe immunosuppressants. Iminosugars as a new class of immunosuppressants are less explored. In this report, 24 new N-arylated iminosugar derivatives, including d-talo and d-galacto epimers, were designed and synthesized, and their immunosuppressive effects were evaluated by MTT assay. The experimental data demonstrated that compound 20 showed the strongest inhibition effect (IC50 = 6.94 μM). Further studies revealed that the inhibitory effects on splenocyte proliferation may come from the suppression of both IFN-γ and IL-4 cytokines. The preliminary structure-activity relationship (SAR) analysis suggested that N-arylated d-galacto-type iminosugars showed better inhibitory activities than d-talo-type analogues. The SAR analysis also showed that the inhibition effect of iminosugars can be improved by decreasing the polarity or increasing the hydrophobicity. These results may be beneficial to the discovery of new iminosugar derivatives as immunosuppressive agents.

3-Butenyloxycarbonyl (Bloc) has been identified as a new hydroxyl protecting group, which can be introduced under mild conditions in high yields and selectively removed by OsO4/NaIO4/2,6-lutidine in CH3CN–H2O without affecting most commonly-used protecting groups. Moreover, this new protecting group is inert under glycosylation conditions.

Glucagon-like peptide-1 (GLP-1) is an endogenous insulinotropic hormone with wonderful glucose-lowering activity. However, its clinical use in type II diabetes is limited due to its rapid degradation at the N-terminus by dipeptidyl peptidase IV (DPP-IV). Among the N-terminal modifications of GLP-1, backbone-based modification was rarely reported. Herein, we employed two backbone-based strategies to modify the N-terminus of tGLP-1. Firstly, the amide N-methylated analogues 2–6 were designed and synthesized to make a full screening of the N-terminal amide bonds, and the loss of GLP-1 receptor (GLP-1R) activation indicated the importance of amide H-bonds. Secondly, with retaining the N-terminal amide H-bonds, the β-peptide replacement strategy was used and analogues 7–13 were synthesized. By two rounds of screening, analogue 10 was identified. Analogue 10 greatly improved the DPP-IV resistance with maintaining good GLP-1R activation in vitro, and showed approximately a 4-fold prolonged blood glucose-lowering activity in vivo in comparison with tGLP-1. This modification strategy will benefit the development of GLP-1-based anti-diabetic drugs.

O-Linked N-acetylglucosamine (O-GlcNAc) is an abundant posttranslationalmonosaccaride-modification found on Ser or Thr residues of intracellular proteins in most eukaryotes. The dynamic nature of O-GlcNAc has enabled researchers to modulate the stoichiometry of O-GlcNAc on proteins in order to investigate its function. Cell permeable small moleculars have proven invaluable tools to increase O-GlcNAc levels. Herein, using in vitro substrate screening, we identified GlcNAcF

Antibiotic resistance is one of the biggest threats to public health, and new antibacterial agents hence are in an urgent need to combat infectious diseases caused by multidrug-resistant (MDR) pathogens. Utilizing dimerization strategy, we rationally designed and efficiently synthesized a new series of small molecule dimeric lysine alkylamides as mimics of AMPs. Evaluation of these mimics against a panel of Gram-positive and Gram-negative bacteria including MDR strains was performed, and a broad-spectrum and potent compound 3d was identified. This compound displayed high specificity toward bacteria over mammalian cell. Time-kill kinetics and mechanistic studies suggest that compound 3d quickly eliminated bacteria in a bactericidal mode by disrupting bacterial cell membrane. In addition, lead compound 3d could inhibit biofilm formation and did not develop drug resistance in S. aureus and E. coli over 14 passages. These results suggested that dimeric lysine nonylamide has immense potential as a new type of novel small molecular agent to combat antibiotic resistance.

Novel indolo-quinoline compounds were efficiently prepared via a Povarov-type reaction, and the structures were further modified by a Suzuki coupling reaction. The corresponding BF2-rigidified complexes were prepared and their spectroscopic properties were characterized with large Stokes shifts (up to 211 nm) and up to near-infrared (NIR) wavelength (667 nm). The synthetic complexes could be used as new fluorescent dyes.

An efficient method for the construction of cyclopropane-fused dihydroquinolines was established by a novel Povarov-type three-component reaction of aromatic aldehydes, anilines and cyclopropenes in the presence of trifluoromethanesulfonic acid. The reaction proceeded in a regioselective and diastereoselective manner. Furthermore, the dihy-droquinolines were smoothly converted to benzazepine derivatives via a ring opening/isomerization sequence, further expanding the synthetic scope.

A convenient approach to the synthesis of novel triazole- N -glycoside derivatives was developed via CuSCN-catalyzed click reaction and Ullmann-type coupling reaction for the first time. The SGLT2 inhibitory activities of these synthetic N -glycosides were evaluated, and some compounds showed moderate SGLT2 inhibition activities at 100 nM. The results could benefit the discovery of new SGLT2 inhibitors for the treatment of diabetes.

The 3-butenyloxycarbonyl group can be introduced into carbohydrates such as (I) under mild conditions.

A monoselective synthesis of aryl-C-Δ1,2-glycosides from 1-iodoglycals via palladium-catalyzed ortho-C–H activation of N-quinolyl benzamides has been developed. An amino acid derivative was used as a crucial ligand to improve the yield and monoselectivity of the coupling reaction. The utility of this protocol was demonstrated by a concise synthesis of key moieties of some natural products.

A monoselective synthesis of aryl-C-Δ(1,2)-glycosides from 1-iodoglycals via palladium-catalyzed ortho-C-H activation of N-quinolyl benzamides has been developed. An amino acid derivative was used as a crucial ligand to improve the yield and monoselectivity of the coupling reaction. The utility of this protocol was demonstrated by a concise synthesis of key moieties of some natural products.

An efficient method for the construction of cyclopropane-fused dihydroquinolines was established by a novel Povarov-type three-component reaction of aromatic aldehydes, anilines and cyclopropenes in the presence of trifluoromethanesulfonic acid. The reaction proceeded in a regioselective and diastereoselective manner. Furthermore, the dihy-droquinolines were smoothly converted to benzazepine derivatives via a ring opening/isomerization sequence, further expanding the synthetic scope.

Sialylconjugates on cell surfaces are involved in many biological events such as cellular recognition, signal transduction, and immune response. It has been reported that aberrant sialylation at the nonreducing end of glycoconjugates and overexpression of sialyltransferases (STs) in cells are correlated with the malignance, invasion, and metastasis of tumors. Therefore, inhibitors of STs would provide valuable leads for the discovery of antitumor drugs. On the basis of the transition state of the enzyme-catalyzed sialylation reaction, we proposed that the cyclopentane skeleton in its two puckered conformations might mimic the planar structure of the donor (CMP-Neu5Ac) in the transition state. A series of cyclopentane-containing compounds were designed and synthesized by coupling different cyclopentane α-hydroxyphosphonates with cytidine phosphoramidite. Their inhibitory activities against recombinant human ST6Gal-I were assayed, and a potent inhibitor 48l with a Ki of 0.028 ± 0.006 μM was identified. The results show that the cyclopentanoid-type compounds could become a new type of sialyltransferase inhibitors as biological probes or drug leads.

The creation and development of nonnatural peptidomimetics has become an area of increasing significance in bioorganic and chemical biology. A wide range of new peptide mimics with novel structures and functions are urgently needed to be explored in order to identify potential drug candidates and targeted probes, and to study protein functions. AApeptides are a new class of peptide mimics based on chiral PNA backbone. They are resistant to proteolytic degradation and have limitless potential for diversification. They have been found to have a wide variety of biological applications including cellular translocation, disruption of protein-protein interactions, formation of nanostructures, antimicrobial activity, etc. The synthesis of AApeptides is modular and straightforward. In this chapter, methods for the synthesis of AApeptides (including different subclasses) are described.