Ligand-Controlled Monoselective <i>C</i>‑Aryl Glycoside Synthesis via Palladium-Catalyzed C–H Functionalization of <i>N</i>‑Quinolyl Benzamides with 1‑Iodoglycals

A monoselective synthesis of aryl-<i>C</i>-Δ^1,2-glycosides from 1-iodoglycals via palladium-catalyzed <i>ortho</i>-C–H activation of <i>N</i>-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

Highly Substituted Cyclopentane–CMP Conjugates as Potent Sialyltransferase Inhibitors

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 <b>48</b><i><b>l</b></i> with a <i>K</i>_i 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

Solid-Phase Synthesis of γ-AApeptides Using a Submonomeric Approach

The solid-phase synthesis of γ-AApeptides using a novel submonomeric approach that utilizes an allyl protection is reported. The strategy successfully circumvents the necessity of preparing γ-AApeptide building blocks in order to prepare γ-AApeptide sequences. This method will maximize the potential of developing chemically diverse γ-AApeptide libraries and thereby facilitate the biological applications of γ-AApeptides in the future

Rational Design of Dimeric Lysine <i>N</i>‑Alkylamides as Potent and Broad-Spectrum Antibacterial Agents

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 <b>3d</b> was identified. This compound displayed high specificity toward bacteria over mammalian cell. Time–kill kinetics and mechanistic studies suggest that compound <b>3d</b> quickly eliminated bacteria in a bactericidal mode by disrupting bacterial cell membrane. In addition, lead compound <b>3d</b> could inhibit biofilm formation and did not develop drug resistance in <i>S. aureus</i> and <i>E. coli</i> 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

Rational Design of Dimeric Lysine <i>N</i>‑Alkylamides as Potent and Broad-Spectrum Antibacterial Agents

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 <b>3d</b> was identified. This compound displayed high specificity toward bacteria over mammalian cell. Time–kill kinetics and mechanistic studies suggest that compound <b>3d</b> quickly eliminated bacteria in a bactericidal mode by disrupting bacterial cell membrane. In addition, lead compound <b>3d</b> could inhibit biofilm formation and did not develop drug resistance in <i>S. aureus</i> and <i>E. coli</i> 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

Cellular Translocation of a γ-AApeptide Mimetic of Tat Peptide

Cell-penetrating peptides including the trans-activating transcriptional activator (Tat) from HIV-1 have been used as carriers for intracellular delivery of a myriad of cargoes including drugs, molecular probes, DNAs and nanoparticles. Utilizing fluorescence flow cytometry and confocal fluorescence microscopy, we demonstrate that a γ-AApeptide mimetic of Tat (48–57) can cross the cell membranes and enter the cytoplasm and nucleus of cells, with efficiency comparable to or better than that of Tat peptide (48–57). Deletion of the four side chains of the γ-AApeptide attenuates translocation capability. We also establish that the γ-AApeptide is even less toxic than the Tat peptide against mammalian cells. In addition to their low toxicity, γ-AApeptides are resistant to protease degradation, which may prove to be advantageous over α-peptides for further development of molecular transporters for intracellular delivery

Cellular Translocation of a γ-AApeptide Mimetic of Tat Peptide

Cell-penetrating peptides including the trans-activating transcriptional activator (Tat) from HIV-1 have been used as carriers for intracellular delivery of a myriad of cargoes including drugs, molecular probes, DNAs and nanoparticles. Utilizing fluorescence flow cytometry and confocal fluorescence microscopy, we demonstrate that a γ-AApeptide mimetic of Tat (48–57) can cross the cell membranes and enter the cytoplasm and nucleus of cells, with efficiency comparable to or better than that of Tat peptide (48–57). Deletion of the four side chains of the γ-AApeptide attenuates translocation capability. We also establish that the γ-AApeptide is even less toxic than the Tat peptide against mammalian cells. In addition to their low toxicity, γ-AApeptides are resistant to protease degradation, which may prove to be advantageous over α-peptides for further development of molecular transporters for intracellular delivery

Lipo-γ-AApeptides as a New Class of Potent and Broad-Spectrum Antimicrobial Agents

There is increasing demand to develop antimicrobial peptides (AMPs) as next generation antibiotic agents, as they have the potential to circumvent emerging drug resistance against conventional antibiotic treatments. Non-natural antimicrobial peptidomimetics are an ideal example of this, as they have significant potency and in vivo stability. Here we report for the first time the design of lipidated γ-AApeptides as antimicrobial agents. These lipo-γ-AApeptides show potent broad-spectrum activities against fungi and a series of Gram-positive and Gram-negative bacteria, including clinically relevant pathogens that are resistant to most antibiotics. We have analyzed their structure–function relationship and antimicrobial mechanisms using membrane depolarization and fluorescent microscopy assays. Introduction of unsaturated lipid chain significantly decreases hemolytic activity and thereby increases the selectivity. Furthermore, a representative lipo-γ-AApeptide did not induce drug resistance in <i>S. aureus</i>, even after 17 rounds of passaging. These results suggest that the lipo-γ-AApeptides have bactericidal mechanisms analogous to those of AMPs and have strong potential as a new class of novel antibiotic therapeutics

Nanorods Formed from a New Class of Peptidomimetics

Although peptide amphiphiles have been explored as nanomaterials for different applications, nanostructures formed by hierarchical molecular assembly of sequence-specific peptidomimetics are much less developed. Such protein-like nanomaterials could enhance the current application of peptide-based amphiphiles by enriching the diversity of nanostructures, increasing <i>in vivo</i> stability for biomedical applications, and facilitating the understanding of biomacromolecular self-assembly. Herein we present a biomimetic γ-AApeptide amphiphile which forms nanorods. Our results demonstrate the capability of γ-AApeptide amphiphiles as a potential scaffold for the preparation of biomimetic and bioinspired nanostructures. The programmability and biocompatibility of γ-AApeptides could lead to novel nanomaterials for a wide variety of applications