Synthesis and Mechanism of Hypoglycemic Activity of Benzothiazole Derivatives

Adenosine 5′-monophosphate activated protein kinase (AMPK) has emerged as a major potential target for novel antidiabetic drugs. We studied the structure of 2-chloro-5-((<i>Z</i>)-((<i>E</i>)-5-((5-(4,5-dimethyl-2-nitrophenyl)­furan-2-yl)­methylene)-4-oxothiazolidin-2-ylidene)­amino)­benzoic acid (PT-1), which attenuates the autoinhibition of the enzyme AMPK, for the design and synthesis of different benzothiazoles with potential antidiabetic activity. We synthesized several structurally related benzothiazole derivatives that increased the rate of glucose uptake in L6 myotubes in an AMPK-dependent manner. One compound, 2-(benzo­[<i>d</i>]­thiazol-2-ylmethylthio)-6-ethoxybenzo­[<i>d</i>]­thiazole (<b>34</b>), augmented the rate of glucose uptake up to 2.5-fold compared with vehicle-treated cells and up to 1.1-fold compared to PT-1. Concomitantly, it elevated the abundance of GLUT4 in the plasma membrane of the myotubes and activated AMPK. Subcutaneous administration of <b>34</b> to hyperglycemic Kuo Kondo rats carrying the Ay-yellow obese gene (KKAy) mice lowered blood glucose levels toward the normoglycemic range. In accord with its activity, compound <b>34</b> showed a high fit value to a pharmacophore model derived from the PT-1

Multifunctional Cyclic d,l‑α-Peptide Architectures Stimulate Non-Insulin Dependent Glucose Uptake in Skeletal Muscle Cells and Protect Them Against Oxidative Stress

Oxidative stress directly correlates with the early onset of vascular complications and the progression of peripheral insulin resistance in diabetes. Accordingly, exogenous antioxidants augment insulin sensitivity in type 2 diabetic patients and ameliorate its clinical signs. Herein, we explored the unique structural and functional properties of the abiotic cyclic d,l-α-peptide architecture as a new scaffold for developing multifunctional agents to catalytically decompose ROS and stimulate glucose uptake. We showed that His-rich cyclic d,l-α-peptide <b>1</b> is very stable under high H₂O₂ concentrations, effectively self-assembles to peptide nanotubes, and increases the uptake of glucose by increasing the translocation of GLUT1 and GLUT4. It also penetrates cells and protects them against oxidative stress induced under hyperglycemic conditions at a much lower concentration than α-lipoic acid (ALA). In vivo studies are now required to probe the mode of action and efficacy of these abiotic cyclic d,l-α-peptides as a novel class of antihyperglycemic compounds

Mimicking Neuroligin‑2 Functions in β‑Cells by Functionalized Nanoparticles as a Novel Approach for Antidiabetic Therapy

Both pancreatic β-cell membranes and presynaptic active zones of neurons include in their structures similar protein complexes, which are responsible for mediating the secretion of bioactive molecules. In addition, these membrane-anchored proteins regulate interactions between neurons and guide the formation and maturation of synapses. These proteins include the neuroligins (e.g., NL-2) and their binding partners, the neurexins. The insulin secretion and maturation of β-cells is known to depend on their 3-dimensional (3D) arrangement. It was also reported that both insulin secretion and the proliferation rates of β-cells increase when cells are cocultured with clusters of NL-2. Use of full-length NL-2 or even its exocellular domain as potential β-cell functional enhancers is limited by the biostability and bioavailability issues common to all protein-based therapeutics. Thus, based on molecular modeling approaches, a short peptide with the potential ability to bind neurexins was derived from the NL-2 sequence. Here, we show that the NL-2-derived peptide conjugates onto innovative functional maghemite (γ-Fe₂O₃)-based nanoscale composite particles enhance β-cell functions in terms of glucose-stimulated insulin secretion and protect them under stress conditions. Recruiting the β-cells’ “neuron-like” secretory machinery as a target for diabetes treatment use has never been reported before. Such nanoscale composites might therefore provide a unique starting point for designing a novel class of antidiabetic therapeutic agents that possess a unique mechanism of action