Journal of medicinal chemistry
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Iron chelators of the 2'-benzoylpyridine thiosemicarbazone (BpT) class show substantial potential as anticancer agents. To explore structure-activity relationships, new BpT analogues were designed that incorporated halogen substituents on the noncoordinating phenyl group (XBpTs). These XBpT ligands exhibited potent antiproliferative activity with some analogues exceeding that of the parent BpT compound. ⋯ The addition of a halogen led to a halogen-specific increase in the redox potential of XBpT-Fe complexes. Probing for chelator-induced intracellular reactive oxygen species (ROS) with the fluorescent probe, 2',7'-dichlorofluorescein, revealed a 1.5-4.7-fold increase in fluorescence upon incorporation of Cl, Br, or I to the parent analogues. Furthermore, an important structure-activity relationship was deduced where the addition of halogens led to a positive correlation between intracellular ROS generation and antiproliferative activity in the more hydrophilic BpT parent compounds.
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The free fatty acid receptor 1 (FFA1, also known as GPR40) enhances glucose-stimulated insulin secretion from pancreatic β-cells and is recognized as an interesting new target for treatment of type 2 diabetes. Several series of selective FFA1 agonists are already known. ⋯ Aiming for the development of potent, selective, and less lipophilic FFA1 agonists, the terminal phenyl of a known compound series was replaced by nitrogen containing heterocycles. This resulted in the identification of 37, a selective FFA1 agonist with potent activity on recombinant human FFA1 receptors and on the rat insulinoma cell line INS-1E, optimal lipophilicity, and excellent in vitro permeability and metabolic stability.