Journal of medicinal chemistry
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Mycobacterial transcriptional repressor EthR controls the expression of EthA, the bacterial monooxygenase activating ethionamide, and is thus largely responsible for the low sensitivity of the human pathogen Mycobacterium tuberculosis to this antibiotic. We recently reported structure-activity relationships of a series of 1,2,4-oxadiazole EthR inhibitors leading to the discovery of potent ethionamide boosters. ⋯ This work was done using a combination of structure-based drug design and in vitro/ex vivo evaluations of ethionamide boosters on the targeted protein EthR and on the human pathogen Mycobacterium tuberculosis. Thanks to this process, we identified compound 42 (BDM41906), which displays improved efficacy in addition to high exposure to mice after oral administration.
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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.
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This study addresses the hypothesis that the lack of anesthetic activity for (3α,5α)-3-hydroxypregn-16-ene-11,20-dione (Δ(16)-alphaxalone) is explained by the steroid Δ(16) double bond constraining the steroid 20-carbonyl group to a position that prevents it from favorably interacting with γ-aminobutyric acid type A (GABA(A)) receptors. A series of Δ(16) and Δ(17(20)) analogues of Δ(16)-alphaxalone was prepared to evaluate this hypothesis in binding, electrophysiological, and tadpole anesthesia experiments. ⋯ Instead, the results indicate that it is the presence of the C-21 methyl group in Δ(16)-alphaxalone, not the location of the constrained C-20 carbonyl group, that prevents Δ(16)-alphaxalone from interacting strongly with the GABA(A) receptor and having anesthetic activity. Consistent with this conclusion, a Δ(17(20)) analogue of Δ(16)-alphaxalone without a C-21 methyl group was found to be very similar to the anesthetic steroid (3α,5α)-3-hydroxypregnane-11,20-dione (alphaxalone) with regard to time of onset and rate of recovery from anesthesia when administered to mice by tail vein injection.
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Endoplasmic reticulum (ER) stress-induced cancer cell apoptosis has become a novel signaling target for development of cancer therapeutic drugs. Curcumin exhibits growth-suppressive activity against a variety of cancer cells. We previously synthesized a series of monocarbonyl analogues of curcumin with strong cytotoxicity against tumor cells. ⋯ CHOP knockdown by specific siRNA attenuated 19-induced cell apoptosis, further indicating that the apoptotic pathway is ER stress-dependent. In vivo, 19 showed a dramatic 53.5% reduction in H460 xenograft tumor size after 22 days of treatment. Taken together, these mechanistic insights on the novel compound 19, with nontoxicity, may provide us with a novel anticancer candidate.