Journal of medicinal chemistry
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The novel chelators 2-acetylpyridine-4,4-dimethyl-3-thiosemicarbazone (HAp44mT) and di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (HDp44mT) have been examined to elucidate the structure-activity relationships necessary to form copper (Cu) complexes with pronounced antitumor activity. Electrochemical studies demonstrated that the Cu complexes of these ligands had lower redox potentials than their iron complexes. Moreover, the Cu complexes where the ligand/metal ratio was 1:1 rather than 2:1 had significantly higher intracellular oxidative properties and antitumor efficacy. ⋯ Both types of Cu complex showed significantly more antiproliferative activity than the ligand alone. We also demonstrate the importance of the inductive effects of substituents on the carbonyl group of the parent ketone, which influence the Cu(II/I) redox potentials because of their proximity to the metal center. The structure-activity relationships described are important for the design of potent thiosemicarbazone Cu complexes.
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The fatty acid ethanolamides (FAEs) are a family of bioactive lipid mediators that include the endogenous agonist of peroxisome proliferator-activated receptor-alpha, palmitoylethanolamide (PEA). FAEs are hydrolyzed intracellularly by either fatty acid amide hydrolase or N-acylethanolamine-hydrolyzing acid amidase (NAAA). ⋯ Following the hypothesis that these compounds inhibit NAAA by acylation of the catalytic cysteine, we identified several requirements for recognition at the active site and obtained new potent inhibitors. In particular, (S)-N-(2-oxo-3-oxetanyl)biphenyl-4-carboxamide (7h) was more potent than 7a at inhibiting recombinant rat NAAA activity (7a, IC(50) = 420 nM; 7h, IC(50) = 115 nM) in vitro and at reducing carrageenan-induced leukocyte infiltration in vivo.
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(N)-Methanocarba nucleosides containing bicyclo[3.1.0]hexane replacement of the ribose ring previously demonstrated selectivity as A(3) adenosine receptor (AR) agonists (5'-uronamides) or antagonists (5'-truncated). Here, these two series were modified in parallel at the adenine C2 position. N(6)-3-Chlorobenzyl-5'-N-methyluronamides derivatives with functionalized 2-alkynyl chains of varying length terminating in a reactive carboxylate, ester, or amine group were full, potent human A(3)AR agonists. ⋯ In the 5'-truncated nucleoside series, 2-Cl analogues were more potent at A(3)AR than 2-H and 2-F, functional efficacy in adenylate cyclase inhibition varied, and introduction of a 2-alkynyl chain greatly reduced affinity. SAR parallels between the two series lost stringency at distal positions. The most potent and selective novel compounds were amine congener 15 (K(i) = 2.1 nM) and truncated partial agonist 22 (K(i) = 4.9 nM).
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Twenty-two lycorine-related compounds were investigated for in vitro antitumor activity using four cancer cell lines displaying different levels of resistance to proapoptotic stimuli and two cancer cell lines sensitive to proapoptotic stimuli. Lycorine and six of its congeners exhibited potency in the single-digit micromolar range, while no compound appeared more active than lycorine. ⋯ Furthermore, lycorine provided significant therapeutic benefit in mice bearing brain grafts of the B16F10 melanoma model at nontoxic doses. Thus, the results of the current study make lycorine an excellent lead for the generation of compounds able to combat cancers, which are naturally resistant to proapoptotic stimuli, such as glioblastoma, melanoma, non-small-cell-lung cancers, and metastatic cancers, among others.