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Hardigan T.,Georgia Regents University | Spitler K.,University of Iowa | Matsumoto T.,Institute of Medicinal Chemistry | Carrillo-Sepulveda M.A.,Georgia Regents University
Pflugers Archiv European Journal of Physiology

Activation of Toll-like receptor 3 (TLR3), a pattern recognition receptor of the innate immune system, is associated with vascular complications. However, whether activation of TLR3 alters vascular contractility is unknown. We, therefore, hypothesized that TLR3 activation augments vascular contractility and activates vascular smooth muscle cell (VSMC) contractile apparatus proteins. Male mice were treated with polyinosinic-polycytidylic acid (Poly I:C group, 14 days), a TLR3 agonist; control mice received saline (vehicle, 14 days). At the end of protocol, blood pressure was measured by tail cuff method. Aortas were isolated and assessed for contractility experiments using a wire myograph. Aortic protein content was used to determine phosphorylated/total interferon regulatory factor 3 (IRF3), a downstream target of TLR3 signaling, and ERK1/2 using Western blot. We investigated the TLR3/IRF3/ERK1/2 signaling pathway and contractile-related proteins such as phosphorylated/total myosin light chain (MLC) and caldesmon (CaD) in aortic VSMC primary cultures. Poly I:C-treated mice exhibited (vs. vehicle-treated mice) (1) elevated systolic blood pressure. Moreover, Poly I:C treatment (2) enhanced aortic phenylephrine-induced maximum contraction, which was suppressed by PD98059 (ERK1/2 inhibitor), and (3) increased aortic levels of phosphorylated IRF3 and ERK1/2. Stimulation of mouse aortic VSMCs with Poly I:C resulted in increased phosphorylation of IRF3, ERK1/2, MLC, and CaD. Inhibition of ERK1/2 abolished Poly I:C-mediated phosphorylation of MLC and CaD. Our data provide functional evidence for the role of TLR3 in vascular contractile events, suggesting TLR3 as a potential new therapeutic target in vascular dysfunction and regulation of blood pressure. © 2015, Springer-Verlag Berlin Heidelberg. Source

Bertamino A.,University of Salerno | Ostacolo C.,University of Naples Federico II | Ambrosino P.,University of Molise | Musella S.,University of Naples Federico II | And 12 more authors.
Journal of Medicinal Chemistry

Pharmacological modulation of the transient receptor potential melastatin type 8 (TRPM8) is currently under investigation as a new approach for the treatment of pain and other diseases. In this study, a series of N-substituted tryptamines was prepared to explore the structural requirements determining TRPM8 modulation. Using a fluorescence-based screening assay, we identified two compounds acting as an activator (2-(1H-indol-3-yl)-N-(4-phenoxybenzyl)ethanamine, 21) or an inhibitor (N,N-dibenzyl-2-(1H-indol-3-yl)ethanamine, 12) of calcium influx in HEK293 cells. In patch-clamp recordings, compound 21 displayed a significantly higher potency (EC50 = 40 ± 4 μM) and a similar efficacy when compared to menthol; by contrast, compound 12 produced a concentration-dependent inhibition of menthol-induced TRPM8 currents (IC50 = 367 ± 24 nM). Molecular modeling studies using a homology model of a single rat TRPM8 subunit identified a putative binding site located between the VSD and the TRP box, disclosing differences in the binding modes for the agonist and the antagonist. © 2016 American Chemical Society. Source

Gong Y.-G.,Institute of Medicinal Chemistry | Gong Y.-G.,Laboratory Center | Zhang T.-F.,Institute of Medicinal Chemistry | Li M.,Institute of Medicinal Chemistry | And 6 more authors.
Yaoxue Xuebao

Complexes containing cobalt and carbon monoxide ligands, CO releasing molecules (CORMs), have the potential of anti-tumor and anti-inflammatory. In this paper, three hybrid CORMs 1-3 were synthesized and tested for their toxicology in vivo and bioactivities. The results suggest that the complexes have a long half-life in the range of 43-53 min; their oral LD50 to mouse are between 1 500 mg-kg-1 and 5 000 mg-kg-1. After the successive administration, complex 1 exhibited a toxic activity in rats' liver, and induced an injury to liver cells. Complex 1 had a strong growth inhibition activity (IC50 36.20 umol-L-1 and 39.25 umol-L"1) in both HeLa cells and HepG2 cells, complex 2 displayed a lower activity in the inhibition of HeLa cells proliferation than the control 5-FU (IC50 114.19 umol-L-1), but had a higher activity in the inhibition of HepG2 cells than the control 5-FU (IC50 171.34 umol-L-1). The anti-inflammatory study suggests that all of them reduce intracellular nitrite level, complexes 1 and 2 have a stronger activity than complex 3. Their anti-inflammatory activity attributes to the CO molecules of the CORMs, which was confirmed by comparison with the corresponding ligand. Source

Hu Y.-G.,Institute of Medicinal Chemistry | Xu J.,Institute of Medicinal Chemistry | Gao H.-T.,Institute of Medicinal Chemistry | Ma Z.,Institute of Medicinal Chemistry
Journal of Heterocyclic Chemistry

(Chemical Equation Presented) Carbodiimide, obtained from aza-Wittig reaction of iminophosphorane with 4-fluorophenyl isocyanate, reacted with various nucleophiles under mild conditions to give a series of 2-substituted-3-(4-fluorophenyl)-benzofuro [3,2-d] pyrimidin-4(3H)-ones in satisfactory yield. Their structures were confirmed using NMR, EI-Ms, IR, and elementary analysis, and compound 7b was further analyzed by single-crystal. The preliminary bioassays indicated that these compounds showed moderate fungicidal activities against six kinds of fungi at a concentration of 50 mg/L. © 2010 HeteroCorporation. Source

Liu Y.-N.,Institute of Medicinal Chemistry | Wang J.-J.,Shandong University | Ji Y.-T.,Institute of Medicinal Chemistry | Zhao G.-D.,Institute of Medicinal Chemistry | And 4 more authors.
Journal of Medicinal Chemistry

By targeting a new binding region at the interface between αβ-tubulin heterodimers at the colchicine binding site, we designed a series of 7-substituted 1-methyl-1,4-dihydroindeno[1,2-c]pyrazoles as potential tubulin polymerization inhibitors. Among the compounds synthesized, 2-(6-ethoxy-3-(3-ethoxyphenylamino)-1-methyl-1,4-dihydroindeno[1,2-c]pyrazol-7-yloxy)acetamide 6a and 2-(6-ethoxy-3-(3-ethoxyphenylamino)-1-methyl-1,4-dihydroindeno[1,2-c]pyrazol-7-yloxy)-N-hydroxyacetamide 6n showed noteworthy low nanomolar potency against HepG2, Hela, PC3, and MCF-7 cancer cell lines. In mechanism studies, 6a inhibited tubulin polymerization and disorganized microtubule in A549 cells by binding to tubulin colchicine binding site. 6a arrested A549 cells in G2/M phase that was related to the alterations in the expression of cyclin B1 and p-cdc2. 6a induced A549 cells apoptosis through the activation of caspase-3 and PARP. In addition, 6a inhibited capillary tube formation in a concentration-dependent manner. In nonsmall cell lung cancer xenografts mouse model, 6a suppressed tumor growth by 59.1% at a dose of 50 mg/kg (ip) without obvious toxicity, indicating its in vivo potential as anticancer agent. © 2016 American Chemical Society. Source

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