The novel diiron amine complexes [Fe2Cp2(CO)(NH2R')(μ-CO){μ-CN(Me)(Cy)}]CF3SO3 [R' = H, 3; Cy, 4; CH2CH2NH2, 5; CH2CH2NMe2, 6; CH2CH2(4-C6H4OMe), 7; CH2CH2(4-C6H4OH), 8; Cp = η5-C5H5, Cy = C6H11 = cyclohexyl] were synthesized in 49-92 % yields from [Fe2Cp2(CO)2(μ-CO){μ-CN(Me)(Cy)}]CF3SO3, 1a, using a straightforward two-step procedure. They were characterized by IR and multinuclear NMR spectroscopy, and the structure of 7 was confirmed through X-ray diffraction analysis. Complexes 3-8 and the acetonitrile adducts [Fe2Cp2(CO)(NCMe)(μ-CO){μ-CN(Me)(R)}]CF3SO3 (R = Cy, 2a; Me, 2b; Xyl = 2,6-C6H3Me2, 2c) were assessed for their water solubility, octanol-water partition coefficient and stability in physiological-like solutions. The in vitro antiproliferative activity of 2a-c and 3-8 was tested on seven human cancer cell lines (A2780, A2780R, PC3, A549, MCF7, HOS and HT-29), while the selectivity was evaluated using normal MRC-5 cells. Overall, the complexes exhibited variable cytotoxicity, with IC50 values reaching the low micromolar range for 3, 7 and 8 in A2780 and A2780R cells, along with significant selectivity. Targeted experiments covered cell cycle modification, induction of cell death, mitochondrial membrane potential, ROS production and interaction with DNA and bovine serum albumin (BSA) as a model protein. The interaction of 3 with BSA was further investigated through computational studies. Results showed a negligible increase in intracellular ROS levels (except for 2b) and insignificant changes in mitochondrial membrane potential.
- Klíčová slova
- Bioorganometallic chemistry, Cellular effects, Diiron complexes, In vitro cytotoxicity, Labile ligand,
- MeSH
- aminy chemie farmakologie MeSH
- antitumorózní látky * farmakologie chemie chemická syntéza MeSH
- komplexní sloučeniny chemie farmakologie chemická syntéza MeSH
- léky antitumorózní - screeningové testy * MeSH
- lidé MeSH
- ligandy MeSH
- molekulární struktura MeSH
- nádorové buněčné linie MeSH
- proliferace buněk * účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- aminy MeSH
- antitumorózní látky * MeSH
- komplexní sloučeniny MeSH
- ligandy MeSH
A series of eight gold(I) N-heterocyclic carbene (NHC) complexes [Au(IMes)(Ln)] based on 1,3-bis(2,4,6-trimethylphenyl)imidazole-2-ylidene (IMes) and 7-azaindole derivatives (HLn), where n = 1-8 for HL1 = 5-fluoro-7-azaindole, HL2 = 5-bromo-7-azaindole, HL3 = 3-chloro-7-azaindole, HL4 = 3-iodo-7-azaindole, HL5 = 5-bromo-3-chloro-7-azaindole, HL6 = 5-bromo-3-iodo-7-azaindole, HL7 = 4-chloro-2-methyl-7-azaindole and HL8 = 7-azaindole, was prepared, characterised and studied for their in vitro anti-cancer and anti-inflammatory effects. The complexes showed significant cytotoxicity on human ovarian cancer cell lines (A2780, IC50 ≈ 8-19 μM and A2780R, IC50 ≈ 8-19 μM) and lowered toxicity in normal HaCat and MRC-5 cells. Cellular effects of the selected complexes 1 and 7 were evaluated in A2780 cells using flow cytometry. Moreover, the time-dependent cellular uptake in A2780 cells, a shotgun proteomic analysis, an ESI-MS study of hydrolysis and interactions with l-cysteine and reduced glutathione (GSH) were performed. Complexes 1 and 7 revealed remarkable anti-inflammatory effects via inhibition of NF-κB activity in human endothelial cells.
- Klíčová slova
- A2780, Anti-inflammatory, Cellular effects, Cytotoxicity, Gold, NHC, Proteomics,
- MeSH
- antiflogistika * farmakologie chemie MeSH
- antioxidancia * farmakologie chemie MeSH
- antitumorózní látky * farmakologie chemie chemická syntéza MeSH
- apoptóza * účinky léků MeSH
- endoteliální buňky účinky léků metabolismus MeSH
- heterocyklické sloučeniny * chemie farmakologie MeSH
- komplexní sloučeniny farmakologie chemie chemická syntéza MeSH
- lidé MeSH
- methan * analogy a deriváty chemie farmakologie MeSH
- nádorové buněčné linie MeSH
- zlato * chemie farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antiflogistika * MeSH
- antioxidancia * MeSH
- antitumorózní látky * MeSH
- carbene MeSH Prohlížeč
- heterocyklické sloučeniny * MeSH
- komplexní sloučeniny MeSH
- methan * MeSH
- zlato * MeSH
Monocyclic monoterpenoids carvones have been recently identified as atypical negative allosteric modulators of aryl hydrocarbon receptor (AhR). In the current work, we performed AhR antagonist activity screening of 100 natural and synthetic monoterpenoids, and their analogues. Using SAR approach, structural determinants of AhR antagonist activity were assigned, including CO presence/position, planarity, and C3/C5-alkylation. Applying pyramidal selection criteria, including absence of residual agonist activity, no cytotoxicity, strong antagonist potency, and pan-antagonism against diverse AhR agonists, we distilled four lead AhR antagonists (carvacrol, o-cresol, 3-methyl-S-carvone, EN-2). Whereas 3-methyl-S-carvone and EN-2 were non-competitive AhR pan-antagonists, carvacrol and o-cresol were ligand-selective AhR antagonists acting by unclear mechanism. We characterized in detail the effects of lead compounds at cellular functions of AhR, including AhR nuclear translocation, AhR dimerization with ARNT, and the expression of AhR-regulated genes. As a proof of concept, effects of monoterpenoids in the murine macrophages were investigated.
- Klíčová slova
- Allosteric binding, Aryl hydrocarbon receptor, Monoterpenoids, Therapeutic targeting,
- Publikační typ
- časopisecké články MeSH
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor, which plays numerous and pivotal roles in human physiology and pathophysiology. Therefore, pharmacotherapeutic targeting of the AhR is a highly pertinent issue. The identification of new AhR ligands and the characterization of the interactions between the AhR ligands and AhR protein requires appropriate methodology. In spite the AhR is monomeric intracellular soluble receptor, the full-length human AhR protein has not been crystallized so far, and its isolation in a form applicable in the binding assays is highly challenging. Recent advances, including crystallization of AhR fragments, recombinant protein technologies, and cryogenic electron microscopy, allowed for exploitation of diverse experimental techniques for studying interactions between ligands and the AhR. In the current paper, we review existing AhR ligand binding assays, including their description, applicability and limitations.
- Klíčová slova
- aryl hydrocarbon receptor, interactions, ligands, protein binding,
- MeSH
- lidé MeSH
- ligandy MeSH
- receptory aromatických uhlovodíků * metabolismus MeSH
- transkripční faktory bHLH metabolismus chemie MeSH
- vazba proteinů * MeSH
- vazebná místa MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- AHR protein, human MeSH Prohlížeč
- ligandy MeSH
- receptory aromatických uhlovodíků * MeSH
- transkripční faktory bHLH MeSH
Chronic intestinal inflammation significantly contributes to the development of colorectal cancer and remains a pertinent clinical challenge, necessitating novel therapeutic approaches. Indole-based microbial metabolite mimics Felix Kopp Kortagere 6 (FKK6), which is a ligand and agonist of the pregnane X receptor (PXR), was recently demonstrated to have PXR-dependent anti-inflammatory and protective effects in a mouse model of dextran sodium sulfate (DSS)-induced acute colitis. Here, we examined the therapeutic potential of FKK6 in a mouse model (C57BL/6 FVB humanized PXR mice) of colitis-associated colon cancer (CAC) induced by azoxymethane and DSS. FKK6 (2 mg/kg) displayed substantial antitumor activity, as revealed by reduced size and number of colon tumors, improved colon histopathology, and decreased expression of tumor markers (c-MYC, β-catenin, Ki-67, and cyclin D) in the colon. In addition, we carried out a chronic toxicity (30 days) assessment of FKK6 (1 mg/kg and 2 mg/kg) in C57BL/6 mice. Histological examination of tissues, biochemical blood analyses, and immunohistochemical staining for Ki-67 and γ-H2AX showed no difference between FKK6-treated and control mice. Comparative metabolomic analyses in mice exposed for 5 days to DSS and administered with FKK6 (0.4 mg/kg) revealed no significant effects on several classes of metabolites in the mouse fecal metabolome. Ames and micronucleus tests showed no genotoxic and mutagenic potential of FKK6 in vitro. In conclusion, anticancer effects of FKK6 in azoxymethane/DSS-induced CAC, together with FKK6 safety data from in vitro tests and in vivo chronic toxicity study, and comparative metabolomic study, are supportive of the potential therapeutic use of FKK6 in the treatment of CAC. SIGNIFICANCE STATEMENT: Microbial metabolite mimicry proposes that chemical mimics of microbial metabolites that serve to protect hosts against aberrant inflammation in the gut could serve as a new paradigm for the development of drugs targeting inflammatory bowel disease if, like the parent metabolite, is devoid of toxicity but more potent against the microbial metabolite receptor. We identified a chemical mimic of Felix Kopp Kortagere 6, and we propose that Felix Kopp Kortagere 6 is devoid of toxicity yet significantly reduces tumor formation in an azoxymethane-dextran sodium sulfate model of murine colitis-induced colon cancer.
- Klíčová slova
- Colon cancer, Inflammation, Microbial metabolites, Pregnane X receptor,
- MeSH
- azoxymethan toxicita MeSH
- chronická nemoc MeSH
- indoly farmakologie terapeutické užití MeSH
- kolitida farmakoterapie chemicky indukované metabolismus patologie MeSH
- kolorektální nádory * farmakoterapie metabolismus patologie MeSH
- modely nemocí na zvířatech * MeSH
- molekulární mimikry MeSH
- myši inbrední C57BL * MeSH
- myši MeSH
- nádory asociované s kolitidou patologie farmakoterapie metabolismus MeSH
- síran dextranu toxicita MeSH
- zánět farmakoterapie metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- azoxymethan MeSH
- indoly MeSH
- síran dextranu MeSH
The new diiron complexes [Fe2Cp2(CO)(L)(μ-CO){μ-CN(Me)(Cy)}]CF3SO3 (L = pyridine, 3a; 4-aminopyridine, 3b; 4-dimethylaminopyridine, 3c; 4-trifluoromethylpyridine, 3d; nicotinic acid, 4; Cp = η5-C5H5, Cy = C6H11 = cyclohexyl) were synthesized in moderate to high yields using two distinct synthetic routes from the precursors 1 (L = CO, for 4) and 2 (L = NCMe, for 3a-d), respectively. All products were characterized by IR and multinuclear NMR spectroscopy, and the structures of 3b and 3d were ascertained by X-ray diffraction studies. The behavior of the complexes in aqueous solutions (solubility, Log Pow, stability) was assessed using NMR and UV-Vis methods. The in vitro antiproliferative activity of 3a-c and 4 was evaluated against seven human cancer cell lines (A2780, A2780R, A549, MCF-7, PC3, HOS and HT-29) and one normal cell line (MRC-5), following 24 h of incubation (MTT test). Overall, 3-4 demonstrated stronger cytotoxicity than cisplatin, with 3c emerging as the most potent compound. The activity seems primarily linked to the inhibition of metabolic processes in the cancer cells, including depletion of reactive oxygen species (ROS) levels. However, subtle differences have been observed between the complexes, with 4 exerting its cytotoxicity through a distinct multimodal mechanism.
- Klíčová slova
- Bioorganometallic chemistry, Cellular effects, Diiron complexes, In vitro cytotoxicity, Metals in medicine, Pyridine ligand,
- MeSH
- antitumorózní látky * farmakologie chemie chemická syntéza MeSH
- komplexní sloučeniny farmakologie chemie chemická syntéza MeSH
- léky antitumorózní - screeningové testy MeSH
- lidé MeSH
- ligandy MeSH
- nádorové buněčné linie MeSH
- proliferace buněk účinky léků MeSH
- pyridiny * chemie farmakologie chemická syntéza MeSH
- železo chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antitumorózní látky * MeSH
- komplexní sloučeniny MeSH
- ligandy MeSH
- pyridine MeSH Prohlížeč
- pyridiny * MeSH
- železo MeSH
The aryl hydrocarbon receptor (AhR) is a cytosolic ligand-activated transcription factor integral to various physiological and pathological processes. Among its diverse ligands, indole-based compounds have garnered attention due to their significant biological activity and potential therapeutic applications. This study explores the activation of AhR by structurally diverse halogenated indoles. We evaluated the transcriptional activity of AhR and cell viability in the human LS174T-AhR-luc reporter cell line. Among the tested compounds, 4-FI, 7-FI, 6-BrI, 7-BrI, 6-Cl-2-ox, 5-Br-2-ox, and 6-Br-2-ox activated AhR in a concentration-dependent manner, displaying high efficacy and potency. Molecular docking analysis revealed moderate binding affinities of these compounds to the PAS-B domain of AhR, corroborated by competitive radioligand binding assays. Functional assays showed that halogenated indoles induce the formation of AhR-ARNT heterodimer and enhance the binding of the AhR to the CYP1A1 promoter. Additionally, 4-FI and 7-FI exhibited anti-inflammatory properties in Caco-2 cell models, highlighting their potential for therapeutic applications. This study underscores the significance of the type and position of halogen moiety in indole scaffold, suggesting their potential as candidates for developing therapeutics drugs to treat conditions such as inflammatory bowel disease via AhR activation.
- Klíčová slova
- Aryl hydrocarbon receptor, Halogen, Indole derivatives, Inflammation,
- MeSH
- cytochrom P-450 CYP1A1 metabolismus MeSH
- halogenace MeSH
- indoly * chemie farmakologie MeSH
- lidé MeSH
- molekulární struktura MeSH
- receptory aromatických uhlovodíků * metabolismus chemie MeSH
- simulace molekulového dockingu * MeSH
- transkripční faktory bHLH MeSH
- viabilita buněk účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- AHR protein, human MeSH Prohlížeč
- cytochrom P-450 CYP1A1 MeSH
- indoly * MeSH
- receptory aromatických uhlovodíků * MeSH
- transkripční faktory bHLH MeSH
BACKGROUND: Modern trends in reconstructive surgery involve the use of free perforator flaps to reduce the donor site morbidity. The course of perforator vessels has a great anatomic variability and demands detailed knowledge of the anatomical relationships and the variability of the course of the perforators. The numerous modifications to perforator nomenclature proposed by various authors resulted in confusion rather than simplification. In our study, we focused on the hypothesis that a septocutaneous perforator traverses from the given source vessel to the deep fascia adherent to but not to within the septum itself. METHODS: Sixty-nine septocutaneous perforators from three different limb donor sites (lateral arm flap, anterolateral thigh flap, and radial forearm free flap) were collected from the gross pathology specimens of 14 fresh cadavers. The gross picture and the cross-sections with the histological cross-sections on different levels were examined to determine the position of the vessel to the septal tissue. RESULTS: Of the observed 69 septal perforators, 61 (88.5%) perforators were adherent to but not within the septum. The remaining eight (12.5%) perforators passed through the septum. All these eight perforators were found in multiple different cross-section levels (2 of 19 in lateral arm flap, 3 of 27 in anterolateral thigh flap, and 3 of 23 in radial forearm free flap). CONCLUSION: Although septocutaneous vessels appear identical macroscopically, microscopically two types of vessels with paraseptal and intraseptal pathways are observed. The majority of these vessels are merely adherent to the septum having a paraseptal pathway, while a minority are within the septum and are "true" septocutaneous perforators. It is advisable to dissect with a piece of the septum in order to avoid damage or injury to the perforator.
- Publikační typ
- časopisecké články MeSH
A series of potassium isothiocyanato-(N-salicylidene-aminoacidato) cuprates (1-5) with the general formula of the monomeric unit K[Cu(sal-aa)(NCS)] ⋅ xH2O (x=0 or 2), containing a Schiff-base ligand (H2sal-aa) derived from natural amino acids such as glycine, DL-α-alanine, DL-valine, DL-phenylalanine and β-alanine, and salicylaldehyde, was screened for in vitro antiradical and major cellular effects against selected cancerous and normal cells. The complexes exhibited strong antioxidant properties against superoxide in vitro and a protective effect on DNA under Fenton-like reaction conditions. Screening of their cellular effects revealed moderate in vitro cytotoxicity against human cancer cell lines (A2780, A2780R and MCF-7), with IC50 values of 25-35 μM, and relatively low toxicity to normal fibroblast MRC-5 cells (with IC50 values>50 μM). Additional experiments performed on A2780 cells revealed that the most potent complex 5 significantly increased the number of A2780 cells arrested in the G2/M phase of the cell cycle and triggered intracellular oxidative stress. The selected flow cytometry experiments (detection of apoptosis/autophagy and activation of caspases 3/7 and depletion of mitochondrial membrane potential) did not reveal the dominant mechanism underlying the cytotoxicity of the complexes but clearly differentiated their molecular effects from those of the reference drug cisplatin. All the complexes exerted anti-inflammatory effects by modulating the levels of the proinflammatory cytokines TNF-α and IL-1β in LPS-activated THP-1 macrophage-like cells. Complex 5 also slightly influenced the activity of the upstream NF-κB transcription factor, while no effect on PPARγ activation was detected.
- Klíčová slova
- Cellular effects, Copper complex, Cytotoxicity, Inflammation, Schiff base,
- MeSH
- antiflogistika nesteroidní farmakologie chemie chemická syntéza MeSH
- antiflogistika farmakologie chemie chemická syntéza MeSH
- antioxidancia farmakologie chemie chemická syntéza MeSH
- antitumorózní látky * farmakologie chemie chemická syntéza MeSH
- apoptóza účinky léků MeSH
- kationty chemie farmakologie MeSH
- komplexní sloučeniny * farmakologie chemie chemická syntéza MeSH
- léky antitumorózní - screeningové testy * MeSH
- lidé MeSH
- měď * chemie farmakologie MeSH
- molekulární struktura MeSH
- nádorové buněčné linie MeSH
- proliferace buněk * účinky léků MeSH
- Schiffovy báze * chemie farmakologie chemická syntéza MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antiflogistika nesteroidní MeSH
- antiflogistika MeSH
- antioxidancia MeSH
- antitumorózní látky * MeSH
- kationty MeSH
- komplexní sloučeniny * MeSH
- měď * MeSH
- Schiffovy báze * MeSH
Copper(ii) and zinc(ii) complexes with lapachol (HLap) of the composition [M(Lap)2(N-N)] and [Cu(Lap)(H2O)(terpy)]NO3 (4), where M = Cu (1-3) or Zn (for 5-7), and N-N stands for bathophenanthroline (1 and 5), 5-methyl-1,10-phenanthroline (2 and 6), 2,2'-bipyridine (3), 2,2';6',2''-terpyridine (terpy, 4) and 1,10-phenanthroline (7), were synthesised and characterised. Complexes 1-5 revealed strong in vitro antiproliferative effects against A2780, A2780R, MCF-7, PC-3, A549 and HOS human cancer lines and MRC-5 normal cells, with IC50 values above 0.5 μM, and reasonable selectivity index (SI), with SI > 3.8 for IC50(MRC-5)/IC50(A2780). Considerable time-dependent cytotoxicity in A2780 cells was observed for complexes 6 and 7, with IC50 > 50 μM (24 h) to ca. 4 μM (48 h). Cellular effects of complexes 1, 5 and 7 in A2780 cells were investigated by flow cytometry revealing that the most cytotoxic complexes (1 and 5) significantly perturbed the mitochondrial membrane potential and the interaction with mitochondrial metabolism followed by the triggering of the intracellular pathway of apoptosis.
- Publikační typ
- časopisecké články MeSH
