RESUMO
The cancer cell mitochondrion could be a promising target for the development of new anticancer agents. 16-([3-chloro-5-(trifluoromethyl)-phenyl]carbamoylamino)hexadecanoic acid (2) is a novel aryl-urea fatty acid that targets the mitochondrion in MDA-MB-231 breast cancer cells and activates cell death. In the present study, the relationships between alkyl chain length in 2 analogues, mitochondrial disruption and cell killing were evaluated. The chain-contracted C13-analogue 7 c optimally disrupted the mitochondrial membrane potential (IC50 4.8±0.8â µM). In addition, annexin V-FITC/7-AAD assays demonstrated that 7 c was the most effective cell killing analogue and C11 BODIPY (581/591) assays demonstrated that 7 c was also most effective in generating reactive oxygen species in MDA-MB-231 cells. Together, carbon chain length is a key factor that determines the capacity of 2 analogues to disrupt the mitochondrial membrane, induce the production of reactive oxygen species and kill breast cancer cells. As an aryl-urea with enhanced activity and improved drug-like properties, 7 c may be a suitable lead molecule for entry into a program of development of these molecules as anticancer agents.
Assuntos
Antineoplásicos , Ácidos Graxos , Potencial da Membrana Mitocondrial , Mitocôndrias , Espécies Reativas de Oxigênio , Ureia , Humanos , Espécies Reativas de Oxigênio/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Ácidos Graxos/química , Ácidos Graxos/farmacologia , Ácidos Graxos/síntese química , Ureia/farmacologia , Ureia/química , Ureia/análogos & derivados , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Estrutura-Atividade , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Carbono/química , Carbono/farmacologia , Sobrevivência Celular/efeitos dos fármacosRESUMO
Since long-chain fatty acids work as the primary energy source for the myocardium, radiolabeled long-chain fatty acids play an important role as imaging agents to diagnose metabolic heart dysfunction and heart diseases. With the aim of developing radiogallium-labeled fatty acids, herein four fatty acid-based tracers, [67Ga]Ga-HBED-CC-PDA, [67Ga]Ga-HBED-CC-MHDA, [67Ga]Ga-DOTA-PDA, and [67Ga]Ga-DOTA-MHDA, which are [67Ga]Ga-HBED-CC and [67Ga]Ga-DOTA conjugated with pentadecanoic acid (PDA) and 3-methylhexadecanoic acid (MHDA), were synthesized, and their potential for myocardial metabolic imaging was evaluated. Those tracers were found to be chemically stable in 0.1 M phosphate buffered saline. Initial [67Ga]Ga-HBED-CC-PDA, [67Ga]Ga-HBED-CC-MHDA, [67Ga]Ga-DOTA-PDA, and [67Ga]Ga-DOTA-MHDA uptakes in the heart at 0.5 min postinjection were 5.01 ± 0.30%ID/g, 5.74 ± 1.02%ID/g, 5.67 ± 0.22%ID/g, and 5.29 ± 0.10%ID/g, respectively. These values were significantly lower than that of [123I]BMIPP (21.36 ± 2.73%ID/g). For their clinical application as myocardial metabolic imaging agents, further structural modifications are required to increase their uptake in the heart.
Assuntos
Ácidos Graxos/síntese química , Radioisótopos de Gálio/farmacologia , Coração/diagnóstico por imagem , Animais , Linhagem Celular Tumoral , Ácido Edético/análogos & derivados , Ácido Edético/química , Ácido Edético/metabolismo , Ácidos Graxos/farmacologia , Gálio/química , Radioisótopos de Gálio/química , Compostos Heterocíclicos com 1 Anel/química , Compostos Heterocíclicos com 1 Anel/metabolismo , Humanos , Japão , Masculino , Camundongos , Miocárdio/patologia , Tomografia por Emissão de Pósitrons/métodos , Radioisótopos , Distribuição Tecidual , Tomografia Computadorizada por Raios X/métodosRESUMO
Fatty acid amides are a diverse family of underappreciated, biologically occurring lipids. Herein, the methods for the chemical synthesis and subsequent characterization of specific members of the fatty acid amide family are described. The synthetically prepared fatty acid amides and those obtained commercially are used as standards for the characterization and quantification of the fatty acid amides produced by biological systems, a fatty acid amidome. The fatty acid amidomes from mouse N18TG2 cells, sheep choroid plexus cells, Drosophila melanogaster, Bombyx mori, Apis mellifera, and Tribolium castaneum are presented.
Assuntos
Amidas/química , Ácidos Graxos/química , Lipídeos/química , Amidas/síntese química , Amidas/metabolismo , Animais , Abelhas/química , Bombyx/química , Linhagem Celular , Drosophila melanogaster/química , Ácidos Graxos/síntese química , Ácidos Graxos/metabolismo , Lipídeos/genética , Camundongos , Ovinos , Tribolium/químicaRESUMO
Hymeglusin, a previously known eukaryotic hydroxymethylglutaryl-CoA (HMG-CoA) synthase inhibitor, was identified as circumventing the ß-lactam drug resistance in methicillin-resistant Staphylococcus aureus (MRSA). We describe the concise total syntheses of a series of natural products, which enabled determination of the absolute configuration of fusarilactoneâ A and provided structure-activity relationship information. Based on previous reports, we speculated that the target protein of this circumventing effect may be MRSA bacterial HMG-CoA synthase (mvaS). We found that this enzyme was dose-dependently inhibited by hymeglusin. Furthermore, overexpression of the MRSA mvaS gene and site-directed mutagenesis studies suggested its binding site and the mechanism of action.
Assuntos
Antibacterianos , Ácidos Graxos , Staphylococcus aureus Resistente à Meticilina , Pironas , Humanos , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Resistência beta-Lactâmica/efeitos dos fármacos , Relação Dose-Resposta a Droga , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pironas/síntese química , Pironas/química , Pironas/farmacologia , Relação Estrutura-Atividade , Ácidos Graxos/síntese química , Ácidos Graxos/química , Ácidos Graxos/farmacologiaRESUMO
N-heterocyclic silver carbene compounds have been extensively studied and shown to be active agents against a host of pathogenic bacteria and fungi. By incorporating hypothesized virulence targeting substituents into NHC-silver systems via salt metathesis, an atom-efficient complexation process can be used to develop new complexes to target the passive and active systems of a microbial cell. The incorporation of fatty acids and an FtsZ inhibitor have been achieved, and creation of both the intermediate salt and subsequent silver complex has been streamlined into a continuous flow process. Biological evaluation was conducted with in vitro toxicology assays showing these novel complexes had excellent inhibition against Gram-negative strains E. coli, P. aeruginosa, and K. pneumoniae; further studies also confirmed the ability to inhibit biofilm formation in methicillin-resistant Staphylococcus aureus (MRSA) and C. Parapsilosis. In vivo testing using a murine thigh infection model showed promising inhibition of MRSA for the lead compound SBC3, which is derived from 1,3-dibenzyl-4,5-diphenylimidazol-2-ylidene (NHC*).
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Prata/química , Prata/farmacologia , Antibacterianos/síntese química , Complexos de Coordenação/síntese química , Ácidos Graxos/síntese química , Ácidos Graxos/química , Ácidos Graxos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Humanos , Metano/análogos & derivados , Metano/síntese química , Metano/química , Metano/farmacologia , Modelos MolecularesRESUMO
A diverse series of 43 novel "soft antimicrobials" based on quaternary ammonium pyridoxine derivatives which include six-membered acetals and ketals of pyridoxine bound via cleavable linker moieties (amide, ester) with a fragment of fatty carboxylic acid was designed. Nine compounds exhibited in vitro promising antibacterial activity against Gram-positive and Gram-negative bacterial strains with MIC values comparable with reference antiseptics miramistin, benzalkonium chloride and chlorohexidine. On various clinical isolates, the lead compounds 6i and 12a exhibited antibacterial activity comparable with that of benzalkonium chloride while higher than that of miramistin. Moreover, 6i and 12a were able to kill bacteria embedded into the matrix of mono- and dual species biofilms. The treatment of bacterial cells by either 6i and 12a lead to fast depolarization of the membrane suggesting that the membrane is an apparent molecular target of compounds. 6i and 12a were non mutagenic neither in SOS-chromotest nor in Ames test and non-toxic in vivo at acute oral (LD50 > 2000 mg/kg) and cutaneous administration (LD50 > 2500 mg/kg) on mice. Taken together, our data allow suggesting described active compounds as promising starting point for the new antibacterial agents development.
Assuntos
Antibacterianos/química , Antibacterianos/síntese química , Ácidos Graxos/síntese química , Piridoxina/síntese química , Compostos de Amônio Quaternário/química , Compostos de Amônio Quaternário/síntese química , Humanos , Estrutura MolecularRESUMO
A series of novel linear aliphatic amine-linked triaryl derivatives as inhibitors of PD-1/PD-L1 were designed, synthesized, and evaluated in vitro and in vivo. In this chemical series, compound 58 showed the most potent inhibitory activity and binding affinity with hPD-L1, with an IC50 value of 12 nM and a KD value of 16.2 pM, showing a binding potency approximately 2000-fold that of hPD-1. Compound 58 could bind with hPD-L1 on the cellular surface and competitively block the interaction of hPD-1 with hPD-L1. In a T cell function assay, 58 restored the T cell function, leading to increased IFN-γ secretion. Moreover, in a humanized mouse model, compound 58 significantly inhibited tumor growth without obvious toxicity and showed moderate PK properties after intravenous injection. These results indicated that 58 is a promising lead for further development of small-molecule PD-1/PD-L1 inhibitors for cancer therapy.
Assuntos
Antineoplásicos/síntese química , Antígeno B7-H1/antagonistas & inibidores , Desenho de Fármacos , Ácidos Graxos/síntese química , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Animais , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antígeno B7-H1/química , Antígeno B7-H1/metabolismo , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Ácidos Graxos/metabolismo , Ácidos Graxos/farmacologia , Feminino , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptor de Morte Celular Programada 1/química , Receptor de Morte Celular Programada 1/metabolismo , Células RAW 264.7 , Ratos Sprague-Dawley , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
The field of bioactive lipids is ever expanding with discoveries of novel lipid molecules that promote human health. Adopting a lipidomic-assisted approach, two new families of previously unrecognized saturated hydroxy fatty acids (SHFAs), namely, hydroxystearic and hydroxypalmitic acids, consisting of isomers with the hydroxyl group at different positions, were identified in milk. Among the various regio-isomers synthesized, those carrying the hydroxyl at the 7- and 9-positions presented growth inhibitory activities against various human cancer cell lines, including A549, Caco-2, and SF268 cells. In addition, 7- and 9-hydroxystearic acids were able to suppress ß-cell apoptosis induced by proinflammatory cytokines, increasing the possibility that they can be beneficial in countering autoimmune diseases, such as type 1 diabetes. 7-(R)-Hydroxystearic acid exhibited the highest potency both in cell growth inhibition and in suppressing ß-cell death. We propose that such naturally occurring SHFAs may play a role in the promotion and protection of human health.
Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ácidos Graxos/farmacologia , Animais , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Citocinas/farmacologia , Ácidos Graxos/síntese química , Ácidos Graxos/química , Expressão Gênica/efeitos dos fármacos , Humanos , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Leite/química , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Ácidos Esteáricos/farmacologia , Estereoisomerismo , Espectrometria de Massas em TandemRESUMO
Throughout the last decade, extracellular vesicles (EVs) have become increasingly popular in several areas of regenerative medicine. Recently, Apis mellifera royal jelly EVs (RJ EVs) were shown to display favorable wound healing properties such as stimulation of mesenchymal stem cell migration and inhibition of staphylococcal biofilms. However, the sustained and effective local delivery of EVs in non-systemic approaches - such as patches for chronic cutaneous wounds - remains an important challenge for the development of novel EV-based wound healing therapies. Therefore, the present study aimed to assess the suitability of type I collagen -a well-established biomaterial for wound healing - as a continuous delivery matrix. RJ EVs were integrated into collagen gels at different concentrations, where gels containing 2 mg/ml collagen were found to display the most stable release kinetics. Functionality of released RJ EVs was confirmed by assessing fibroblast EV uptake and migration in a wound healing assay. We could demonstrate reliable EV uptake into fibroblasts with a sustained pro-migratory effect for up to 7 d. Integrating fibroblasts into the RJ EV-containing collagen gel increased the contractile capacity of these cells, confirming availability of RJ EVs to fibroblasts within the collagen gel. Furthermore, EVs released from collagen gels were found to inhibit Staphylococcus aureus ATCC 29213 biofilm formation. Overall, our results suggest that type I collagen could be utilized as a reliable, reproducible release system to deliver functional RJ EVs for wound healing therapies.
Assuntos
Colágeno Tipo I/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Vesículas Extracelulares , Ácidos Graxos/administração & dosagem , Hidrogéis/administração & dosagem , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Colágeno Tipo I/síntese química , Relação Dose-Resposta a Droga , Vesículas Extracelulares/química , Ácidos Graxos/síntese química , Fibroblastos/efeitos dos fármacos , Fibroblastos/fisiologia , Humanos , Hidrogéis/síntese químicaRESUMO
ω-Hydroxynonanoic acid and α,ω-nonanedioic acid are used for synthesizing diverse chemicals. Although biological methods are developed, their concentrations are low due to the toxicity of high concentrations of the hydrophobic chemicals toward biocatalysts. Here, we constructed a biocatalytic system with high productivity by adding an adsorbent resin and a strong base anion-exchange resin, reducing the solubility of ω-hydroxynonanoic acid and α,ω-nonanedioic acid, feeding ω-hydroxynonanoic acid, and introducing a cofactor regeneration system. The constructed biocatalytic system converted 300 mM (83.9 g L-1) and 154 mM (43.5 g L-1) oleic acid in the olive oil hydrolysate obtained after resin extraction, which were derived from 110 and 54 g L-1 olive oil, respectively, into 202 mM (35.2 g L-1) ω-hydroxynonanoic acid and 103 mM (19.4 g L-1) α,ω-nonanedioic acid, which are 21- and 24-fold higher values than the previously reported results, respectively. This study may contribute to the industrial biosynthesis of ω-hydroxynonanoic acid and α,ω-nonanedioic acid from olive oil.
Assuntos
Ácidos Dicarboxílicos/química , Ácidos Graxos/síntese química , Ácido Oleico/química , Azeite de Oliva/química , Biocatálise , Resinas Sintéticas/químicaRESUMO
Fatty acid oxidation (FAO) produces most of the ATP used to sustain the cardiac contractile work, although glycolysis is a secondary source of ATP under normal physiological conditions. FAO impairment has been reported in the advanced stages of heart failure (HF) and is strongly linked to disease progression and severity. Thus, from a clinical perspective, FAO dysregulation provides prognostic value for HF progression, the assessment of which could be used to improve patient monitoring and the effectiveness of therapy. Positron emission tomography (PET) imaging represents a powerful tool for the assessment and quantification of metabolic pathways inâ vivo. Several FAO PET tracers have been reported in the literature, but none of them is in routine clinical use yet. Metabolically trapped tracers are particularly interesting because they undergo FAO to generate a radioactive metabolite that is subsequently trapped in the mitochondria, thus providing a quantitative means of measuring FAO inâ vivo. Herein, we describe the design, synthesis, tritium labelling and radiofluorination of 4,4,16-trifluoro-palmitate (1) as a novel potential metabolically trapped FAO tracer. Preliminary PET-CT studies on [18 F]1 in rats showed rapid blood clearance, good metabolic stability - confirmed by using [3 H]1 in vitro - and resistance towards defluorination. However, cardiac uptake in rats was modest (0.24±0.04 % ID/g), and kinetic analysis showed reversible uptake, thus indicating that [18 F]1 is not irreversibly trapped.
Assuntos
Desenho de Fármacos , Ácidos Graxos/química , Ácidos Graxos/metabolismo , Miocárdio/química , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Compostos Radiofarmacêuticos/química , Animais , Ácidos Graxos/síntese química , Halogenação , Miocárdio/metabolismo , Oxirredução , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Fatty acid sugar esters are non-ionic surfactant active agents with excellent performance and many uses. This work is devoted to the synthesis of sugar esters by the esterification reaction of sugar with mixed carboxylicpalmitic anhydrides using resin Amberlyst-15 as heterogeneous acid catalyst. These anhydrides should be stable and react as acylating agents. Influence of different reaction parameters, such as the molar ratio (sucrose/anhydride), the type of solvent and the reaction time on the yield of the esterification reaction were studied. The esterification reaction of sucrose with mixed palmitic benzoic anhydride leads to a mixture of sucrose esters of palmitic acid with a good percentage of conversion. The mixed anhydride was both reactive and selective for the preparation of fatty acid ester.
Assuntos
Benzoatos/química , Ácidos Carboxílicos/química , Técnicas de Química Sintética/métodos , Ésteres/síntese química , Ácidos Graxos/síntese química , Ácido Palmítico/química , Sacarose/síntese química , Acilação , Catálise , Esterificação , Solventes , Estirenos , Tensoativos/síntese química , Fatores de TempoRESUMO
2,3,5-Trisubstituted tetrahydrofuran moiety is ubiquitous in natural products. These have served as appealing candidates for total synthesis due to their varied bio- and pharmaceutical activities. This tutorial review delineates the ingenious efforts by many researchers in the total synthesis of selected natural products based on a common 2,3,5-trisubstituted tetrahydrofuran core structure. Many of the syntheses display nuanced interplay between new methods and the ingenuity of planned strategies achieved through catalysis or cascade chemistry. In some cases, the chiron approach has come quite handy, wherein the structural features and the stereochemistry in select molecules could map well with naturally available starting materials. This compilation also aims to enhance the diversity space based on these natural products and further interest in sustainable total synthesis.
Assuntos
Produtos Biológicos/síntese química , Furanos/química , Produtos Biológicos/química , Ácidos Graxos/síntese química , Ácidos Graxos/química , Furanos/síntese química , Lactonas/síntese química , Lactonas/química , Lipídeos/síntese química , Lipídeos/química , Sesquiterpenos/síntese química , Sesquiterpenos/química , EstereoisomerismoRESUMO
A chemo-enzymatic approach for the conversion of oleic acid into azelaic and pelargonic acid is herein described. It represents a sustainable alternative to ozonolysis, currently employed at the industrial scale to perform the reaction. Azelaic acid is produced in high chemical purity in 44% isolation yield after three steps, avoiding column chromatography purifications. In the first step, the lipase-mediated generation of peroleic acid in the presence of 35% H2O2 is employed for the self-epoxidation of the unsaturated acid to the corresponding oxirane derivative. This intermediate is submitted to in situ acid-catalyzed opening, to afford 9,10-dihydroxystearic acid, which readily crystallizes from the reaction medium. The chemical oxidation of the diol derivative, using atmospheric oxygen as a stoichiometric oxidant with catalytic quantities of Fe(NO3)3â9âH2O, (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO), and NaCl, affords 9,10-dioxostearic acid which is cleaved by the action of 35% H2O2 in mild conditions, without requiring any catalyst, to give pelargonic and azelaic acid.
Assuntos
Ácidos Dicarboxílicos/síntese química , Ácidos Graxos/síntese química , Ácido Oleico/química , Biocatálise , Ácidos Graxos Insaturados/química , Lipase/química , Estrutura Molecular , OxirreduçãoRESUMO
Metformin hydrochloride (MFM) is often used as a controlled-release (CR) tablet to reduce dosing frequency. However, the MFM CR tablet contains significant amounts of excipients and the tablet size is also large. Dosing convenience and patient compliance can be increased by reducing the size of the CR tablets. The aim of this study was to prepare and evaluate the MFM controlled-release tablet (MFM-CRT) using two types of release modulators, inner and outer. The MFM-CRT was prepared by coating the MFM granules using a binder solution containing aluminum stearate (ALS) as the inner release-modulator, and polyethylene oxide (PEO) as the outer release-modulator. The dispersion stability of the binder solution was optimized by the dispersion analyzer. The MFM-CRT was evaluated for dissolution rate and tablet volume. Additionally, dissolution behavior and dissolution kinetics of the MFM-CRT were analyzed using micro-computed tomography (micro-CT). Although the optimal MFM-CRT showed no difference in the release rate as compared to the commercially available product of Glucophage® XR 500 mg (f2 value: 72), the length of the long axis was reduced by 6 mm and the weight was reduced by about 27%. We expect patient compliance to improve because of effective sustained release and volume reduction of MFM-CRT.
Assuntos
Portadores de Fármacos/síntese química , Liberação Controlada de Fármacos , Ácidos Graxos/síntese química , Hipoglicemiantes/síntese química , Metformina/síntese química , Preparações de Ação Retardada/síntese química , Preparações de Ação Retardada/metabolismo , Portadores de Fármacos/metabolismo , Ácidos Graxos/metabolismo , Hipoglicemiantes/metabolismo , Metformina/metabolismo , Espectrometria por Raios X/métodos , Microtomografia por Raio-X/métodosRESUMO
Mammary-tissue-restricted cytochrome P450 4Z1 (CYP4Z1) has garnered interest for its potential role in breast cancer progression. CYP4Z1-dependent metabolism of arachidonic acid preferentially generates 14,15-epoxyeicosatrienoic acid (14,15-EET), a metabolite known to influence cellular proliferation, migration, and angiogenesis. In this study, we developed time-dependent inhibitors of CYP4Z1 designed as fatty acid mimetics linked to the bioactivatable pharmacophore, 1-aminobenzotriazole (ABT). The most potent analogue, 8-[(1H-benzotriazol-1-yl)amino]octanoic acid (7), showed a 60-fold lower shifted-half-maximal inhibitory concentration (IC50) for CYP4Z1 compared to ABT, efficient mechanism-based inactivation of the enzyme evidenced by a KI = 2.2 µM and a kinact = 0.15 min-1, and a partition ratio of 14. Furthermore, 7 exhibited low off-target inhibition of other CYP isozymes. Finally, low micromolar concentrations of 7 inhibited 14,15-EET production in T47D breast cancer cells transfected with CYP4Z1. This first-generation, selective mechanism-based inhibitor (MBI) will be a useful molecular tool to probe the biochemical role of CYP4Z1 and its association with breast cancer.
Assuntos
Inibidores das Enzimas do Citocromo P-450/farmacologia , Família 4 do Citocromo P450/antagonistas & inibidores , Ácidos Graxos/farmacologia , Triazóis/farmacologia , Ácido Araquidônico/metabolismo , Linhagem Celular Tumoral , Inibidores das Enzimas do Citocromo P-450/síntese química , Inibidores das Enzimas do Citocromo P-450/metabolismo , Desenho de Fármacos , Ácidos Graxos/síntese química , Ácidos Graxos/metabolismo , Humanos , Microssomos Hepáticos/metabolismo , Oxirredução , Triazóis/síntese química , Triazóis/metabolismoRESUMO
Targeting the tumor cell mitochondrion could produce novel anticancer agents. We designed an aryl-urea fatty acid (1 g; 16({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)hexadecanoic acid) that disrupted the mitochondrion and decreased MDA-MB-231 breast cancer cell viability. To optimize the aryl-ureas the present study evaluated mitochondrial targeting by 1 g analogues containing alkyl chains between 10-17 carbons. Using the dye JC-1, the C12-C17 analogues efficiently disrupted the mitochondrial membrane potential (IC50 s 3.5±1.2 to 7.6±1.1â µM) and impaired ATP production; shorter analogues were less active. 7-Aminoactinomycin D/annexin V staining and flow cytometry showed that these agents activated the killing mechanisms of necrosis and apoptosis to varying extents (7-aminoactinomycin D/annexin V staining ratios 4.3-6.0). Indeed, 1 g and its C17 analogue preferentially activated necrosis and apoptosis, respectively (ratios 2.1 and 16). Taken together, alkyl chain length is a determinant of mitochondrial targeting by aryl-ureas and can be varied to develop analogues that activate apoptosis or necrosis in a regulated fashion.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Carbono/farmacologia , Ácidos Graxos/farmacologia , Ureia/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carbono/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Ácidos Graxos/síntese química , Ácidos Graxos/química , Humanos , Cinética , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Ureia/análogos & derivados , Ureia/químicaRESUMO
Ciprofloxacin (CP) has a confirmed cytotoxic action on some cancerous cells, but in high, non-pharmacological concentrations. Considering features of natural fatty acids, such as biocompatibility, biodegradability and their increased cellular uptake by cancer cells, it seems that combining them with a drug could improve its bioavailability, and thus cytotoxicity. Therefore, the aim of this study was coupling of CP with saturated and unsaturated fatty acids, and evaluation of their cytotoxicity, apoptosis-inducing effects and inhibition of IL-6 release in human primary (SW480) and metastatic (SW620) colon cancer, metastatic prostate cancer (PC3) and normal (HaCaT) cell lines. The PC3 cell line was the most sensitive to the presence of the obtained conjugates. The value of IC50 for oleic acid conjugate (4) was 7.7⯵M, and it was 12 times lower than for CP alone (101.4⯵M). The studied derivatives induced late apoptosis in all cancer cell lines, but not in normal cells. The most potent apoptosis inducer was conjugate 4, that resulted in the highest percentage of PC3 cells in late apoptosis (81.5%⯱â¯3.9), followed by elaidic acid amide 5 (75%⯱â¯4.8). The strongest pro-apoptic effects on SW480â¯cells were demonstrated by conjugates of DHA (8) and sorbic (2) acids, whereas in SW620â¯cell lines, compounds 2 and 5 appeared to be the most effective. To establish the mechanism of cytotoxic action of derivatives 2, 4, 5, the level of interleukin-6 (IL-6) was measured. The compounds with the highest cytotoxic potential significantly decreased the release of IL-6 by cancer cells. Additionally, all conjugates were evaluated for their in vitro antimicrobial activity. Short chain amides - crotonic (1) and sorbic (2) - were the most active against Staphyloccoci. The second-mentioned amide has shown both strong antistaphylococcal and antitumor properties.
Assuntos
Antineoplásicos/farmacologia , Ciprofloxacina/farmacologia , Ácidos Graxos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Antineoplásicos/síntese química , Antineoplásicos/química , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ciprofloxacina/síntese química , Ciprofloxacina/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Ácidos Graxos/síntese química , Ácidos Graxos/química , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Schiff base liquid crystals, known as [4-(hexyloxy)phenylimino)methyl]phenyl palmitate (IA), [4-(hexyloxy)phenylimino)methyl]phenyl oleate (IIA) and [4-(hexyloxy)phenylimino)methyl]phenyl linoleate (IIIA), were synthesized from palmitic, oleic, and linoleic natural fatty acids. The prepared compounds have been investigated for their thermal and optical behavior as well as phase formation using differential scanning calorimetry (DSC) and polarized optical microscopy (POM). Molecular structures of all studied compounds were confirmed via elemental analysis, FT-IR, 1H NMR, and 13C NMR. Smectic phase is the observed mesophase for all compounds; however, their type and range depend upon the terminal alkanoate chains attached to the phenyl ring. Computational calculations, Density functional theory (DFT), energy difference of the frontier molecular orbital (FMOs), as well as the thermodynamic parameters of different molecular configurations isomers were discussed. It was found that the mesophase behavior and the geometrical characteristics were affected by the degree of unsaturation of fatty terminal chains. Furthermore, the geometrical structure of the CH=N linkage plays an important role in the thermal stability and optical transition temperature.
Assuntos
Ésteres/química , Ácidos Graxos/química , Cristais Líquidos/química , Bases de Schiff/química , Varredura Diferencial de Calorimetria , Ésteres/síntese química , Ácidos Graxos/síntese química , Espectroscopia de Ressonância Magnética , Conformação Molecular , Estrutura Molecular , Óptica e Fotônica/métodos , Bases de Schiff/síntese química , Espectroscopia de Infravermelho com Transformada de Fourier , Termodinâmica , Temperatura de TransiçãoRESUMO
Growing health awareness has resulted in the increased use of dietary supplements derived from plants and marine sources, leaving consumers unsure of their best options. There were three objectives of the present study. The first was to design and evaluate an efficient derivatization procedure. The second was to perform a comparative analysis of liquid oils and their corresponding capsules of hemp, chia, and flax seeds. The final objective was to determine the fatty acid (FA) composition of six fish oil products and compare it to the one provided on the label. For the FA profiling, we implemented two efficient, one-step, sustainable methods with high percentage recovery for the synthesis of FA methyl esters (FAME), which use base catalysis and microwave-assisted heating. Our results found no difference in nutritional value between liquid oils and capsules of the seed supplements, with flaxseed and chia offering a higher, beneficial n-3:n-6 ratio compared to hemp oil. Four of the fish oils analyzed contained significantly less eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) than their reported label, and the other two not only agreed with the manufacturers' declaration but were able to fulfill the daily adequate intake (AI) with fewer capsules.