RESUMEN
Quinine (an antimalarial) and aspirin (a nonsteroidal anti-inflammatory drug) were combined into a new drug-drug salt, quininium aspirinate, C20H25N2O2+·C9H7O4-, by liquid-assisted grinding using stoichiometric amounts of the reactants in a 1:1 molar ratio, and water, EtOH, toluene, or heptane as additives. A tetrahydrofuran (THF) solution of the mechanochemical product prepared using EtOH as additive led to a single crystal of the same material obtained by mechanochemistry, which was used for crystal structure determination at 100â K. Powder X-ray diffraction ruled out crystallographic phase transitions in the 100-295â K interval. Neat mechanical treatment (in a mortar and pestle, or in a ball mill at 20 or 30â Hz milling frequencies) gave rise to an amorphous phase, as shown by powder X-ray diffraction; however, FT-IR spectroscopy unambiguously indicates that a mechanochemical reaction has occurred. Neat milling the reactants at 10 and 15â Hz led to incomplete reactions. Thermogravimetry and differential scanning calorimetry indicate that the amorphous and crystalline mechanochemical products form glasses/supercooled liquids before melting, and do not recrystallize upon cooling. However, the amorphous material obtained by neat grinding crystallizes upon storage into the salt reported. The mechanochemical synthesis, crystal structure analysis, Hirshfeld surfaces, powder X-ray diffraction, thermogravimetry, differential scanning calorimetry, FT-IR spectroscopy, and aqueous solubility of quininium aspirinate are herein reported.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Aspirina/síntesis química , Quinina/síntesis química , Antiinflamatorios no Esteroideos/química , Aspirina/química , Rastreo Diferencial de Calorimetría , Cristalografía por Rayos X , Enlace de Hidrógeno , Preparaciones Farmacéuticas , Transición de Fase , Quinina/química , Solubilidad , Espectroscopía Infrarroja por Transformada de Fourier , Termogravimetría , Difracción de Rayos XRESUMEN
L-glutamate is an important component of protein. It can prevent gastrointestinal damage caused by NSAIDs. We constructed two-phase enteric-coated granules of aspirin and L-glutamate compound by extrusion spheronization method and fluidized bed coating. The subliminal effective dose of L-glutamate is 100 mg/kg tested by model of gastric ulcer of rats induced by aspirin and drug administration. HPLC-UV and UV-Vis methods were adopted to determine content and cumulative release of aspirin and L-glutamate as quality analysis method indexes. The prescription and process optimization were carried out with yield, sphericity and dissolution. The two-phase compound granules have good sphericity of 0.93 ± 0.05 (aspirin pellets) and 0.94 ± 0.02 (L-glutamate pellets), content of salicylic acid (0.24 ± 0.03)%, dissolution of aspirin (2.36 ± 0.11)%. Quality evaluation and preliminary stability meet the commercial requirements. The stored environment of compound preparation should be sealed in a cool and dark place.
Asunto(s)
Aspirina , Composición de Medicamentos , Ácido Glutámico , Animales , Aspirina/administración & dosificación , Aspirina/síntesis química , Aspirina/farmacología , Química Farmacéutica/métodos , Química Farmacéutica/normas , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Composición de Medicamentos/métodos , Composición de Medicamentos/normas , Evaluación Preclínica de Medicamentos/métodos , Evaluación Preclínica de Medicamentos/normas , Mucosa Gástrica/efectos de los fármacos , Tracto Gastrointestinal/efectos de los fármacos , Ácido Glutámico/administración & dosificación , Ácido Glutámico/síntesis química , Ácido Glutámico/farmacología , Control de Calidad , Ratas , Ratas Sprague-Dawley , Úlcera Gástrica/tratamiento farmacológico , Úlcera Gástrica/patología , Comprimidos RecubiertosRESUMEN
Gastric cancer is one of the most common and deadly cancers among men and women and is the third leading cause of cancer mortality worldwide. Thus, discovering and developing novel therapeutics for gastric cancer has become a global priority. In this study, we synthesized two novel anthraquinone-based aspirin derivatives, Asp-X3 and Asp-X3-CH3, with therapeutic potential for gastric cancer. The structures of the two compounds were determined by 1D, 2D-NMR, and High-Resolution Mass (HRSM). Asp-X3 and Asp-X3-CH3 could inhibit the growth of gastric cancer cells (SGC7901), yielding IC50 values 10-fold lower than that of Aspirin. Asp-X3 and Asp-X3-CH3 were less toxic to gastric mucosal cells, yielding IC50 values that were about 2-fold higher than the corresponding IC50 values determined with SGC7901 cells. Asp-X3-CH3 and Asp-X3 also induced SGC7901 cells to undergo apoptosis, yielding apoptotic rates that were about twice the rate induced by Aspirin. Asp-X3-CH3 did not cause significant loss of COX-1 expression in gastric mucosal cells, whereas Asp-X3 and Aspirin both caused significant loss of COX-1 expression as demonstrated by Western blot, consistent with their effects on the content of PGE2 in these cells as determined by ELISA assay. However, both Asp-X3-CH3 and Asp-X3 exerted a similar effect on the level of COX-2 in gastric cancer cells, causing as much as 90% and 95% reduction in COX-2 expression, respectively. Taken together, the results suggested that Asp-X3-CH3 and Asp-X3 were potentially better agents than Aspirin for the inhibition of gastric cancer cell growth, but Asp-X3-CH3 was more effective.
Asunto(s)
Antraquinonas/síntesis química , Antraquinonas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Aspirina/análogos & derivados , Aspirina/farmacología , Neoplasias Gástricas/prevención & control , Apoptosis/efectos de los fármacos , Aspirina/síntesis química , Línea Celular Tumoral , Ciclooxigenasa 1/metabolismo , Inhibidores de la Ciclooxigenasa 2/farmacología , Dinoprostona/metabolismo , Mucosa Gástrica/citología , Mucosa Gástrica/efectos de los fármacos , Humanos , Espectroscopía de Resonancia Magnética , Neoplasias Gástricas/inducido químicamente , Relación Estructura-ActividadRESUMEN
An end-to-end continuous pharmaceutical manufacturing process was developed for the production of conventional direct compressed tablets on a proof-of-concept level for the first time. The output reaction mixture of the flow synthesis of acetylsalicylic acid was crystallized continuously in a mixed suspension mixed product removal crystallizer. The crystallizer was directly connected to a continuous filtration carousel device, thus the crystallization, filtration and drying of acetylsalicylic acid (ASA) was carried out in an integrated 2-step process. Steady state was reached during longer operations and the interaction of process parameters was evaluated in a series of experiments. The filtered crystals were ready for further processing in a following continuous blending and tableting experiment due to the good flowability of the material. The ASA collected during the crystallization-filtration experiments was fed into a continuous twin-screw blender along with microcrystalline cellulose as tableting excipient. After continuous blending Near-Infrared spectroscopy was applied to in-line analyze the drug content of the powder mixture. A belt conveyor carried the mixture towards an eccentric lab-scale tablet press, which continuously produced 500 mg ASA-loaded compressed tablets of 100 mg dose strength. Thus, starting from raw materials, the final drug product was obtained by continuous manufacturing steps with appropriate quality.
Asunto(s)
Aspirina/síntesis química , Química Farmacéutica/métodos , Fuerza Compresiva , Cristalización/métodos , Aspirina/análisis , Celulosa/análisis , Celulosa/síntesis química , Filtración/métodos , Espectroscopía Infrarroja Corta/métodos , ComprimidosRESUMEN
In the present work, the synthesis of acetylated salicins, which occur naturally in many Salicaceae species, is reported. The preparation of 2-O-acetylsalicin, 2-O-acetylchlorosalicin, and 2-O-acetylethylsalicin from peracetylated bromosalicin with selective acid-catalyzed deacetylation and one-pot nucleophilic substitution of bromine as the key steps is described. The base-catalyzed O-2 â O-6 acetyl migration afforded 6-O-acetylsalicin derivatives in good yields. Thus, the first synthesis of 6-O-acetylsalicin (fragilin) using acetyl group migration is reported as well as the synthesis of 6-O-acetylchlorosalicin and 6-O-acetylethylsalicin. The NaOMe-catalyzed deacetylation of acetylated glycosides gave salicin, chlorosalicin, and ethylsalicin recently reported from Alangium chinense.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Aspirina/síntesis química , Salicaceae/metabolismo , Acetilación , Catálisis , Estructura Molecular , Salicaceae/químicaRESUMEN
Aspirin is currently the most widely used drug worldwide, and has been clearly one of the most important pharmacological achievements of the twentieth century. Historians of medicine have traced its birth in 1897, but the fascinating history of aspirin actually dates back >3500â¯years, when willow bark was used as a painkiller and antipyretic by Sumerians and Egyptians, and then by great physicians from ancient Greece and Rome. The modern history of aspirin precursors, salicylates, began in 1763 with Reverend Stone - who first described their antipyretic effects - and continued in the 19th century with many researchers involved in their extraction and chemical synthesis. Bayer chemist Felix Hoffmann synthesized aspirin in 1897, and 70â¯years later the pharmacologist John Vane elucidated its mechanism of action in inhibiting prostaglandin production. Originally used as an antipyretic and anti-inflammatory drug, aspirin then became, for its antiplatelet properties, a milestone in preventing cardiovascular and cerebrovascular diseases. The aspirin story continues today with the growing evidence of its chemopreventive effect against colorectal and other types of cancer, now awaiting the results of ongoing primary prevention trials in this setting. This concise review revisits the history of aspirin with a focus on its most remote origins.
Asunto(s)
Antiinflamatorios no Esteroideos/historia , Antipiréticos/historia , Aspirina/historia , Fármacos Cardiovasculares/historia , Inhibidores de Agregación Plaquetaria/historia , Salix , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/aislamiento & purificación , Antiinflamatorios no Esteroideos/uso terapéutico , Antipiréticos/síntesis química , Antipiréticos/aislamiento & purificación , Antipiréticos/uso terapéutico , Aspirina/síntesis química , Aspirina/aislamiento & purificación , Aspirina/uso terapéutico , Fármacos Cardiovasculares/síntesis química , Fármacos Cardiovasculares/aislamiento & purificación , Fármacos Cardiovasculares/uso terapéutico , Historia del Siglo XVIII , Historia del Siglo XIX , Historia del Siglo XX , Historia del Siglo XXI , Historia Antigua , Humanos , Corteza de la Planta , Hojas de la Planta , Inhibidores de Agregación Plaquetaria/síntesis química , Inhibidores de Agregación Plaquetaria/aislamiento & purificación , Inhibidores de Agregación Plaquetaria/uso terapéutico , Salix/químicaRESUMEN
Colorectal cancer (CRC) is a leading cause of mortality worldwide. Current treatments of CRC involve anti-cancer agents with relatively good efficacy but unselectively target both cancer and non-cancer cells. Thus, there is a need to discover and develop novel CRC therapeutics that have potent anti-cancer effects, but show reduced off-target cell effects. Here, a novel series of cinnamaldehyde-based aspirin derivatives were designed and synthesized. Biological evaluation indicated that the most active compound 1f exhibited more than 10-fold increase in the anti-proliferation efficacy in HCT-8 cells compared to the parent compounds. Its effects were similarly reproduced in another CRC cell line, DLD-1, but with 7- to 11-fold less inhibitory activity in non-tumorigenic colon cells. Flow cytometry analysis showed that 1f induced cell cycle arrest and apoptosis, which was further validated with immunoblot analysis of the relative protein levels of cleaved caspase 3 and PARP as well as the ROS production in CRC cells. More so, 1f significantly inhibited the growth of implanted CRC in vivo in mouse xenograft model. Taken together, our results show that cinnamaldehyde-based aspirin derivatives such as 1f show promise as novel anti-CRC agent for further pharmaceutical development.
Asunto(s)
Acroleína/análogos & derivados , Antineoplásicos/farmacología , Aspirina/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Acroleína/química , Acroleína/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Aspirina/síntesis química , Aspirina/química , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/patología , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Relación Estructura-ActividadRESUMEN
Acetylsalicylic acid (ASA) causes adverse haemorrhagic reactions in the upper gastrointestinal (GI) tract, and previous results have suggested that combination therapy with 2-amino-2-(hydroxymethyl)-1,3-propanediol (Tris) could provide protection in this scenario. Based on this hypothesis, our aim was to develop a new compound from ASA and Tris precursors and to characterize the biological effects of ASA-Tris and the derivatives ASA-bis- and mono-hydroxymethyl-aminomethane (ASA-Bis, ASA-Mono, respectively) using in vivo and in vitro test systems. ASA or ASA conjugates (0.55mmol/kg, each) were administered intragastrically to Sprague-Dawley rats. Changes in the mucosal structure and in the serosal microcirculation were detected by in vivo imaging techniques, the plasma TNF-alpha, tissue xanthine oxidoreductase and myeloperoxidase activities, and liver cytochrome c changes were also determined. In two separate series, platelet aggregation and carrageenan arthritis-induced inflammatory pain were measured in control, ASA and ASA-Tris-treated groups. Severe mucosal injury and a significant decrease in serosal red blood cell velocity developed in the ASA-treated group and an ~2-fold elevation in proinflammatory mediator levels evolved. ASA-Tris did not cause bleeding, microcirculatory dysfunction, mucosal injury or an elevation in proinflammatory markers. The ASA-Mono and ASA-Bis conjugates did not cause macroscopic bleeding, but the inflammatory activation was apparent. ASA-Tris did not influence the cyclooxygenase-induced platelet aggregation significantly, but the inflammatory pain was reduced as effectively as in the case of equimolar ASA doses. ASA-Tris conjugation is an effective approach through which the GI side-effects of ASA are controlled by decreasing the cytokine-mediated progression of pro-inflammatory events.
Asunto(s)
Aspirina/efectos adversos , Aspirina/química , Mucosa Gástrica/efectos de los fármacos , Metilaminas/química , Animales , Aspirina/síntesis química , Técnicas de Química Sintética , Complejo IV de Transporte de Electrones/metabolismo , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Mucosa Gástrica/fisiopatología , Gastritis/inducido químicamente , Gastritis/metabolismo , Gastritis/patología , Gastritis/fisiopatología , Masculino , Malondialdehído/metabolismo , Microcirculación/efectos de los fármacos , Nocicepción/efectos de los fármacos , Agregación Plaquetaria/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Antiplatelet drugs are the cornerstone of therapy in many cardiovascular conditions. With the current success and increased use of transcatheter aortic valve implantation (TAVI), the use of antiplatelet therapy is considered part of the medical therapy for these patients. Clinicians caring for these patients need to have a thorough understanding of the pharmacology, pharmacokinetics, pharmacodynamic, and clinical efficacy and safety of commonly used antiplatelet therapy. While aspirin therapy is widely used, dual antiplatelet therapy with clopidogrel has become part of standard of care. Despite the extensive experience with clopidogrel, there are limitations such as drug interactions, metabolism genetic polymorphisms, and variability in the antiplatelet response. More predictable and more potent antiplatelet agents, prasugrel and ticagrelor, have demonstrated superior reductions in ischemic endpoints as part of dual antiplatelet therapy compared to clopidogrel, but at the cost of more major bleeding in patients with an acute coronary syndrome. Significant research needs to be conducted in the setting of TAVI to help define the optimal antiplatelet regimen.
Asunto(s)
Adenosina/análogos & derivados , Aspirina/uso terapéutico , Enfermedades Cardiovasculares/terapia , Inhibidores de Agregación Plaquetaria/uso terapéutico , Clorhidrato de Prasugrel/uso terapéutico , Ticlopidina/análogos & derivados , Reemplazo de la Válvula Aórtica Transcatéter/efectos adversos , Adenosina/síntesis química , Adenosina/química , Adenosina/uso terapéutico , Aspirina/síntesis química , Aspirina/química , Clopidogrel , Humanos , Inhibidores de Agregación Plaquetaria/síntesis química , Inhibidores de Agregación Plaquetaria/química , Clorhidrato de Prasugrel/síntesis química , Clorhidrato de Prasugrel/química , Ticagrelor , Ticlopidina/síntesis química , Ticlopidina/química , Ticlopidina/uso terapéuticoRESUMEN
INTRODUCTION: Activation of cyclooxygenase (COX)/prostaglandin and nuclear factor κB (NFκB) pathways can promote breast tumor initiation, growth, and progression to drug resistance and metastasis. Thus, anti-inflammatory drugs have been widely explored as chemopreventive and antineoplastic agents. Aspirin (ASA), in particular, is associated with reduced breast cancer incidence but gastrointestinal toxicity has limited its usefulness. To improve potency and minimize toxicity, ASA ester prodrugs have been developed, in which the carboxylic acid of ASA is masked and ancillary pharmacophores can be incorporated. To date, the effects of ASA and ASA prodrugs have been largely attributed to COX inhibition and reduced prostaglandin production. However, ASA has also been reported to inhibit the NFκB pathway at very high doses. Whether ASA prodrugs can inhibit NFκB signaling remains relatively unexplored. METHODS: A library of ASA prodrugs was synthesized and screened for inhibition of NFκB activity and cancer stem-like cell (CSC) properties, an important PGE2-and NFκB-dependent phenotype of aggressive breast cancers. Inhibition of NFκB activity was determined by dual luciferase assay, RT-QPCR, p65 DNA binding activity and Western blots. Inhibition of CSC properties was determined by mammosphere growth, CD44(+)CD24(-)immunophenotype and tumorigenicity at limiting dilution. RESULTS: While we identified multiple ASA prodrugs that are capable of inhibiting the NFκB pathway, several were associated with cytotoxicity. Of particular interest was GTCpFE, an ASA prodrug with fumarate as the ancillary pharmacophore. This prodrug potently inhibits NFκB activity without innate cytotoxicity. In addition, GTCpFE exhibited selective anti-CSC activity by reducing mammosphere growth and the CD44(+)CD24(-)immunophenotype. Moreover, GTCpFE pre-treated cells were less tumorigenic and, when tumors did form, latency was increased and growth rate was reduced. Structure-activity relationships for GTCpFE indicate that fumarate, within the context of an ASA prodrug, is essential for anti-NFκB activity, whereas both the ASA and fumarate moieties contributed to attenuated mammosphere growth. CONCLUSIONS: These results establish GTCpFE as a prototype for novel ASA-and fumarate-based anti-inflammatory drugs that: (i) are capable of targeting CSCs, and (ii) may be developed as chemopreventive or therapeutic agents in breast cancer.
Asunto(s)
Aspirina/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , FN-kappa B/genética , Profármacos/administración & dosificación , Aspirina/síntesis química , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Femenino , Fumaratos/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Células MCF-7 , FN-kappa B/antagonistas & inhibidores , FN-kappa B/biosíntesis , Células Madre Neoplásicas/efectos de los fármacos , Profármacos/síntesis química , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
We recently reported the synthesis of NOSH-aspirin, a novel hybrid compound capable of releasing both nitric oxide (NO) and hydrogen sulfide (H2S). In NOSH-aspirin, the two moieties that release NO and H2S are covalently linked at the 1, 2 positions of acetyl salicylic acid, i.e., ortho-NOSH-aspirin. Here we report on the synthesis of meta- and para-NOSH-aspirins. We also made a head-to-head evaluation of the effects of these three positional isomers of NOSH-aspirin on colon cancer cell kinetics and induction of reactive oxygen species, which in recent years has emerged as a key event in causing cancer cell regression. Electron donating/withdrawing groups incorporated about the benzoate moiety significantly affected the potency of these compounds with respect to colon cancer cell growth inhibition.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Aspirina/análogos & derivados , Disulfuros/farmacología , Sulfuro de Hidrógeno/metabolismo , Nitratos/farmacología , Óxido Nítrico/metabolismo , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Aspirina/síntesis química , Aspirina/química , Aspirina/farmacología , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Disulfuros/síntesis química , Disulfuros/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HT29 , Humanos , Estructura Molecular , Nitratos/síntesis química , Nitratos/química , Especies Reactivas de Oxígeno/metabolismo , Relación Estructura-ActividadRESUMEN
We recently reported the synthesis of NOSH-aspirin, a novel hybrid that releases both nitric oxide (NO) and hydrogen sulfide (H2S). In NOSH-aspirin, the two moieties that release NO and H2S are covalently linked at the 1, 2 positions of acetyl salicylic acid, i.e. ortho-NOSH-aspirin (o-NOSH-aspirin). In the present study, we compared the effects of the positional isomers of NOSH-ASA (o-NOSH-aspirin, m-NOSH-aspirin and p-NOSH-aspirin) to that of aspirin on growth of HT-29 and HCT 15 colon cancer cells, belonging to the same histological subtype, but with different expression of cyclooxygenase (COX) enzymes; HT-29 express both COX-1 and COX-2, whereas HCT 15 is COX-null. We also analyzed the effect of these compounds on proliferation and apoptosis in HT-29 cells. Since the parent compound aspirin, inhibits both COX-1 and COX-2, we also evaluated the effects of these compounds on COX-1 and COX-2 enzyme activities and also performed modeling of the interactions between the positional isomers of NOSH-aspirin and COX-1 and COX-2 enzymes. We observed that the three positional isomers of NOSH aspirin inhibited the growth of both colon cancer cell lines with IC50s in the nano-molar range. In particular in HT-29 cells the IC50s for growth inhibition were: o-NOSH-ASA, 0.04±0.011 µM; m-NOSH-ASA, 0.24±0.11 µM; p-NOSH-ASA, 0.46±0.17 µM; and in HCT 15 cells the IC50s for o-NOSH-ASA, m-NOSH-ASA, and p-NOSH-ASA were 0.062 ±0.006 µM, 0.092±0.004 µM, and 0.37±0.04 µM, respectively. The IC50 for aspirin in both cell lines was >5mM at 24h. The reduction of cell growth appeared to be mediated through inhibition of proliferation, and induction of apoptosis. All 3 positional isomers of NOSH-aspirin preferentially inhibited COX-1 over COX-2. These results suggest that the three positional isomers of NOSH-aspirin have the same biological actions, but that o-NOSH-ASA displayed the strongest anti-neoplastic potential.
Asunto(s)
Antineoplásicos/química , Aspirina/análogos & derivados , Ciclooxigenasa 1/química , Ciclooxigenasa 2/química , Inhibidores de la Ciclooxigenasa/química , Disulfuros/química , Nitratos/química , Donantes de Óxido Nítrico/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Aspirina/síntesis química , Aspirina/química , Aspirina/farmacología , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ciclooxigenasa 1/genética , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa/síntesis química , Inhibidores de la Ciclooxigenasa/farmacología , Disulfuros/síntesis química , Disulfuros/farmacología , Expresión Génica , Células HT29 , Humanos , Sulfuro de Hidrógeno/química , Sulfuro de Hidrógeno/metabolismo , Concentración 50 Inhibidora , Simulación del Acoplamiento Molecular , Nitratos/síntesis química , Nitratos/farmacología , Óxido Nítrico/química , Óxido Nítrico/metabolismo , Donantes de Óxido Nítrico/síntesis química , Donantes de Óxido Nítrico/farmacología , Ovinos , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
We here report synthesis for the first time of the acetyl salicylic acid dimer 5,5'-methylenebis(2-acetoxybenzoic acid) (DAS). DAS inhibits aberrant complement activation by selectively blocking factor D of the alternative complement pathway and C9 of the membrane attack complex. We have previously identified aurin tricarboxylic and its oligomers as promising agents in this regard. DAS is much more potent, inhibiting erythrocyte hemolysis by complement-activated serum with an IC50 in the 100-170 nanomolar range. There are numerous conditions where self-damage from the complement system has been implicated in the pathology, including such chronic degenerative diseases of aging as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and age-related macular degeneration. Consequently, there is a high priority for the discovery and development of agents that can successfully treat such conditions. DAS holds considerable promise for being such an agent.
Asunto(s)
Aspirina/análogos & derivados , Compuestos de Bencidrilo/farmacología , Activación de Complemento/efectos de los fármacos , Factor D del Complemento/antagonistas & inhibidores , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/etiología , Animales , Aspirina/síntesis química , Aspirina/farmacología , Ácido Aurintricarboxílico , Compuestos de Bencidrilo/síntesis química , Gatos , Células Cultivadas , Complemento C6/antagonistas & inhibidores , Complejo de Ataque a Membrana del Sistema Complemento , Vía Alternativa del Complemento , Perros , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Eritrocitos/efectos de los fármacos , Hemólisis/efectos de los fármacos , Humanos , Degeneración Macular/tratamiento farmacológico , Degeneración Macular/etiología , Terapia Molecular Dirigida , RatasRESUMEN
The already known Ag(I)-Sb(III) compound of the formula {Ag(Ph3Sb)3(NO3)} (1) and two novel mixed metal Ag(I)-Sb(III) metallotherapeutics of the formulae {Ag(Ph3Sb)3(SalH)}(2) and {Ag(Ph3Sb)3(Asp)}(3) (SalH2=salicylic acid, AspH=aspirin or 2-acetylsalicylic acid and Ph3Sb=triphenyl antimony(III)) have been synthesised and characterised by m.p., vibrational spectroscopy (mid-FT-IR), (13)C-,(1)H-NMR, UV-visible (UV-vis) spectroscopic techniques, high resolution mass spectroscopy (HRMS) and X-ray crystallography. Compounds 1,-3 were treated with the surfactant cetyltrimethylammonium bromide (CTAB) in order to enhance their solubility and as a consequence their bioactivity. The resulting micelles a-c were characterised with X-ray powder diffraction (XRPD) analysis, X-ray fluorescence (XRF) spectroscopy, Energy-dispersive X-ray spectroscopy (EDX), conductivity, Thermal gravimetry-differential thermal analysis (TG-DTA), and atomic absorption. Compounds 1-3 and the relevant micelles a-c were evaluated for their in vitro cytotoxic activity against human cancer cell lines: MCF-7 (breast, estrogen receptor (ER) positive), MDA-MB-231 (breast, ER negative) and MRC-5 (normal human fetal lung fibroblast cells) with sulforhodamine B (SRB) colorimetric assay. The results show significant increase in the activity of micelles compared to that of the initial compounds. Moreover, micelles exhibited lower activity against normal cells than tumor cells. The binding affinity of a-c towards the calf thymus (CT)-DNA, lipoxygenase (LOX) and glutathione (GSH) was studied by the fluorescent emission light and UV-vis spectroscopy.
Asunto(s)
Antimonio/química , Antineoplásicos/farmacología , Aspirina/farmacología , Complejos de Coordinación/farmacología , Ácido Salicílico/farmacología , Plata/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Aspirina/síntesis química , Aspirina/química , Cetrimonio , Compuestos de Cetrimonio/química , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Glutatión/química , Humanos , Cinética , Ácido Linoleico/química , Lipooxigenasa/metabolismo , Células MCF-7 , Micelas , Espectroscopía de Protones por Resonancia Magnética , Receptores de Estrógenos/metabolismo , Ácido Salicílico/síntesis química , Ácido Salicílico/química , Solubilidad , Espectrometría por Rayos X , Tensoactivos/químicaRESUMEN
Hypersensitivity reactions to acetylsalicylic acid and non-steroidal anti-inflammatory drugs constitute a major medical concern worldwide. This article presents an overview of the observations that led to the discovery of cyclooxygenase inhibitors, as a prerequisite to better understand the basic concepts supporting seminal investigations carried out in order to elucidate the clinical features, pathogenic mechanisms, diagnosis and modern management of these common conditions. There are some unmet needs in this clinical area which will have to be solved in the future, especially concerning the pathogenesis of these reactions and the availability of novel in vitro diagnostic methods sparing both patient and physician of the risks inherent to in vivo provocation tests.
Asunto(s)
Antiinflamatorios no Esteroideos/efectos adversos , Aspirina/efectos adversos , Hipersensibilidad a las Drogas/etiología , Antiinflamatorios no Esteroideos/historia , Aspirina/síntesis química , Aspirina/historia , Ciclooxigenasa 1/química , Ciclooxigenasa 1/metabolismo , Historia del Siglo XIX , Historia del Siglo XX , Historia Antigua , HumanosRESUMEN
Structural modifications of nonsteroidal anti-inflammatory drugs (NSAIDs) have successfully reduced the side effect of gastrointestinal ulceration without affecting anti-inflammatory activity, but they may increase the risk of myocardial infarction with chronic use. The fact that nitroxyl (HNO) reduces platelet aggregation, preconditions against myocardial infarction, and enhances contractility led us to synthesize a diazeniumdiolate-based HNO-releasing aspirin and to compare it to an NO-releasing analogue. Here, the decomposition mechanisms are described for these compounds. In addition to protection against stomach ulceration, these prodrugs exhibited significantly enhanced cytotoxcity compared to either aspirin or the parent diazeniumdiolate toward nonsmall cell lung carcinoma cells (A549), but they were not appreciably toxic toward endothelial cells (HUVECs). The HNO-NSAID prodrug inhibited cylcooxgenase-2 and glyceraldehyde 3-phosphate dehydrogenase activity and triggered significant sarcomere shortening on murine ventricular myocytes compared to control. Together, these anti-inflammatory, antineoplasic, and contractile properties suggest the potential of HNO-NSAIDs in the treatment of inflammation, cancer, or heart failure.
Asunto(s)
Aspirina/síntesis química , Aspirina/farmacología , Compuestos Azo/química , Óxido Nítrico/química , Óxidos de Nitrógeno/química , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Aspirina/química , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Ciclooxigenasa 2/metabolismo , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Gliceraldehído 3-Fosfato Deshidrogenasa (NADP+)/metabolismo , Humanos , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Químicos , Estructura Molecular , Miocitos Cardíacos/citología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Profármacos/síntesis química , Profármacos/química , Profármacos/farmacología , Sarcómeros/efectos de los fármacos , Sarcómeros/metabolismoRESUMEN
Reaction of Bi(O(t)Bu)3 with aspirin (acetylsalicylic acid = aspH) in dry toluene results in the bismuth(III) complex, [Bi(O2C(C6H4)OAc)3]∞ 1 (O2C(C6H4)OAc = asp), minimum inhibitory concentration (MIC) against Helicobacter pylori ≥ 6.25 µg mL(-1), while the inclusion of a stoichiometric equivalent of KO(t)Bu leads to crystals of the bismuthate salt [KBi(O2C(C6H4)OAc)4]∞ 2.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Aspirina/análogos & derivados , Aspirina/química , Bismuto/química , Complejos de Coordinación/síntesis química , Complejos de Coordinación/farmacología , Helicobacter pylori/efectos de los fármacos , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/farmacología , Antibacterianos/química , Aspirina/síntesis química , Aspirina/farmacología , Técnicas de Química Sintética , Complejos de Coordinación/química , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Conformación Molecular , Compuestos Organometálicos/química , Relación Estructura-ActividadRESUMEN
Glucose-aspirin (GA) was synthesized by conjugating aspirin (ASA) to the 3-carbon of glucose to produce a stable water-soluble aspirin derivative. The in vivo activities were compared with those of aspirin. The mouse tail flick assay showed that at 120 min., both aspirin and GA showed the maximum possible effect, and the higher dose (200 mg/kg) generally had less of an effect than the lower dose (100 mg/kg). Per cent inhibition of paw oedema was 63% and 69% for ASA and GA at 100 mg/kg, respectively. In the tail immersion test, the increase in reaction time was significantly greater with GA as compared to aspirin (100 mg/kg) at 60 min. In conclusion, there was significant anti-inflammatory and analgesic activity for GA at the doses studied under the experimental conditions.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Aspirina/análogos & derivados , Glucósidos/uso terapéutico , Agua/química , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Aspirina/síntesis química , Aspirina/química , Aspirina/farmacología , Aspirina/uso terapéutico , Carragenina/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Edema/tratamiento farmacológico , Glucósidos/síntesis química , Glucósidos/química , Glucósidos/farmacología , Hidrólisis , Ratones , Estructura Molecular , Umbral del Dolor/efectos de los fármacos , Ratas , SolubilidadRESUMEN
Glucose-aspirin (GA) was synthesized by conjugating aspirin (ASA) to glucose. The water solubility and biological activity of GA was studied in comparison to aspirin. The human serum protease activity on the ester showed a slower hydrolysis rate, compared to ASA. Glucose-aspirin was sevenfold more water soluble than aspirin and it was about 8- to 9-fold more active in inhibiting cell growth than aspirin in their anti-cancer cell culture activity on breast (SKBR3), pancreatic (PANC-1), and prostate (PC3) cell lines, whereas the activity was similar on a benign non-cancerous cell line (WI 38). In conclusion, GA is a highly water soluble derivative of aspirin. Although the serum hydrolysis for GA was slower, there was significant anti-cancer activity at the doses studied under the experimental conditions.
Asunto(s)
Antineoplásicos/síntesis química , Aspirina/análogos & derivados , Aspirina/síntesis química , Glucosa/química , Glucósidos/síntesis química , Antineoplásicos/farmacología , Aspirina/química , Aspirina/uso terapéutico , Línea Celular Tumoral , Detección Precoz del Cáncer , Glucosa/uso terapéutico , Glucósidos/química , Glucósidos/uso terapéutico , Humanos , Hidrólisis , Péptido Hidrolasas/sangre , Péptido Hidrolasas/metabolismo , SolubilidadRESUMEN
Analogues of aspirin were synthesized through an efficient one-step reaction in which the carboxyl group was replaced by an ethyl ester, and/or the acetoxy group was replaced by an N-substituted sulfonamide (SO(2)NHOR(2):R(2) =H, Me, CH(2)Ph) pharmacophore. These analogues were designed for evaluation as dual cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) inhibitors. In vitro COX-1/COX-2 isozyme inhibition studies identified compounds 11 (CO(2) H, SO(2)NHOH), 12 (CO(2)H, SO(2)NHOCH(2)Ph), and 16 (CO(2)Et, SO(2)NHOH) as highly potent and selective COX-2 inhibitors (IC(50) range: 0.07-0.7 µM), which exhibited appreciable in vivo anti-inflammatory activity (ED(50) range: 23.1-31.4 mg kg(-1)). Moreover, compounds 11 (IC(50) =0.2 µM) and 16 (IC(50) =0.3 µM), with a sulfohydroxamic acid (SO(2)NHOH) moiety showed potent 5-LOX inhibitory activity. Furthermore, the SO(2)NHOH moiety present in compounds 11 and 16 was found to be a good nitric oxide (NO) donor upon incubation in phosphate buffer at pH 7.4. Molecular docking studies in the active binding site of COX-2 and 5-LOX provided complementary theoretical support for the experimental biological structure-activity data acquired.