ABSTRACT
BACKGROUND: Lung cancer has become the prominent cause of the cancer-related deaths globally. More than 80 % of all lung cancers have been diagnosed with Non- Small Cell Lung Cancer (NSCLC). The USFDA approved osimertinib to treat patients with metastatic T790M EGFR NSCLC on a regular basis in March 2017. Recently, C797S mutation to osimertinib has been reported, which indicates the need for structural modification to overcome the problem of mutation. METHODS: In this bioinformatics study, we have evaluated the impact of various acrylamide as an electrophilic warhead on the activity and selectivity of osimertinib. RESULT: Osimertinib analouge 48, 50, 60, 61, 67, 75, 80, 86, 89, 92, 93, 116 and 124 were the most active and selective compounds against T790M EGFR mutants compared to Osimertinib. CONCLUSION: These compounds also showed less inclination towards WT-EGFR.
Subject(s)
ErbB Receptors , Lung Neoplasms , Acrylamide/pharmacology , Acrylamide/therapeutic use , Acrylamides/chemistry , Acrylamides/pharmacology , Acrylamides/therapeutic use , Aniline Compounds/chemistry , ErbB Receptors/genetics , Humans , Lung Neoplasms/genetics , Mutation , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacologyABSTRACT
Al declarar la acrilamida como un probable carcinógeno en humanos, diferentes trabajos han tratado de esclarecer si la exposición dietética en humanos puede constituir un riesgo para la salud, no obstante, las publicaciones sobre la población española han sido englobadas en macroestudios no específicos o se refieren exclusivamente a población infantil. El objetivo del presente trabajo fue realizar una evaluación del riesgo de exposición dietética a la acrilamida en la población española y valenciana. A partir de la revisión de la información sobre la toxicidad de acrilamida y su presencia en alimentos se calculó la exposición dietética al tóxico a través del método determinista. Los alimentos que presentan mayor contribución al consumo diario de acrilamida son el pan, el pan tostado, las galletas, las patatas crisps y los cereales de desayuno, seguidos del café tostado y la cerveza. La población adulta española duplica la exposición estimada por el estudio europeo EPIC. La población más expuesta es la infantil seguida de la femenina. La población valenciana está menos expuesta que la española aunque ambas se encuentran en el mismo nivel que la población europea. Los adultos españoles presentan el mismo riesgo de neurotoxicidad y menor riesgo de tumores mamarios que el calculado a nivel internacional en 2011 por la FAO/OMS. En cambio la población infantil presenta un riesgo de neurotoxicidad cuatro veces menor. El principio de precaución debe prevalecer en tanto no se obtengan datos más concluyentes de toxicidad (AU)
As a result of declaring acrylamide as a probable human carcinogen, different studies attempted to clarify whether dietary exposure in humans can establish a health risk. However, the literature concerning Spanish population has been subsumed in non-specific macro studies or it refers exclusively to children. The aim of this study was to make a risk assessment of dietary exposure to acrylamide in the Spanish and Valencian population. Based on reviewing the information about the toxicity of acrylamide and its presence in food, dietary exposure to the toxic substance was calculated by a deterministic method. Foods that have a higher contribution to daily intake of acrylamide are bread, toasted bread, biscuits, crisps and breakfast cereals, followed by roasted coffee and beer. The Spanish adult population doubles the exposure estimated by the EPIC study. The most exposed population is children followed by the female one. The Valencian population is less exposed than the Spanish as a whole though both are on the same level, as the European population. Spanish adults have the same risk of neurotoxicity and lower risk of mammary tumors than the international value calculated in 2011 by the FAO/WHO. However the child population has a risk of neurotoxicity four times lower. The precautionary principle must prevail while more conclusive toxicity data is not achieved (AU)
Subject(s)
Humans , Male , Female , Acrylamide/therapeutic use , Nutrition for Vulnerable Groups , Risk Assessment/methods , Risk Assessment , Diet Therapy/methods , Diet Therapy/trends , Dietetics/methods , Dietetics/trends , Diet/instrumentation , Diet/methods , Diet , Risk Factors , Neurotoxicity Syndromes/complicationsABSTRACT
Oxamniquine is an antiparasitic agent commonly used in therapeutics against Schistosoma mansoni. Although it is well tolerated, some adverse effects justify the search for new compounds with prolonged biological action, so that monomeric and polymeric oxamniquine prodrugs were designed. Synthetic results assisted by molecular modeling study showed the possibility to obtain the corresponding monomeric forms of the oxamniquine methacrylate (1) and oxamniquine acrylamide (2). Successful copolymerization procedure only occurred on the methacrylic compound, generating the oxamniquine methacrylate copolymer (3). Submitted to a preliminary in vivo biological evaluation, a similar oxamniquine profile was observed to the monomeric forms although an inadequate drug release may be responsible for the methacrylic copolymer failure.
Subject(s)
Acrylamide/chemical synthesis , Drug Design , Methacrylates/chemical synthesis , Oxamniquine/chemical synthesis , Prodrugs/chemical synthesis , Schistosomicides/therapeutic use , Acrylamide/chemistry , Acrylamide/therapeutic use , Animals , Drug Evaluation, Preclinical , Male , Mesenteric Veins/drug effects , Methacrylates/chemistry , Methacrylates/therapeutic use , Mice , Models, Molecular , Oxamniquine/chemistry , Oxamniquine/therapeutic use , Prodrugs/chemistry , Prodrugs/therapeutic use , Schistosoma mansoni/drug effects , Schistosomiasis mansoni/drug therapy , Schistosomicides/chemical synthesis , Structure-Activity RelationshipABSTRACT
We previously developed linear polymers bearing clustered trisaccharides of globotriaosylceramide (Gb3) as orally applicable Shiga toxin (Stx) neutralizers. Here, using a Gb3 polymer with a short spacer tethering the trisaccharide to the core, we found that shortening the spacer length markedly reduced the binding affinity for Stx2 but not Stx1. Moreover, mutational analysis revealed that the essential binding sites of the terminal trisaccharides were completely different between Stx1 and Stx2. These results provide the molecular basis for the interaction between Stx B subunits and Gb3 polymers.
Subject(s)
Escherichia coli O157/chemistry , Shiga Toxin 1/chemistry , Shiga Toxin 2/chemistry , Trisaccharides/chemistry , Acrylamide/chemistry , Acrylamide/therapeutic use , Animals , Chlorocebus aethiops , Polymers/chemistry , Protein Subunits/chemistry , Protein Subunits/metabolism , Shiga Toxin 1/metabolism , Shiga Toxin 2/metabolism , Trisaccharides/therapeutic use , Vero CellsABSTRACT
Shiga toxin (Stx) is a major virulence factor in infection with Stx-producing Escherichia coli (STEC). We developed a series of linear polymers of acrylamide, each with a different density of trisaccharide of globotriaosylceramide (Gb3), which is a receptor for Stx, and identified Gb3 polymers with highly clustered trisaccharides as Stx adsorbents functioning in the gut. The Gb3 polymers specifically bound to both Stx1 and Stx2 with high affinity and markedly inhibited the cytotoxic activities of these toxins. Oral administration of the Gb3 polymers protected mice after administration of a fatal dose of E. coli O157:H7, even when the polymers were administered after the infection had been established. In these mice, the serum level of Stx was markedly reduced and fatal brain damage was substantially suppressed, which suggests that the Gb3 polymers entrap Stx in the gut and prevent its entrance into the circulation. These results indicate that the Gb3 polymers can be used as oral therapeutic agents that function in the gut against STEC infections.
