RESUMO
The new asperorlactone (1), along with the known illudalane sesquiterpene echinolactone D (2), two known pyrones, 4-(hydroxymethyl)-5-hydroxy-2H-pyran-2-one (3) and its acetate 4, and 4-hydroxybenzaldehyde (5), were isolated from a culture of Aspergillus oryzae, collected from Red Sea marine sediments. The structure of asperorlactone (1) was elucidated by HR-ESIMS, 1D, and 2D NMR, and a comparison between experimental and DFT calculated electronic circular dichroism (ECD) spectra. This is the first report of illudalane sesquiterpenoids from Aspergillus fungi and, more in general, from ascomycetes. Asperorlactone (1) exhibited antiproliferative activity against human lung, liver, and breast carcinoma cell lines, with IC50 values < 100 µM. All the isolated compounds were also evaluated for their toxicity using the zebrafish embryo model.
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Aspergillus oryzae/metabolismo , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Sesquiterpenos/toxicidade , Animais , Organismos Aquáticos/química , Ascomicetos , Linhagem Celular Tumoral/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Fungos/química , Sedimentos Geológicos , Humanos , Oceano Índico , Concentração Inibidora 50 , Células MCF-7 , Estrutura Molecular , Sesquiterpenos Policíclicos , Peixe-ZebraRESUMO
Several derivatives containing morpholine/piperidine, anilines, and dipeptides as pending moieties were prepared using s-triazine as a scaffold. These compounds were evaluated for their anticancer activity against two human breast cancer cell lines (MCF-7 and MDA-MB-231), a colon cancer cell line (HCT-116), and a non-tumorigenic cell line (HEK 293). Tamoxifen was used as a reference. Animal toxicity tests were carried out in zebrafish embryos. Most of these compounds showed a higher activity against breast cancer than colon cancer. Compound 3a-which contains morpholine, aniline, and glycylglycinate methyl ester-showed a high level of cytotoxicity against MCF-7 cells with IC50 values of less than 1 µM. This compound showed a much lower level of toxicity against the non-tumorigenic HEK-293 cell line, and in the in vivo studies using zebrafish embryos. Furthermore, it induced cell cycle arrest at the G2/M phase, and apoptosis in MCF-7 cells. On the basis of our results, 3a emerges as a potential candidate for further development as a therapeutic drug to treat hormone receptor-positive breast cancer.
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Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Dipeptídeos/farmacologia , Triazinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Dipeptídeos/síntese química , Dipeptídeos/química , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Triazinas/síntese química , Triazinas/química , Peixe-Zebra/embriologiaRESUMO
Here we report on a small library based on a 4-aminobenzonitile-s-triazine moiety. We used a straightforward orthogonal synthetic pathway to prepare di- and tri-substituted s-triazine derivatives, whose basic structure was modified. The newly synthesized compounds were fully characterized by 1H NMR, 13C NMR and elemental analysis. They showed strong anticancer activity against two human breast cancer cell lines (MIDA-MB-231 and MCF-7), with IC50 values less than 1⯵M. These s-triazine compounds were generally more selective towards hormone receptor-positive breast cancer cell line MCF-7 than the triple negative MDA-MB-231 cell line. Zebrafish embryos were used to test the developmental toxicity of the target compounds in vivo. The phenotype of embryos treated with the derivatives resembled that of those treated with estrogen disruptors. This observation strongly supports the notion that that these compounds induce their anticancer activity in human breast cancer cells via targeting the estrogen and progesterone receptors.
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Antineoplásicos/farmacologia , Triazinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Desenvolvimento Embrionário/efeitos dos fármacos , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Triazinas/síntese química , Triazinas/química , Peixe-Zebra/embriologiaRESUMO
s-Triazine is considered a privileged structure, as it is found in several FDA-approved drugs. In the framework of our ongoing medicinal chemistry project based on the use of s-triazine as a scaffold, we synthesized a series of mono- and di-pyrazolyl-s-triazine derivatives and tested them against four human cancer cell lines, namely Human breast carcinoma (MCF 7 and MDA-MB-231), hepatocellular carcinoma (HepG2), colorectal carcinoma (LoVo), and leukemia (K562). The cell viability assay revealed that most of the s-triazine compounds induced cytotoxicity in all four types of human cancer cell lines, however, compounds 4a, and 6g, both of them have a piperidine moiety in their structure were most effective. These two compounds affected the cell viability of cancer cells, with IC50 values within the range between 5 to 9⯵M. The cell cycle analysis showed that 4a and 6g induced S and G2/M phase cell cycle arrest in K562 cells. This could be the mechanism by which these molecules induced cytotoxicity in tested cancer cells. The prepared compounds were tested in zebrafish embryos to evaluate in vivo and developmental toxicity of the pyrazolyl-s-triazine derivatives in animals. None of the derivatives were lethal in the concentration range tested.
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Antineoplásicos/farmacologia , Desenho de Fármacos , Embrião não Mamífero/efeitos dos fármacos , Pirazóis/farmacologia , Triazinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Pirazóis/química , Relação Estrutura-Atividade , Triazinas/síntese química , Triazinas/química , Células Tumorais Cultivadas , Peixe-ZebraRESUMO
BACKGROUND: Bitter gourd (Momordica charantia) has attracted the focus of researchers owing to its excellent anti-diabetic action. The beneficial effect of Momordica charantia on heart has been reported by in vitro and in vivo studies. However the developmental toxicity or potential risk of M. charantia on fetus heart development is largely unknown. Hence this study was designed to find out the developmental toxicity of M. charantia using zebrafish (Danio rerio) embryos. METHODS: The crude extracts were prepared from fruit and seeds of M. charantia. The Zebrafish embryos were exposed to serial dilution of each of the crude extract. The biologically active fractions were fractionated by C18 column using high pressure liquid chromatography. Fourier-transform infrared spectroscopy and gas chromatography coupled with mass spectrophotometry was done to identify chemical constituents in fruit and seed extract of M. charantia. RESULTS: The seed extract of M. charantia was lethal with LD50 values of 50 µg/ml to zebrafish embryos and multiple anomalies were observed in zebrafish embryos at sub-lethal concentration. However, the fruit extract was much safe and exposing the zebrafish embryos even to 200 µg/ml did not result any lethality. The fruit extract induced severe cardiac hypertrophy in treated embryos. The time window treatment showed that M. charantia perturbed the cardiac myoblast specification process in treated zebrafish embryos. The Fourier-transform infrared spectroscopy analyses revealed diverse chemical group in the active fruit fraction and five new type of compounds were identified in the crude seeds extract of M. charantia by gas chromatography and mass spectrophotometry. CONCLUSION: The teratogenicity of seeds extract and cardiac toxicity by the fruit extract of M. charantia warned that the supplementation made from the fruit and seeds of M. charantia should be used with much care in pregnant diabetic patients to avoid possible damage to developing fetus.
Assuntos
Momordica charantia/química , Extratos Vegetais/toxicidade , Peixe-Zebra/embriologia , Animais , Feminino , Frutas/química , Frutas/toxicidade , Humanos , Dose Letal Mediana , Masculino , Momordica charantia/toxicidade , Extratos Vegetais/análise , Sementes/química , Sementes/toxicidadeRESUMO
BACKGROUND: Rhazya stricta Decne. is a medicinal plant that is widespread in Saudi Arabia and desert areas of the Arabian Peninsula. Its extract contains alkaloids, tannins, and flavonoids that are involved in different biological activities. The study aim was to evaluate the effects of Rhazya stricta plant extracts on the proliferation and differentiation of NTERA-2 (NT2) pluripotent embryonal carcinoma cells. METHODS: Soxhlet extraction was carried out using different solvents to extract stems, leaves and fruit parts of this plant. Cytotoxicity was evaluated by an MTS cell viability assay. The ability of the plant extract to induce cell differentiation was examined phenotypically using an inverted light microscope. The expression of pluripotency markers was investigated by reverse transcriptase polymerase chain reaction (RT-PCR) and immunocytochemistry. Phytochemical screening of chloroform stem extracts was carried out and a chromatographic fingerprint was generated using gas chromatography - mass spectrometry (GC-MS). RESULTS: Chloroform stem extract induced differentiation of NT2 cells at 5 µg/ml, and the differentiated cells exhibited neurite formation. Following induction of differentiation, there was significant down-regulation of the pluripotency marker genes Oct4 and Sox2. In addition, the surface antigen pluripotency marker, TRA-1-60, was strongly down-regulated. Phytochemical analysis of the extract showed the presence of alkaloids and saponins. The chromatogram revealed the presence of fifteen compounds with different retention times. CONCLUSION: Our results demonstrate for the first time that chloroform stem extract of R. stricta can induce neuronal differentiation of stem cells at an early stage and may contain potential therapeutic agent that can be used in neurodegenerative diseases.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apocynaceae/química , Carcinoma Embrionário/fisiopatologia , Diferenciação Celular/efeitos dos fármacos , Extratos Vegetais/farmacologia , Antineoplásicos Fitogênicos/isolamento & purificação , Carcinoma Embrionário/tratamento farmacológico , Carcinoma Embrionário/genética , Carcinoma Embrionário/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Fator 3 de Transcrição de Octâmero/genética , Fator 3 de Transcrição de Octâmero/metabolismo , Extratos Vegetais/isolamento & purificação , Folhas de Planta/química , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismoRESUMO
N-Heterocyclic carbene (NHC) metal complexes possess diverse biological activities but have yet to be extensively explored as potential chemotherapeutic agents. We have previously reported the synthesis of a new class of NHC metal complexes N-heterocyclic with acetate [IPr(BIAN)AuOAc] and chloride [IPr(BIAN)AuCl] ligands. In the experiments reported herein, the zebrafish embryos were exposed to serial dilutions of each of these complexes for 10-12 h. One hundred percent mortality was observed at concentrations≥50 µM. At sub-lethal concentrations (10-30 µM), both compounds influenced zebrafish embryonic development. However, quite diverse categories of abnormalities were found in exposed embryos with each compound. Severe brain deformation and notochord degeneration were evident in the case of [IPr(BIAN)AuOAc]. The zebrafish embryos treated with [IPr(BIAN)AuCl] exhibited stunted growth and consequently had smaller body sizes. A depletion of 30%-40% glutathione was detected in the treated embryos, which could account for one of the possible mechanism of neurotoxicity. The fact that these compounds are capable of both affecting the growth and also compromising antioxidant systems by elevating intracellular ROS production implies that they could play an important role as a new breed of therapeutic molecules.
Assuntos
Ouro/química , Compostos Heterocíclicos/química , Metano/análogos & derivados , Animais , Embrião não Mamífero/efeitos dos fármacos , Ouro/farmacologia , Compostos Heterocíclicos/farmacologia , Metano/química , Metano/farmacologia , Estrutura Molecular , Estresse Oxidativo/efeitos dos fármacos , Peixe-Zebra/embriologiaRESUMO
Eight novel N'-(2-oxoindolin-3-ylidene)-2-propylpentane hydrazide-hydrazone derivatives 4a-h were synthesized and fully characterized by IR, NMR ((1)H-NMR and (13)C-NMR), elemental analysis, and X-ray crystallography. The cyto-toxicity and in vitro anti-cancer evaluation of the prepared compounds have been assessed against two different human tumour cell lines including human liver (HepG2) and leukaemia (Jurkat), as well as in normal cell lines derived from human embryonic kidney (HEK293) using MTT assay. The compounds 3e, 3f, 4a, 4c, and 4e revealed promising anti-cancer activities in tested human tumour cells lines (IC50 values between 3 and 7 µM) as compared to the known anti-cancer drug 5-Fluorouracil (IC50 32-50 µM). Among the tested compounds, 4a showed specificity against leukaemia (Jurkat) cells, with an IC50 value of 3.14 µM, but this compound was inactive in liver cancer and normal cell lines.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Hidrazonas/química , Hidrazonas/farmacologia , Isatina/análogos & derivados , Ácido Valproico/análogos & derivados , Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Fluoruracila/farmacologia , Células HEK293 , Células Hep G2 , Humanos , Hidrazonas/síntese química , Isatina/síntese química , Isatina/química , Isatina/farmacologia , Células Jurkat , Ácido Valproico/síntese química , Ácido Valproico/farmacologiaRESUMO
For centuries, macrofungi have been used as food and medicine in different parts of the world. This is mainly attributed to their nutritional value as a potential source of carbohydrates, proteins, amino acids, and minerals. In addition, they also include many bioactive metabolites which make mushrooms and truffles common components in folk medicine, especially in Africa, the Middle East, China, and Japan. The reported medicinal effects of mushrooms include anti-inflammatory effects, with anti-inflammatory compounds of mushrooms comprising a highly diversified group in terms of their chemical structure. They include polysaccharides, terpenoids, phenolic compounds, and many other low molecular weight molecules. The aims of this review are to report the different types of bioactive metabolites and their relevant producers, as well as the different mechanisms of action of mushroom compounds as potent anti-inflammatory agents.
Assuntos
Agaricales/química , Anti-Inflamatórios/química , Fungos/química , Inflamação/tratamento farmacológico , Animais , Anti-Inflamatórios/uso terapêutico , Linhagem Celular , Humanos , Concentração Inibidora 50 , Camundongos , Modelos Químicos , Conformação Molecular , Peptídeos/química , Polissacarídeos/química , Transdução de SinaisRESUMO
Status epilepticus (SE) is a recurrent generalized convulsion condition and is regarded as a medical emergency with around 50% of the cases occurring in children. Besides neurobehavioral and motor deficits, SE is reportedly associated with imbalance in a number of neurochemicals in several areas of the brain. Furthermore, neuronal hyperactivity and/or excitotoxicity in such brain areas have been associated with excessive generation of free radicals. Proglumide (Pgm) is a known cholecystokinin (CCK) antagonist and any changes in the level of CCK and in the number of CCK receptors has been linked with SE. The present study was designed to investigate the possible neuroprotective effects of Pgm (0, 250, 500 and 750mg/ml/kg i.p.) on epileptic seizure activities, some neurobehavioral tests, and on some oxidative stress related parameters like lipid peroxides measured as thiobarbituric acid-reactive substance (TBARS) and total glutathione (GSH) in brain (hippocampus and striatum) of young rats that were experimentally induced with SE by lithium (Li) in 3mEq/ml/kg dose, i.p. followed 20h later by pilocarpine (Pc) in 20mg/ml/kg dose, s.c.). Besides significant anti-epileptic effect, Pgm significantly ameliorated SE-induced deterioration in cognitive behavior (in water-maze), motor performance (on rotarod), and biochemical changes in brain. It is concluded from the present study that Pgm has significant neuroprotective effects against SE and this effect may probably be due to its antioxidant activity. Pgm may prove to be a potentially effective antiepileptic drug, however, further studies are needed to ascertain this possibility.
Assuntos
Proglumida/uso terapêutico , Estado Epiléptico/tratamento farmacológico , Animais , Cognição/efeitos dos fármacos , Modelos Animais de Doenças , Glutationa/metabolismo , Lítio , Masculino , Atividade Motora/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Pilocarpina , Proglumida/farmacologia , Ratos , Ratos Sprague-Dawley , Estado Epiléptico/metabolismo , Estado Epiléptico/psicologiaRESUMO
The study examined how adding phytase to nonphytate phosphorus (NPP) diets affected performance, egg quality, reproductive hormones, and plasma biochemical indices in 73- to 80-wk-old laying hens. Six treatments with 5 replicates of 18 Hy-Line brown laying hens each were randomly assigned. Three isonitrogenous, isocaloric diets containing consistent calcium levels (3.8%) were formulated to contain 0.20, 0.25, and 0.30% NPP, treated with or without phytase supplementation (1,000 FYT per kg feed, Ronozyme HiPhos-L, Aspergillus oryzae 6-phytase). The results showed that the addition of phytase to the diet containing 0.20, 0.25, and 0.30% NPP increased egg production by 1.50, 1.64, and 0.97%, respectively, and improved eggshell thickness. Also, use of phytase in the diet contain 0.25, and 0.30% NPP increased the plasma concentration of albumin (ALB), high-density lipoprotein (HDL), phosphorus (P), and plasma follicle-stimulating hormone (FSH), plasma calcium (Ca), estradiol-17ß (E2ß), and luteinizing hormone (LH). In contrast, the egg weight, feed intake, egg mass, feed conversion ratio, albumen height, Haugh unit, yolk, and shell color were unaffected. It can be advisable to use phytase supplementation in an elderly laying hen's diet contain 0.25, and 0.30% NPP to improve shell quality and positively impact reproductive hormones leading to the persistence of egg production.
Assuntos
6-Fitase , Fósforo , Feminino , Animais , Galinhas , Cálcio , Ração Animal/análise , Oviposição , Óvulo , Dieta/veterinária , Hormônio Luteinizante , Envelhecimento , Suplementos NutricionaisRESUMO
The present study explored the influence of supplemental herbal mixtures on cow milk production, quality, and blood parameters in dairy cows under high ambient temperatures. Thirty Holstein cows were randomly assigned into three experimental groups of 10 each. The first control group was supplied with the commercial basal diet, whereas two treatment groups were provided with the commercial basal diet supplemented with 50 and 100 g/head/day of the herbal mixture, respectively. The results showed that the mixture of herbal supplementation did not influence weekly milk production. Milk total fat, triglyceride, and total protein values were not affected (p < 0.05) in cows fed on basal diets supplemented with herbal mixture; however, milk cholesterol was decreased significantly by 100 mg/head/day of the herbal mixture. On the other hand, lactose has increased significantly by adding 100 mg/head/day of herbal mixture. Furthermore, the total cholesterol level in serum was decreased by adding 100 mg/head/day of the herbal mixture, while plasma prolactin, cortisol, GOT, and GPT were unaffected. Regarding fatty acids (C18, C18:1 (c9), 18:1 (c11), 18:2 (c9, c12), 18:2 (t9, t12), and CLA (c9, t11)), there was no significant variation between the groups. Meanwhile, both C19:00 and 18:3 (c6, c9, and c12) were noticeably higher (p < 0.05) in the group that received 100gm, followed by 50 mg, compared to the control. In conclusion, the supplement with a herbal mixture positively affected milk quality by decreasing total cholesterol and increasing lactose, milk fatty acid profile by increasing unsaturated fatty acids content, and plasma cholesterol levels.
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To investigate the effect of bee venom (BV) as a natural growth promotor on growing rabbits as an alternative to antibiotics, sixty 35-day-old Californian male rabbits with an average body weight of 584 ± 9 gm were randomly divided into five equal groups as follows: The 2nd group received drinking water supplied with 10 mg Oxytetracycline (OXT), while the 3rd, 4th, and 5th groups received 2, 4 and 8 mg bee venom (BV)/kg body weight/day in drinking water, and the first group was served as a control group. The growth performance features were positively impacted by adding BV (p ≤ 0.01) compared to the control, whereas LBW and BWG increased and FI reduced. Significantly improved carcass characteristics (p ≤ 0.01) as a result of the BV supplementation. Blood characteristics showed a significant reduction (p ≤ 0.01) in liver enzyme activities and Cholesterol, Triglycerides, and Low-density lipoproteins Cholesterol (LDL) as affected by BV treatment; inversely, total protein and globulin were significantly increased (p ≤ 0.01). Similarly, BV had a positive effect (p ≤ 0.01) on anti-oxidant status (Total anti-oxidant capacity (TAC), Glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT)). In contrast, the lipid peroxidation biomarker (Malondialdehyde (MDA)) was significantly decreased. The immunoglobulin (IgG and IgM) was significantly increased (p ≤ 0.01) by BV treatment. There was a positive effect of low BV levels on decreasing both cecum TBC and pathogenic bacterial count (Salmonella spp., E.coli spp., Proteus spp., and Clostridia spp.) that was significant (p ≤ 0.01). In conclusion, BV can be a natural growth promoter to enhance growth performance traits, immunological and anti-oxidative responses, and reduce pathogenic bacteria in the hindgut of growing rabbits.
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This study aimed to show the effect of bile acid (BA) and xylanase (Xyl) supplementation on the growth, fat digestibility, serum lipid metabolites, and ileal digesta viscosity of broilers. A total of 720 1â¯d old male broilers were allocated to one of nine treatments with four replicates in each under a factorial design arrangement of three levels of BA (0â¯%, 0.25â¯%, and 0.50â¯%) and three levels of Xyl (0â¯%, 0.05â¯%, and 0.10â¯%) supplementation. The duration of the experiment was 35â¯d (7-42â¯d). Growth performance, blood lipids, fat digestibility, and ileal digesta viscosity were determined. The experimental treatments did not affect feed intake (FI) and weight gain (WG). Supplementation of BA or Xyl did not significantly ameliorate the feed conversion rate (FCR) (p<0.05). The addition of BA linearly increased fat digestibility. At 7-21â¯d of age, the addition of BA or Xyl had a significant (p<0.05) increase in serum cholesterol (Chol) but no significant difference for other serum lipid parameters in broiler chickens fed with Xyl in the starter and grower periods. However, the supplementation of 0.5â¯% BA at 7-21â¯d of age significantly increased the Chol and low-density-lipoprotein (LDL) levels. The results of this trial revealed that the supplementation of xylanases had a great effect on the degradation of arabinoxylan from wheat, which led to a relatively greater reduction in ileal digesta viscosity; it was also found that supplementation of BA significantly increased the concentration of serum lipid metabolites, whereas BA and Xyl supplementation linearly increased the fat digestibility of the birds fed wheat and tallow diets.
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Von Willebrand A domain-containing protein 8 (VWA8), also named KIAA0564, is a poorly characterized, mitochondrial matrix-targeted protein having a putative ATPase activity. VWA8 is comprising of ATPase-associated domains and a VWFA domain associated with ATPase activity inside the cell. In the present study, we describe a large consanguineous family of Saudi origin segregating a complex developmental syndrome in an autosomal recessive fashion. All the affected individuals exhibited severe developmental disorders. DNA from three patients was subjected to whole-exome sequencing followed by Sanger sequencing. VWA8 knock-down zebrafish morpholinos were used to study the phenotypic effect of this gene on zebrafish development. A homozygous missense variant [c.947A > G; p.(Asp316Gly)] was identified in exon 8 of the VWA8 gene, which perfectly segregated with the disease phenotype. Using zebrafish morpholino, we observed delayed development at an early stage, lack of movement, light sensitivity, severe skeletal deformity such as scoliosis, and facial dysmorphism. This is the first homozygous variant identified in the VWA8 gene underlying global developmental delay, microcephaly, scoliosis, limbs, and cardiovascular malformations in humans. We provide genetic and molecular evidence using zebrafish morpholino for a homozygous variant in the VWA8 gene, associated with such a complex developmental syndrome in humans.
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The present protocol describes the synthesis of di and tri-substituted s-triazine derivativesâ¢s-Triazine undergoes sequential nucleophilic substitution reaction but order of nucleophile is very crucial.â¢It is very difficult to substitute any nucleophile except amine once amine is incorporated onto s-triazine.â¢During the synthesis of O,N-type substituted s-triazine, always O-type should be incorporated first.
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A first example of 5-component 5-center reactions with isonitriles [Ugi-5CRs] is described. The extended Ugi type reactions involve selenoaldehydes as well as ammonia, both challenging reactants in multicomponent (MCR) systems, to generate methionine and Se-methionine moieties and derivatives as protected building blocks or for direct ligation in peptides or peptoids. The peptoid/peptide building blocks proved to be non-cytotoxic but increased the expression of genes encoding for stress protective selenoproteins (Gpx1).
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BACKGROUND: Nanoparticles of gold and silver are offering revolutionary changes in the field of cancer therapy. N-heterocyclic carbene (NHC) metal complexes possess diverse biological activities and are being investigated as potential chemotherapeutic agents. The purpose of this study was to examine the cytotoxicity and possible mechanisms of action of two types of newly synthesized nanofiber composites containing BIAN N-heterocyclic gold carbene complexes in two types of human cancer cells, namely breast cancer (MCF7) and liver cancer (HepG2) cells and also in normal human embryonic kidney cells (HEK 293). MATERIALS AND METHODS: Cytotoxicity was assessed by MTT cell viability assay and oxidative stress by checking the total glutathione level. RESULTS: Both compounds affected the cell survival of the tested cell lines at very low concentrations (IC50 values in the micro molar range) as compared to a well-known anti-cancer drug, 5 fluorouracil. A 60-80% depletion in total glutathione level was detected in treated cells. CONCLUSIONS: Reduction in total glutathione level is one of the biochemical pathways for the induction of oxidative stress which in turn could be a possible mechanism of action by which these compounds induce cytotoxicity in cancer cell lines. The in vitro toxicity towards cancer cells found here means that these molecules could be potential anticancer candidates.
Assuntos
Acenaftenos/farmacologia , Antineoplásicos/farmacologia , Ouro/farmacologia , Compostos Heterocíclicos/farmacologia , Metano/análogos & derivados , Estresse Oxidativo/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Fluoruracila/farmacologia , Glutationa/metabolismo , Células HEK293 , Células Hep G2 , Humanos , Concentração Inibidora 50 , Células MCF-7 , Metano/farmacologia , NanofibrasRESUMO
BACKGROUND: Valproic acid (VPA) is a potent anticancer and antiangiogenic agent. However, design and synthesis of chemical derivatives with improved antiangiogenic and anticancer activities are still necessary. In this study a library of novel derivatives of VPA was synthesized and tested. METHODS: A human liver cancer cell line (HepG2) and a human normal embryonic kidney cell line (HEK 293) were exposed to various concentrations of VPA derivatives for 24 hours and cell viability was checked by MTT colorimetric assay. Anti-angiogenic properties were evaluated in transgenic zebrafish embryos. RESULTS: N-valproylglycine derivatives suppressed survival almost 70% (p value 0.001) in HepG2 cells but only 10-12% in HEK 293 cells (p value 0.133). They also suppressed angiogenic blood vessel formation by 80% when used between 2-20 µM in zebrafish embryos. Valproic acid hydrazides showed moderate level of anticancer activity by affecting 30-50% (p value 0.001) of cell viability in HepG2 cells and 8-10% in HEK293 cells (p value 0.034). CONCLUSION: The majority of compounds in this study showed potent and stronger antiangiogenic and anticancer activity than VPA. They proved selectively toxic to cancer cells and safer for normal cells. Moreover, these compounds inhibited developmental angiogenesis in zebrafish embryos. Based on the fact that liver is a highly vascularized organ, in case of liver carcinoma these compounds have the potential to target the pathological angiogenesis and could be an effective strategy to treat hepatocellular carcinoma.
Assuntos
Inibidores da Angiogênese/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Embrião não Mamífero/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Neovascularização Patológica/prevenção & controle , Ácido Valproico/farmacologia , Inibidores da Angiogênese/química , Animais , Animais Geneticamente Modificados , Anticonvulsivantes/farmacologia , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/patologia , Células Cultivadas , Embrião não Mamífero/citologia , Células HEK293 , Humanos , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/patologia , Estrutura Molecular , Peixe-ZebraRESUMO
AIMS: The study was designed to find out the protein complex(s) associated with HDAC3 in liver cancer using a modified form of affinity purification coupled with a mass spectrometry technique in HepG2 cells. The organ-specific requirement for HDAC1 and HDAC3 during liver formation in zebrafish and their altered expression in liver cancer tissues indicates they are indispensible for hepato-organogenesis and hepatocarcinogenesis. However, how they exert their function is unknown. MATERIAL & METHODS: HepG2 cells were transfected with either mock or construct-containing HDAC3 using a C-terminal strepIII-HA tag as bait. The bait proteins were purified by double affinity columns and were analyzed on a Thermo LTQ Orbitrap™ (Thermo Scientific, MA, USA) chromatography system. RESULTS: Affinity purification coupled with mass spectrometry resulted in the identification of 24 putative binders of HDAC3 in HepG2 cells. The majority (83%) of these are novel interactions are reported for the first time in this study. CONCLUSION: This is the first study reporting the affinity purification and identification of protein complexes with two closely related proteins in one cell line. The novel HDAC1 and HDAC3 complexes identified in HepG2 cells could serve as a platform for the design of future therapeutic medicine for the treatment of liver cancer.