RESUMEN
This study evaluated the ability of isolated or semisynthesized trichothecene sesquiterpenes to prevent cancer emergence and proliferation and inhibit signal transducer and activator of transcription-3 (STAT3) phosphorylation through in vitro assays. Trichothecinol A (TTC-A), which bears a hydroxy group at C3, exhibited greater cancer prevention, antiproliferation, and STAT3 phosphorylation inhibition effects than trichothecin (TTC), which lacks a hydroxy group at C3. Furthermore, trichothecinol B (TTC-B), which is a reduced derivative of TTC and has similar cytotoxic effect, showed substantially weaker chemoprotection and STAT3 phosphorylation inhibition effects than TTC. These results clearly indicate that the hydroxy group at C3 and carbonyl group at C8 are crucial for inducing both potent chemoprevention and STAT3 phosphorylation inhibition.
Asunto(s)
Proliferación Celular , Factor de Transcripción STAT3 , Tricotecenos , Factor de Transcripción STAT3/antagonistas & inhibidores , Factor de Transcripción STAT3/metabolismo , Tricotecenos/química , Tricotecenos/farmacología , Tricotecenos/antagonistas & inhibidores , Humanos , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Fosforilación/efectos de los fármacos , Línea Celular Tumoral , Estructura Molecular , Ensayos de Selección de Medicamentos Antitumorales , Relación Dosis-Respuesta a Droga , Antineoplásicos/farmacología , Antineoplásicos/químicaRESUMEN
Based on previous studies, we synthesized a novel class of ortho- and para-naphthoquinones derivatives bearing a phenolic hydroxy or sulfonamide moiety and evaluated their in vitro antiproliferative and signal transducer and activator of transcription-3 (STAT3) phosphorylation inhibitory activities. The biological evaluations of these naphthoquinones revealed that ortho-naphthoquinones containing a phenolic hydroxyl group exhibited greater antiproliferative activity compared to compounds without a phenolic hydroxyl group. Among the synthesized para-naphthoquinones, 21, which has a condensed sulfonamide structure, showed substantially higher antiproliferative activity than that of the parent compound, and was also found to inhibit the phosphorylation of STAT3(Y705) in a dose-dependent manner. A docking simulation using AutoDock Vina suggested that 21 could directly bind to the hinge region of STAT3.
Asunto(s)
Antineoplásicos , Naftoquinonas , Antineoplásicos/química , Línea Celular Tumoral , Relación Estructura-Actividad , Simulación del Acoplamiento Molecular , Naftoquinonas/química , Factor de Transcripción STAT3/metabolismoRESUMEN
The enzymatic recycling of polyethylene terephthalate (PET) can be a promising approach to tackle the problem of plastic waste. The thermostability and activity of PET-hydrolyzing enzymes are still insufficient for practical application. Pretreatment of PET waste is needed for bio-recycling. Here, we analyzed the degradation of PET films, packages, and bottles using the newly engineered cutinase Cut190. Using gel permeation chromatography and high-performance liquid chromatography, the degradation of PET films by the Cut190 variant was shown to proceed via a repeating two-step hydrolysis process; initial endo-type scission of a surface polymer chain, followed by exo-type hydrolysis to produce mono/bis(2-hydroxyethyl) terephthalate and terephthalate from the ends of fragmented polymer molecules. Amorphous PET powders were degraded more than twofold higher than amorphous PET film with the same weight. Moreover, homogenization of post-consumer PET products, such as packages and bottles, increased their degradability, indicating the importance of surface area for the enzymatic hydrolysis of PET. In addition, it was required to maintain an alkaline pH to enable continuous enzymatic hydrolysis, by increasing the buffer concentration (HEPES, pH 9.0) depending on the level of the acidic products formed. The cationic surfactant dodecyltrimethylammonium chloride promoted PET degradation via adsorption on the PET surface and binding to the anionic surface of the Cut190 variant. The Cut190 variant also hydrolyzed polyethylene furanoate. Using the best performing Cut190 variant (L136F/Q138A/S226P/R228S/D250C-E296C/Q123H/N202H/K305del/L306del/N307del) and amorphous PET powders, more than 90 mM degradation products were obtained in 3 days and approximately 80 mM in 1 day.
RESUMEN
In this study, based on our previous study, derivatives of naphtho[2,3-b]furan-4,9-diones were synthesized and their antimicrobial activities were evaluated. The screening of these naphthoquinones revealed that the fluorine-containing NQ008 compound exhibited potent and broad antimicrobial activities against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA), Gram-negative bacteria, and fungi. The results of the ratio of the minimum bactericidal concentration (MBC) to the minimum inhibitory concentrations (MICs) and time-kill assays suggest that the mode of action of NQ008 is bactericidal. Additionally, the results of a drug resistance study revealed that NQ008 exhibited potent antibacterial activity and may delay the development of bacteria resistance. Furthermore, NQ008 exhibited preliminary antiviral activity against the swine influenza virus and Feline calicivirus.
Asunto(s)
Antiinfecciosos/química , Naftoquinonas/química , Tabebuia/química , Antiinfecciosos/síntesis química , Antiinfecciosos/farmacología , Farmacorresistencia Bacteriana/efectos de los fármacos , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Naftoquinonas/síntesis química , Naftoquinonas/farmacología , Relación Estructura-Actividad , Tabebuia/metabolismoRESUMEN
An enzyme, Cut190, from a thermophilic isolate, Saccharomonospora viridis AHK190 could depolymerize polyethylene terephthalate (PET). The catalytic activity and stability of Cut190 and its S226P/R228S mutant, Cut190*, are regulated by Ca2+ binding. We previously determined the crystal structures of the inactive mutant of Cut190*, Cut190*S176A, in complex with metal ions, Ca2+ and Zn2+, and substrates, monoethyl succinate and monoethyl adipate. In this study, we determined the crystal structures of another mutant of Cut190*, Cut190**, in which the three C-terminal residues of Cut190* are deleted, and the inactive mutant, Cut190**S176A, in complex with metal ions. In addition to the previously observed closed, open and engaged forms, we determined the ejecting form, which would allow the product to irreversibly dissociate, followed by proceeding to the next cycle of reaction. These multiple forms would be stable or sub-stable states of Cut190, regulated by Ca2+ binding, and would be closely correlated with the enzyme function. Upon the deletion of the C-terminal residues, we found that the thermal stability increased while retaining the activity. The increased stability could be applied for the protein engineering of Cut190 for PET depolymerization as it requires the reaction above the glass transition temperature of PET.
Asunto(s)
Actinobacteria/enzimología , Calcio/metabolismo , Hidrolasas de Éster Carboxílico/química , Hidrolasas de Éster Carboxílico/metabolismo , Tereftalatos Polietilenos/metabolismo , Ingeniería de Proteínas/métodos , Cristalografía por Rayos X , Estabilidad de Enzimas , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Tereftalatos Polietilenos/química , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Relación Estructura-Actividad , TemperaturaRESUMEN
The extract of Tabebuia avellanedae has been used as a folk medicine, and the various biological activities of T. avellanedae have been extensively studied. However, few studies have reported which natural products play a role in their biological effects. In this study, we evaluated representative naphthoquinones isolated from T. avellanedae and found that furanonaphthoquinones were the key structures required to exhibit STAT3 phosphorylation inhibitory activities. Our SAR analysis indicated that removal of a hydroxyl group enhanced the STAT3 phosphorylation inhibitory activity. In addition, the combined results of a mobility shift assay, SH2 domain binding assay, and docking simulation by Autodock 4.2.6 suggested that (S)-5-hydroxy-2-(1-hydroxyethyl)naphtho[2,3-b]furan-4,9-dione (1) could directly bind to the hinge region of STAT3.
Asunto(s)
Naftoquinonas/farmacología , Factor de Transcripción STAT3/antagonistas & inhibidores , Tabebuia/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Naftoquinonas/química , Naftoquinonas/aislamiento & purificación , Factor de Transcripción STAT3/metabolismo , Relación Estructura-ActividadRESUMEN
Endurance capacity is important for maintenance of quality of life as well as performance of endurance athletes. In order to improve endurance, intake of nutritional supplements as well as exercise training is also important. Indeed, polyphenolic extracts from plants are known to improve endurance capacity via increase of fatty acid utilization, mitochondrial biogenesis or inhibition of oxidative stress. Taheebo, the extract obtained from inner bark of Tabebuia avellanedae has been reported to have beneficial effects for treatment of inflammation, oxidative stress and obesity. Here, we investigated the effects and mechanisms of polyphenol fraction of taheebo (taheebo polyphenol; TP) on endurance capacity of mice. Single dose administration of TP significantly increased running time until exhaustion. Acute TP administration increased blood glucose and muscle glycogen levels (p < 0.05) through alteration on expression level of genes involved with glycogen metabolism and gluconeogenesis. Furthermore, TP administration decreased exercise-induced increase of protein carbonyls in skeletal muscle. These results suggest that TP administration improve endurance capacity via up-regulation of skeletal muscle glycogen levels and maintenance of blood glucose by acceleration of gluconeogenesis as well as inhibition of exercise-induced oxidative stress. Single administration of TP also increased phosphorylation of AMP-activated protein kinase (AMPK) and gene expression level of sirtuin 1 (SIRT1) but did not change the marker of mitochondrial biogenesis.
Asunto(s)
Glucemia/efectos de los fármacos , Suplementos Dietéticos , Glucógeno/metabolismo , Músculo Esquelético/metabolismo , Resistencia Física/efectos de los fármacos , Extractos Vegetales/administración & dosificación , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Condicionamiento Físico Animal , Polifenoles/farmacología , Carbonilación Proteica/efectos de los fármacosRESUMEN
HDAC inhibitors enable histones to maintain a high degree of acetylation. The resulting looser state of chromatin DNA may increase the accessibility of DNA drug targets and consequently improve the efficiency of anticancer drugs targeting DNA, such as Topo II inhibitors. A novel class of nucleoside-SAHA derivatives has been designed and synthesized based on the synergistic antitumor effects of topoisomerase II and histone deacetylase inhibitors. Their inhibitory activities toward histone deacetylases and Topo II, and their cytotoxicities in cancer cell lines, were evaluated. Among the synthesized hybrid compounds, compound 16b showed the potent HDAC inhibitory activity at a low nanomolar level and exhibited antiproliferative activity toward cancer cell lines including MCF-7 (breast), HCT-116 (colon), and DU-145 (prostate) cancer cells at a low micromolar level. Moreover, compound 16a showed HDAC6-selectivity 20-fold over HDAC1.
Asunto(s)
Antineoplásicos/síntesis química , ADN-Topoisomerasas de Tipo II/metabolismo , Inhibidores de Histona Desacetilasas/síntesis química , Histona Desacetilasas/metabolismo , Inhibidores de Topoisomerasa II/síntesis química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , ADN-Topoisomerasas de Tipo II/química , Células HCT116 , Histona Desacetilasa 1/antagonistas & inhibidores , Histona Desacetilasa 1/genética , Histona Desacetilasa 1/metabolismo , Histona Desacetilasa 6/antagonistas & inhibidores , Histona Desacetilasa 6/genética , Histona Desacetilasa 6/metabolismo , Inhibidores de Histona Desacetilasas/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/química , Humanos , Células MCF-7 , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/química , Proteínas Recombinantes/aislamiento & purificación , Relación Estructura-Actividad , Inhibidores de Topoisomerasa II/metabolismo , Inhibidores de Topoisomerasa II/farmacologíaRESUMEN
[This corrects the article on p. 63 in vol. 4, PMID: 29312947.].
RESUMEN
We developed novel nucleoside-based topoisomerase II selective inhibitors and showed that small structural units, such as catechols, are essential for DNA topoisomerase II inhibitory activity. Moreover, nucleoside analogues containing TBS and 1,3-dithian moieties had potent and selective DNA topoisomerase II inhibitory activities. In further experiments, compound 25b having a beta configuration of the thymine moiety showed relatively strong growth inhibitory activity against cancer cell lines, and was more potent against all cancer cell lines than compound 26b, which carries a thymine moiety in the alpha configuration.
Asunto(s)
Diseño de Fármacos , Nucleótidos/antagonistas & inhibidores , Inhibidores de Topoisomerasa II/farmacología , Espectroscopía de Resonancia Magnética con Carbono-13 , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Espectrometría de Masas , Espectroscopía de Protones por Resonancia Magnética , Espectrofotometría Infrarroja , Inhibidores de Topoisomerasa II/químicaRESUMEN
AIM OF STUDY: Taheebo polyphenols (TP) are water extracts of Tabebuia spp. (Bignoniaceae), taken from the inner bark of the Tabebuia avellanedae tree, used extensively as folk medicine in Central and South America. Some anti-inflammatory drugs act by inhibiting both cyclooxygenase-2 (COX-2) and COX-1 enzymes. COX-2 syntheses prostaglandin (PG) E2, which is a species of endogenous pain-producing substance, whereas COX-1 acts as a house-keeping enzyme. Inhibiting both COX-1 and -2 simultaneously can have side effects such as gastrointestinal bleeding and renal dysfunction. Some polyphenols have been reported for its selective inhibiting activity toward COX-2 expression. Our study aimed to demonstrate the potential and mechanisms of TP as an anti-inflammation action without the side effects of COX-1 inhibition. MATERIALS AND METHODS: Free fatty acid-stimulated macrophage cell lines were employed to mimic macrophage behaviors during lifestyle-related diseases such as atherosclerosis and non-alcoholic steatohepatitis. Real-time polymerase chain reaction was used to detect expression of inflammatory cytokine mRNA. Griess assay was used to measure the production of nitric oxide (NO). ELISA was used to measure PG E2 production. Molecular docking was adopted to analyze the interactions between compounds from T. avellanedae and COX-2. RESULTS: TP significantly suppressed the production of NO production, blocked the mRNA expression of iNOS, and COX-2 in both cell lines, blocked the mRNA expression of TNF-α, IL-1ß, IL-6, and PGE2 in the murine cell line. However, there was no inhibitory effect on COX-1. Molecular docking result indicated that the inhibitory effects of TP on COX-2 and PGE2 could be attributed to acteoside, which is the main compound of TP that could bind to the catalytic zone of COX-2. After the interaction, catalytic ability of COX-2 is possibly inhibited, followed by which PGE2 production is attenuated. COX inhibitor screening assay showed TP as a selective inhibitor of COX-2 enzyme. CONCLUSION: The anti-inflammatory effects of TP can possibly regulate macrophages due to the targeted inhibition of COX-2 activity, without affecting COX-1 activity with other anti-inflammatory effects including suppression of iNOS and inflammatory cytokines. As such, TP is potentially useful in prevention and treatment of lifestyle-related disease by attenuating inflammation caused by macrophages infiltration.
RESUMEN
Estrogen deficiency-induced obesity has a high risk of visceral fat accumulation and body weight gain. It is also associated with many adverse health conditions. Taheebo extract from Tabebuia avellanedae has been recognized as playing several biological and pharmacological roles. Therefore, we investigated whether the intake of n-BuOH extract of Taheebo shows anti-obesity effect in ovariectomized (OVX) mice. After 16 weeks of feeding, the mice administrated with 0.5% n-BuOH extract of Taheebo showed significantly decreased body weight compared with that of the control mice, and the fat mass also showed a significant decrease. In 3T3-L1 cells, supplementation with n-BuOH extract of Taheebo significantly reduced the triglyceride (TG) levels. Furthermore, bioassay-guided purification of the n-BuOH extract based on the TG levels in 3T3-L1 cells led to the isolation of compound 2 (1-dehydroxy-3,4-dihydroaucubigenin). These results suggested that the anti-obesity effect of Taheebo extract is due to its capability in preventing the accumulation of adipocyte in mice. Taheebo extract might be a promising functional food resources capable of protecting against OVX-induced obesity.
Asunto(s)
Fármacos Antiobesidad/uso terapéutico , Obesidad/tratamiento farmacológico , Extractos Vegetales/uso terapéutico , Tabebuia/química , 1-Butanol/química , Células 3T3-L1 , Animales , Fármacos Antiobesidad/farmacología , Peso Corporal/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Heces/química , Femenino , Hígado/efectos de los fármacos , Hígado/metabolismo , Ratones , Obesidad/sangre , Tamaño de los Órganos/efectos de los fármacos , Ovariectomía , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Triglicéridos/metabolismoRESUMEN
Ten new 3,4-seco betulinic acid (BA) derivatives were designed and synthesized. Among them, compounds 7-15 exhibited enhanced chemopreventive ability in an in vitro short-term 12-O-tetradecanoylphorbol-13-acetate (TPA) induced Epstein-Barr virus early antigen (EBV-EA) activation assay in Raji cells. Specifically, analogs with a free C-28 carboxylic acid, including 7, 8, 11, and 13, inhibited EBV-EA activation significantly. The most potent compound 8 displayed 100% inhibition at 1×10(3) mol ratio/TPA and 73.4%, 35.9%, and 8.4% inhibition at 5×10(2), 1×10(2), and 1×10 mol ratio/TPA, respectively, comparable with curcumin at high concentration and better than curcumin at low concentration. The potent chemopreventive activity of novel seco A-ring BAs (8 and 11) was further confirmed in an in vivo mouse skin carcinogenesis assay.
Asunto(s)
Anticarcinógenos/química , Anticarcinógenos/farmacología , Neoplasias/prevención & control , Triterpenos/química , Triterpenos/farmacología , Animales , Línea Celular , Herpesvirus Humano 4/efectos de los fármacos , Humanos , Ratones , Triterpenos Pentacíclicos , Triterpenos/síntesis química , Ácido BetulínicoRESUMEN
Although a wide variety of cytotoxic plant extracts and phytochemicals are known to act synergistically with anticancer drug doxorubicin (D), their clinical application is hindered by safety concerns of such combination therapy. Our earlier studies showed that red beetroot (Beta vulgaris L.) extract (B), approved by Food and Drug Administration and European Union as red food color E162, reduced multi-organ tumor formations in various animal models when administered in drinking water. This led us to postulate that a long-term daily exposure to low doses of B through diet might be safe and sufficient to produce cancer chemopreventive effect in humans. Further, our recent comparative cytotoxic investigation with B and D in several human cancer cell lines indicated their potential for synergistic activity. Since B is considered safe for human use with no known toxicity, we conducted the present study to evaluate its synergistic antiproliferative activity with D against pancreatic (PaCa), breast (MCF-7) and prostate (PC-3) tumor cells of human origin. Different concentrations of B and D (0.29-290 µg/ml) and in various combinations (B:D ratio = 1:0, 1:1, 5:1, 1:5 and 0:1) were tested for cytotoxic effects against the three cancer cells. The viability of cells was assessed after 72 h incubation with various combinations of B and D using the trypan-blue staining method. The cytotoxic data were analyzed by the combination index method of Chou and Talalay to establish synergy between B and D. The results indicated that an overall positive reduction in drug concentration was achieved by D when combined with B in its cytotoxicity profile in the three human cancer cells tested. The synergistic cytotoxicity was best when the B:D ratio of 1:5 was used in PaCa cells at IC50, IC75 and IC90 dose levels and in MCF-7 cells at IC90 dose level. These results warrant further studies on the potential of red beetroot extract-doxorubicin combination in treating human cancers.
Asunto(s)
Antineoplásicos/uso terapéutico , Beta vulgaris , Neoplasias de la Mama/tratamiento farmacológico , Doxorrubicina/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Fitoterapia , Neoplasias de la Próstata/tratamiento farmacológico , Antineoplásicos/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/farmacología , Combinación de Medicamentos , Sinergismo Farmacológico , Femenino , Interacciones de Hierba-Droga , Humanos , Células MCF-7 , Masculino , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéuticoRESUMEN
In continuation of our studies with chemoprevention potential of plant-derived naphthoquinone derivatives, leaf powder of the medicinal plant Lawsonia inermis L, commonly known as 'henna', was evaluated by its inhibition of the Epstein-Barr virus early antigen (EBV-EA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells. Lawsone (2-hydroxy- 1,4-naphthoquinone), the reddish orange pigment artifact formed during the extraction or preparation of the dye from henna leaves and believed to be the active component, was also assessed in this in vitro assay. Both showed a profound inhibition (>88%) of EBV-EA activation. In the in vivo two-stage mouse skin carcinogenesis study using UV-B radiation for initiation and TPA for tumor promotion, oral feeding of henna (0.0025%) in drinking water ad libitum decreased tumor incidence by 66% and multiplicity by 40% when compared to the positive control at 10 weeks of treatment. Similarly, in the above mouse model, orally fed lawsone (0.0025%) decreased tumor incidence by 72% and multiplicity by 50%. The tumor inhibitory trend continued throughout the 20-week test period. Similar antitumor activities were observed when henna (0.5 mg/ml) was applied topically on the back skin in the UV-B initiated, TPA promoted and peroxynitrite initiated, TPA promoted mouse skin carcinogenesis models. Topically applied lawsone (0.015 mg/ml) also exhibited similar protection against tumor formation in the 7,12-dimtehylbenz(a)anthracene induced and TPA promoted skin cancer in mice. Also, there was a delay of 1 to 2 weeks in tumor appearance in both henna and lawsone treated groups compared to control in all three test models. This study ascertains the skin cancer chemopreventive activity of henna leaf powder and lawsone when administered by either oral (through drinking water) or topical (by application on the back skin) routes. Further, it emphasizes the need for the evaluation of these henna-derived green chemopreventive candidates in combination with currently used sunscreen agents for complementary anticancer potential against UV-induced skin carcinogenesis.
Asunto(s)
Antineoplásicos Fitogénicos/administración & dosificación , Carcinogénesis/efectos de los fármacos , Lawsonia (Planta)/química , Naftoquinonas/administración & dosificación , Papiloma/prevención & control , Extractos Vegetales/administración & dosificación , Hojas de la Planta/química , Neoplasias Cutáneas/prevención & control , 9,10-Dimetil-1,2-benzantraceno/toxicidad , Administración Cutánea , Administración Oral , Animales , Antígenos Virales/biosíntesis , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Linfocitos B/efectos de los fármacos , Linfocitos B/patología , Linfocitos B/virología , Carcinogénesis/patología , Línea Celular Tumoral , Femenino , Herpesvirus Humano 4/efectos de los fármacos , Herpesvirus Humano 4/fisiología , Humanos , Masculino , Naftoquinonas/química , Naftoquinonas/aislamiento & purificación , Papiloma/inducido químicamente , Papiloma/patología , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Neoplasias Cutáneas/inducido químicamente , Neoplasias Cutáneas/patología , Acetato de Tetradecanoilforbol/farmacología , Rayos UltravioletaRESUMEN
BACKGROUND: Sunscreen compounds with added benefit of skin cancer prevention have both public and commercial interests. Our earlier study using the Epstein-Barr virus early antigen in vitro assay reported on skin cancer chemoprevention potential of benzophenone sunscreens. We now report the in vivo antitumor activity of two of the benzophenone sunscreens which tested positively in the in vitro assay, octabenzone (UV-1) and dioxybenzone (UV-2), in the two-stage mouse skin carcinogenesis model using (±)-(E)-4-methyl-2-[-(E)-hydroxyamino]-5-nitro-6-methoxy-3-hexanamide (NOR-1) as inducer and 12-O-tetradecanoyl-phorbol-13-acetate (TPA) as promoter. MATERIALS AND METHODS: Pathogen-free, female hairless mice of HOS:HR-1 strain, 15 animals per control and test groups, were used. Skin tumors were induced by a single dose of NOR-1 (390 nmol in 100 µl of acetone). One week later, TPA (1.7 nmol in 100 µl of acetone) was applied to skin twice weekly for 20 weeks as tumor a promoter. The test compounds UV-I or UV-2 were administered at 0.0025% to mice through drinking water ad libitum, starting one week prior to and stopping one week after tumor initiation. All animals were examined weekly for the development of skin papillomas. RESULTS: In both UV-1- and UV-2-treated mice, a two-week delay in tumor appearance, and significant inhibition (p<0.001) of tumor incidence (50% and 60%, respectively) and tumor burden (papilloma inhibition/mouse, 50% and 70%, respectively) were observed when compared to the positive control group. UV-2 (dihydroxy derivative) was a more potent inhibitor of skin tumor than UV-1 (monohydroxy derivative), which followed their antioxidant activity ranking. CONCLUSION: The results affirm the skin cancer chemoprevention potential of orally-ingested benzophenone sunscreens in mice and warrant studies in humans to validate synergistic protection achievable by complementation of oral and topical sunscreen usage.
Asunto(s)
Anticarcinógenos/administración & dosificación , Benzofenonas/administración & dosificación , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/prevención & control , Protectores Solares/administración & dosificación , Animales , Anticarcinógenos/uso terapéutico , Benzofenonas/uso terapéutico , Transformación Celular Neoplásica , Agua Potable , Femenino , Ratones , Ratones Pelados , Protectores Solares/uso terapéuticoRESUMEN
A concise method for the synthesis of heterocycle-fused naphthoquinones such as naphtho[2,3-b]-furan-4,9-dione, 1H-benz[f]indole-4,9-dione, and naphtho[2,3-b]thiophene-4,9-dione was developed. This method employed Sonogashira coupling and tandem addition-elimination/intramolecular cyclization, and it enabled the preparation of versatile heterocycle-fused naphthoquinones from one substrate.
Asunto(s)
Naftoquinonas/química , Acetileno/química , Catálisis , Ciclización , Naftoquinonas/síntesis químicaRESUMEN
The cancer chemopreventive potential of sarcophine-diol in a chemical carcinogen initiation-promotion experimental tumor model in mice was evaluated. Sarcophine-diol, when given orally, afforded significant protection in the mouse skin cancer model initiated by the topical administration of (+/-)-(E)-4-methyl-2-[(E)-hydroxyamino]-5-nitro-6-methoxy-3-hexanamide (NOR-1) and promoted by 12-O-tetradecanoylphorbol-13-acetate (TPA). These findings, along with our initial reports, suggest that sarcophine-diol is an effective cancer chemopreventive agent, even when administered orally and at a very low dose and thus indicating possible potential human applications in the control of malignancy.
Asunto(s)
Anticarcinógenos/farmacología , Diterpenos/farmacología , Hidroxilaminas/farmacología , Neoplasias Cutáneas/prevención & control , Animales , Femenino , Ratones , Ratones Pelados , Acetato de TetradecanoilforbolRESUMEN
CONTEXT: Dimethyl dicarboxylate biphenyl (DDB) is a clinically used hepatoprotectant and has also been found to have chemopreventive activity. MATERIALS AND METHODS: Sixteen novel analogs (5-20) were designed, synthesized, and evaluated for their cancer preventive activity. The 2,2'-bismethyl ester (5-18) and ether (19, 20) DDB analogs were synthesized by insertion of various linear alkyl, short fatty acid, polar, and aromatic groups. All synthesized analogs were evaluated in an in vitro short-term 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced Epstein Barr virus early antigen (EBA-EA) activation assay. Three of the most potent compounds were also tested for inhibitory effects on skin tumor promotion in an in vivo two-stage mouse-skin carcinogenesis test using 7,12-dimethylbenz[a]anthracene (DMBA) as an initiator and TPA as a promoter. RESULTS: Compound 19 with bisprenyl ethers had the most significant cancer preventive activity (100% inhibition of activation at 1 × 10(3) mol ratio/TPA, 78.4%, 49.7%, and 10.9% inhibition at 5 × 10(2), 1 × 10(2), 1 × 10 mol ratio/TPA, respectively) in vitro. Compound 19 also exhibited a remarkable inhibitory effect on skin tumor promotion in the in vivo two-stage mouse-skin carcinogenesis test. DISCUSSION AND CONCLUSIONS: Thus, DDB analog 19 could be a valuable candidate as a cancer preventive agent or as a lead for the development of new antitumor promoter drugs.
Asunto(s)
Anticarcinógenos/farmacología , Dioxoles/farmacología , Neoplasias Cutáneas/prevención & control , 9,10-Dimetil-1,2-benzantraceno/toxicidad , Animales , Anticarcinógenos/síntesis química , Anticarcinógenos/química , Antígenos Virales/metabolismo , Dioxoles/síntesis química , Dioxoles/química , Femenino , Humanos , Ratones , Ratones Endogámicos ICR , Acetato de Tetradecanoilforbol/farmacologíaRESUMEN
In this paper, a concise one-pot method for the construction of benzo[f]indole-4,9-dione motifs is described. These transformations proceed via a sequential palladium- and copper-catalyzed coupling reaction of 1,4-naphthoquinones with terminal acetylenes, followed by a copper-catalyzed intramolecular cyclization reaction of the resulting coupling product.