RESUMEN
Breast cancer has the highest incidence and mortality in females, while prostate cancer has the second-highest incidence in males. Studies have shown that compounds from Brazilian green propolis have antitumor activities and can selectively inhibit the AKR1C3 enzyme, overexpressed in hormone-dependent prostate and breast tumors. Thus, in an attempt to develop new cytotoxic inhibitors against these cancers, three prenylated compounds, artepillin C, drupanin and baccharin, were isolated from green propolis to synthesize new derivatives via coupling reactions with different amino acids. All obtained derivatives were submitted to antiproliferative assays against four cancer cells (MCF-7, MDA MB-231, PC-3, and DU145) and two normal cell lines (MCF-10A and PNT-2) to evaluate their cytotoxicity. In general, the best activity was observed for compound6e, derived from drupanin, which exhibited half-maximal inhibitory concentration (IC50) of 9.6 ± 3 µM and selectivity index (SI) of 5.5 against MCF-7 cells.In silicostudies demonstrated that these derivatives present coherent docking interactions and binding modes against AKR1C3, which might represent a possible mechanism of inhibition in MCF-7 cells.
Asunto(s)
Aminoácidos/farmacología , Antineoplásicos Fitogénicos/farmacología , Cinamatos/farmacología , Fenilpropionatos/farmacología , Própolis/química , Tricotecenos/farmacología , Aminoácidos/análisis , Aminoácidos/síntesis química , Antineoplásicos Fitogénicos/análisis , Antineoplásicos Fitogénicos/síntesis química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cinamatos/análisis , Cinamatos/síntesis química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Fenilpropionatos/análisis , Fenilpropionatos/síntesis química , Própolis/análisis , Própolis/síntesis química , Própolis/farmacología , Relación Estructura-Actividad , Tricotecenos/análisis , Tricotecenos/síntesis químicaRESUMEN
Conjugation of deoxynivalenol (DON) with sulfur compounds is recognized as a significant reaction pathway, and putative DON-glutathione (DON-GSH) conjugates have been reported in planta. To understand and control the reaction of trichothecenes with biologically important thiols, we studied the reaction of DON, T-2 tetraol, and de-epoxy-DON with a range of model thiols. Reaction conditions were optimized for DON with 2-mercaptoethanol. Major reaction products were identified using HRMS and NMR spectroscopy. The results indicate that thiols react reversibly with the double bond (Michael addition) and irreversibly with the epoxide group in trichothecenes. These reactions occurred at different rates, and multiple isomers were produced including diconjugated forms. LC-MS analyses indicated that glutathione and cysteine reacted with DON in a similar manner to the model thiols. In contrast to DON, none of the tested mercaptoethanol adducts displayed toxicity in human monocytes or induced pro-inflammatory cytokines in human macrophages.
Asunto(s)
Micotoxinas/química , Compuestos de Sulfhidrilo/química , Tricotecenos/química , Línea Celular , Citocinas/inmunología , Humanos , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Espectroscopía de Resonancia Magnética , Estructura Molecular , Monocitos/efectos de los fármacos , Monocitos/inmunología , Micotoxinas/síntesis química , Micotoxinas/farmacología , Tricotecenos/síntesis química , Tricotecenos/farmacologíaRESUMEN
Inhibitors of a human member (AKR1C3) of the aldo-keto reductase superfamily are regarded as promising therapeutics for the treatment of prostatic and breast cancers. Baccharin [3-prenyl-4-(dihydrocinnamoyloxy)cinnamic acid], a component of propolis, was shown to be both potent (Ki 56 nM) and highly isoform-selective inhibitor of AKR1C3. In this study, a series of derivatives of baccharin were synthesized by replacing the 3-prenyl moiety with aryl and alkyl ether moieties, and their inhibitory activities for the enzyme were evaluated. Among them, two benzyl ether derivatives, 6m and 6n, showed an equivalent inhibitory potency to baccharin. The molecular docking of 6m in AKR1C3 has allowed the design and synthesis of (E)-3-{3-[(3-hydroxybenzyl)oxy]-4-[(3-phenylpropanoyl)oxy]phenyl}acrylic acid (14) with improved potency (Ki 6.4 nM) and selectivity comparable to baccharin. Additionally, 14 significantly decreased the cellular metabolism of androsterone and cytotoxic 4-oxo-2-nonenal by AKR1C3 at much lower concentrations than baccharin.
Asunto(s)
3-Hidroxiesteroide Deshidrogenasas/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Hidroxiprostaglandina Deshidrogenasas/antagonistas & inhibidores , Tricotecenos/farmacología , 3-Hidroxiesteroide Deshidrogenasas/metabolismo , Miembro C3 de la Familia 1 de las Aldo-Ceto Reductasas , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Hidroxiprostaglandina Deshidrogenasas/metabolismo , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Tricotecenos/síntesis química , Tricotecenos/química , Células Tumorales CultivadasRESUMEN
The reaction of D-fructose with ammonium carbonate and 2,4-pentanedione leads in one step to 3-acetyl-5-(D-arabino-tetrahydroxybutyl)-2-methylpyrrole. This compound has been found to display anticancer activity.
Asunto(s)
Antibióticos Antineoplásicos/síntesis química , Antibióticos Antineoplásicos/química , Carbonatos/farmacología , Química Farmacéutica , Fructosa/farmacología , Indicadores y Reactivos/farmacología , Métodos , Pentanonas/farmacología , Tricotecenos/síntesis química , Tricotecenos/químicaRESUMEN
Forty-two analogues and reaction products derived from T-2 toxin or neosolaniol were assayed for their cytotoxicity to cultured mouse lymphoma cells. Structure-activity relationships confirmed the stereospecific nature of the cytotoxic action of T-2. Cytotoxicity was particularly susceptible to changes at C3, C4, C9, and C10 but was relatively unaffected by changes at C8, which appears to represent a region of steric tolerance in the interaction of T-2 with a cellular constituent. The most potent compounds were T-2, diacetoxyscirpenol, and a series of C8 ester analogues 11 and 31-35.
Asunto(s)
Antineoplásicos/síntesis química , Sesquiterpenos/síntesis química , Tricotecenos/síntesis química , Animales , Antineoplásicos/uso terapéutico , Fenómenos Químicos , Química , Ensayos de Selección de Medicamentos Antitumorales , Linfoma/tratamiento farmacológico , Ratones , Relación Estructura-Actividad , Toxina T-2 , Tricotecenos/uso terapéutico , Células Tumorales CultivadasRESUMEN
The Fusarium mycotoxin, 4-deoxynivalenol, is an abundant, natural contaminant of corn and wheat. 8-Oxo-12,13-epoxytrichothecenes related to 4-deoxynivalenol were synthesized; they either lacked the 7-hydroxyl but contained a hydroxyl at C-4 (7-deoxynivalenol) or lacked substituents at C-3 and C-7 (3,7-dideoxynivalenol). The ability of these synthetic analogs and their acetylated derivatives to inhibit protein synthesis by cultured mammalian cells was compared to that of 4-deoxynivalenol. Whereas the 50% inhibitory dose (ID50) for murine erythroleukemia cells was about 1 microgram/ml for 4-deoxynivalenol and 3,7-dideoxynivalenol, all of the other analogs were at least 10-fold less potent. When tested at their ID50 dose, all of the 8-oxotrichothecenes, except 4-deoxynivalenol and 3,7-dideoxynivalenol, caused polysome 'run-off', indicating that, at this dose, they are inhibitors of polypeptide chain initiation. With 4-deoxynivalenol and 3,7-dideoxynivalenol, polysomes remained at control levels indicating that these toxins prevent polypeptide chain elongation. From these results and comparisons to previous studies of 8-oxo-12,13-epoxytrichothecenes (trichothecolone, trichothecin, nivalenol and fusarenone X), trichothecenes with substituents at both C-3 and C-4 predominantly inhibit polypeptide chain initiation, whereas those lacking one substituent at either site are inhibitors of chain elongation.
Asunto(s)
Biosíntesis de Proteínas , Sesquiterpenos/farmacología , Tricotecenos/farmacología , Células Cultivadas , Biosíntesis de Péptidos , Extensión de la Cadena Peptídica de Translación/efectos de los fármacos , Iniciación de la Cadena Peptídica Traduccional/efectos de los fármacos , Polirribosomas/efectos de los fármacos , Espectrofotometría Infrarroja , Relación Estructura-Actividad , Tricotecenos/síntesis químicaRESUMEN
Amine-containing trichothecanes were prepared by reductive aminations of 3-ketoanguidin. In in vivo tests against P388 leukemia, most of them showed an improved activity compared to anguidin though their potency was decreased. 3-Ketoanguidin also produced some unexpected structures: oxazoline 5, dioxalane 7, and alpha-amino nitrile 13.
Asunto(s)
Aminas , Leucemia P388/tratamiento farmacológico , Leucemia Experimental/tratamiento farmacológico , Sesquiterpenos/síntesis química , Tricotecenos , Tricotecenos/síntesis química , Animales , Fenómenos Químicos , Química , Relación Estructura-Actividad , Tricotecenos/uso terapéuticoRESUMEN
4-Deoxyverrucarol (4) has been synthesized for use in studies for the preparation and development of monoclonal antibodies for trichothecenes. Both verrucarol (1) and anguidine (2) have been converted to deoxyverrucarol (DOVE) (4) by deoxygenation at C3 and at C3 and C4, respectively.
Asunto(s)
Antineoplásicos Fitogénicos/síntesis química , Sesquiterpenos/síntesis química , Tricotecenos/síntesis química , Animales , Fenómenos Químicos , Química , Dosificación Letal Mediana , Ratones , Tricotecenos/toxicidadRESUMEN
Various 8 beta-hydroxy, 16-hydroxy, and 9 beta,10 beta-epoxy derivatives of roridins A and H and verrucarins A and J have been prepared and tested in vivo against P388 mouse leukemia. The 9 beta,10 beta-epoxy derivatives and 16-hydroxy derivatives consistently exhibit very high activity. The 8 beta-hydroxy-9 beta,10 beta-epoxy and 16-hydroxy-9 beta,10 beta-epoxy derivatives of verrucarin A and roridin A exhibit extraordinary activity against P388. The 8 beta-hydroxy-9 beta,10 beta-epoxy and 16-hydroxy-9 beta,10 beta-epoxy derivatives of verrucarin A and roridin A exhibit extraordinary against P388.
Asunto(s)
Leucemia Experimental/tratamiento farmacológico , Sesquiterpenos/síntesis química , Tricotecenos/síntesis química , Animales , Línea Celular , Fenómenos Químicos , Química , Compuestos Epoxi , Hidroxilación , Ratones , Relación Estructura-Actividad , Tricotecenos/uso terapéuticoRESUMEN
Approximately 60 derivatives of anguidin were prepared for evaluation of antitumor activities. Positions 3, 4, 8-10, and 15 were modified, and the resultant derivatives were screened against P-388 leukemia. It was found that introduction of the C3-keto and C3,C8-diketo groups markedly improved the antileukemic activity, whereas epoxidation of the C9-C10 double bond or oxidation of the C15 position diminished its activity. Selected derivatives were further tested in the L1210, B16, Lewis lung, Colon 36, and Colon 38 tumor lines. Among these compounds, 4 beta, 15-diacetoxyscirpene-3,8-dione (54) and 4 beta-(chloroacetoxy)-15-acetoxyscirpene-3,8-dione (55) were found to be most active in various tumors. Inhibitory action of several analogues on protein synthesis was also examined using H-HeLa cells.
Asunto(s)
Antineoplásicos/síntesis química , Sesquiterpenos/síntesis química , Tricotecenos/síntesis química , Animales , Fenómenos Químicos , Química , Células HeLa/metabolismo , Humanos , Leucina/metabolismo , Leucemia L1210/tratamiento farmacológico , Leucemia P388/tratamiento farmacológico , Ratones , Proteínas de Neoplasias/biosíntesis , Neoplasias Experimentales/tratamiento farmacológico , Relación Estructura-Actividad , Tricotecenos/farmacologíaRESUMEN
Seven 1,5-dioxaspiro[2.5]octanes were synthesized and tested in the mouse P388 lymphocytic leukemia screen and the mouse Ehrlich ascites screen. These compounds possess the "epoxypyran" structure which has been believed to be the active portion of the trichothecene class of sesquiterpene tumor inhibitors. Three of the compounds were found to have marginal to moderate activity in the Ehrlich ascites screen (inhibition 74.1-86.3%) and low activity in the P388 screen (T/C = 126-131). A carbocyclic analogue, 1-oxaspiro[2.5]octane (9), was moderately active in both screens (inhibition 78.8%, T/C = 140). In the Ehrlich ascites screen, T-2 toxin (2) was about 25 times more potent than 9. None of the spirooctanes studied caused any skin irritation in 10-mg doses on the skin of rabbits, whereas 2 caused extensive necrosis at 0.1-mg doses.