RESUMEN
The first example of one-electron oxidation of thia-bridged triarylamine heterohelicenes to the corresponding exceptionally stable radical cations, fully characterized, as hexafluoroantimonate salts, by means of UV-Vis, EPR, ENDOR, density functional theory calculations and X-ray analyses, is reported. Chemical and electrochemical reversible redox processes are solidly demonstrated.
RESUMEN
The aim of this study was to demonstrate that oligo-branched peptides can be effective either for spotlighting tumor cells that overexpress peptide receptors, or for killing them, simply by exchanging the functional moiety coupled to the conserved receptor-targeting core. Tetra-branched peptides containing neurotensin (NT) sequence are described here as selective targeting agents for human colon, pancreas and prostate cancer. Fluorophore-conjugated peptides were used to measure tumor versus healthy tissue binding in human surgical samples, resulting in validation of neurotensin receptors as highly promising tumor-biomarkers. Drug-armed branched peptides were synthesized with different conjugation methods, resulting in uncleavable adducts or drug-releasing molecules. Cytotoxicity on human cell lines from colon (HT-29), pancreas (PANC-1) or prostate (PC-3) carcinoma indicated branched NT conjugated with MTX and 5-FdU as the most active agents on PANC-1 (EC(50) 4.4e-007 M) and HT-29 (1.1e-007 M), respectively. Tetra-branched NT armed with 5-FdU was used for in vivo experiments in HT-29-xenografted mice and produced a 50% reduction in tumor growth with respect to animals treated with the free drug. An unrelated branched peptide carrying the same drug was completely ineffective. In vitro and in vivo results indicated that branched peptides are valuable tools for tumor selective targeting.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias del Colon/tratamiento farmacológico , Portadores de Fármacos/farmacología , Neurotensina/análogos & derivados , Oligopéptidos/farmacología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias de la Próstata/tratamiento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Anciano , Anciano de 80 o más Años , Animales , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/uso terapéutico , Transporte Biológico , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Portadores de Fármacos/uso terapéutico , Femenino , Humanos , Concentración 50 Inhibidora , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Oligopéptidos/química , Oligopéptidos/metabolismo , Oligopéptidos/uso terapéutico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Neoplasias de la Próstata/metabolismo , Receptores de Péptidos/metabolismo , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
2,3-dihydrobenzo[b][1,4]oxathiine represents a valuable pharmacophoric heterocyclic nucleus known since very long time. Initially, together with some patents reporting the use of these compounds as herbicides or lipogenesis inhibitors, several papers reported their ability as melatonin, histamine and serotonin receptor ligands, alpha-adrenoreceptor blockers as well as non-glycoside sweeteners. This wide range of biological activities has been recently further improved by studies stating their activity as antimycotics, multi-defense antioxidants and estrogen receptor ligands. The last insights regarding the preparation, the biological activity and the structure activity relationship (SAR) of derivatives containing the dihydrobenzoxathiine skeleton will be discussed in this review.
Asunto(s)
Antagonistas Adrenérgicos alfa/química , Herbicidas/química , Compuestos Heterocíclicos/química , Oxatiinas/química , Antagonistas Adrenérgicos alfa/síntesis química , Antagonistas Adrenérgicos alfa/farmacología , Antiinfecciosos/síntesis química , Antiinfecciosos/química , Antiinfecciosos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Antioxidantes/síntesis química , Antioxidantes/química , Antioxidantes/farmacología , Herbicidas/síntesis química , Herbicidas/farmacología , Oxatiinas/síntesis química , Oxatiinas/farmacología , Receptores de Estrógenos/química , Receptores de Estrógenos/metabolismo , Edulcorantes/síntesis química , Edulcorantes/química , Edulcorantes/farmacologíaRESUMEN
BACKGROUND AND PURPOSE: Maintenance of poly(ADP-ribose) (PAR) polymers at homoeostatic levels by PAR glycohydrolase (PARG) is central in cell functioning and survival. Yet the pharmacological relevance of PARG inhibitors is still debated. Gallotannin, a complex mixture of hydrolysable tannins from oak gall, inhibits PARG but which of its constituents is responsible for the inhibition and whether the pharmacodynamic properties are due to its antioxidant properties, has not yet been established. EXPERIMENTAL APPROACH: A structure-activity relationship study was conducted on different natural and synthetic tannins/galloyl derivatives as potential PARG inhibitors, using a novel in vitro enzymic assay. Cytotoxicity was assayed in cultured HeLa cells. KEY RESULTS: Mono-galloyl glucose compounds were potent inhibitors of PARG, with activities similar to that of ADP-(hydroxymethyl) pyrrolidinediol, the most potent PARG inhibitor yet identified. When tested on HeLa cells exposed to the PAR polymerase (PARP)-1-activating compound 1-methyl-3-nitro-1-nitrosoguanidine (MNNG), 3-galloyl glucose weakly inhibited PAR degradation. Conversely, the more lipophilic, 3-galloyl-1,2-O-isopropylidene glucose, despite being inactive on the pure enzyme, efficiently prolonged the half-life of the polymers in intact HeLa cells. Also, PARG inhibitors, but not radical scavengers, reduced, in part, cell death caused by MNNG. CONCLUSIONS AND IMPLICATIONS: Taken together, our findings identify mono-galloyl glucose derivatives as potent PARG inhibitors, and emphasize the active function of this enzyme in cell death.
Asunto(s)
Muerte Celular/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Glicósido Hidrolasas/antagonistas & inhibidores , Taninos Hidrolizables/farmacología , Poli(ADP-Ribosa) Polimerasas/metabolismo , Cromatografía Líquida de Alta Presión , Células HeLa , Humanos , Espectroscopía de Resonancia Magnética , Espectrometría de Masa por Ionización de Electrospray , Relación Estructura-ActividadRESUMEN
The synthesis of "naked" ellagitannin analogues 1 and 2, having a preferred sense of twist of the diphenyl moiety, with a rhamnose and a glucose template, is reported. A clear induction in the chirality of the diphenyl moiety, mediated through a 10-membered ring via ester linkages, was observed. The chiral scaffold of glucose (diequatorial 2,3-hydroxyl groups) exerts a remarkable stronger atropdiastereoselective effect onto the diphenoyl group than the rhamnose ring (axial-equatorial 2,3-hydroxyl groups), according to the Schmidt-Haslam hypothesis.
Asunto(s)
Compuestos de Bifenilo/química , Carbohidratos/química , Taninos Hidrolizables , Taninos/síntesis química , Dicroismo Circular , Indicadores y Reactivos , Espectrofotometría Ultravioleta , EstereoisomerismoRESUMEN
We extracted, purified and characterized 8 sesquiterpene fractions from Commyphora molmol. In particular, we focused our attention on a mixture of furanodiene-6-one and methoxyfuranoguaia-9-ene-8-one, which showed antibacterial and antifungal activity against standard pathogenic strains of Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and Candida albicans, with minimum inhibitory concentrations ranging from 0.18 to 2.8 micrograms/ml. These compounds also had local anaesthetic activity, blocking the inward sodium current of excitable mammalian membranes.
Asunto(s)
Anestésicos/farmacología , Antibacterianos/farmacología , Antifúngicos/farmacología , Sesquiterpenos/farmacología , Terpenos/química , Animales , Bacterias/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Ratas , Ratas Wistar , Sesquiterpenos/aislamiento & purificaciónRESUMEN
[reaction: see text] Glycals are effective starting materials for the synthesis of enantiopure beta-ketone-delta-lactones. They are easily transformed, through a two-step, one-pot reaction, into the corresponding alpha,alpha'-dioxothiones which in turn can be quantitatively trapped with dienophiles in inverse electron-demand [4 + 2] cycloadditions. The reaction of dioxothione 8b with endo and exo glucals allowed the elaboration of a new protocol to prepare 2-thio- or 2-deoxydisaccharides stereoselectively.
RESUMEN
[formula: see text] This letter describes the reduction to practice of a novel concept for functionalization of the anomeric carbon of carbohydrates with a nitrogen substituent. Thus, bisheterodienes with a thiono sulfur terminus and a sulfonylimine terminus are shown to undergo cycloaddition smoothly and stereoselectively to three different glycals.