RESUMEN
The cytotoxic activity of (-)-chlorizidineâ A, a marine alkaloid containing a unique fusion between a pyrroloisoindolone and dehydropyrrolizine, was explored by using a combination of cellular and molecular methods. Our studies began by applying preliminary SAR evidence gathered from semisynthetic bioactivity evaluations to prepare an active immunoaffinity fluorescent (IAF) probe. This probe was then used to identify two cytosolic proteins, GAPDH and hENO1, as the targets of (-)-chlorizidineâ A.
Asunto(s)
Productos Biológicos/farmacología , Biomarcadores de Tumor/metabolismo , Proteínas de Unión al ADN/metabolismo , Gliceraldehído-3-Fosfato Deshidrogenasa (Fosforilante)/metabolismo , Glucólisis/efectos de los fármacos , Alcaloides Indólicos/farmacología , Fosfopiruvato Hidratasa/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Secuencia de Aminoácidos , Productos Biológicos/química , Biomarcadores de Tumor/química , Proteínas de Unión al ADN/química , Descubrimiento de Drogas , Células HCT116 , Humanos , Alcaloides Indólicos/química , Datos de Secuencia Molecular , Terapia Molecular Dirigida , Fosfopiruvato Hidratasa/química , Proteínas/química , Proteínas/metabolismo , Streptomyces/química , Proteínas Supresoras de Tumor/químicaRESUMEN
Cultivation of an obligate marine Streptomyces strain has provided the cytotoxic natural product chlorizidine A. X-ray crystallographic analysis revealed that the metabolite is composed of a chlorinated 2,3-dihydropyrrolizine ring attached to a chlorinated 5H-pyrrolo[2,1-a]isoindol-5-one. The carbon stereocenter in the dihydropyrrolizine is S-configured. Remarkably, the 5H-pyrrolo[2,1-a]isoindol-5-one moiety has no precedence in the field of natural products. The presence of this ring system, which was demonstrated to undergo facile nucleophilic substitution reactions at the activated carbonyl group, is essential to the molecule's cytotoxicity against HCT-116 human colon cancer cells.
Asunto(s)
Antineoplásicos/aislamiento & purificación , Antineoplásicos/farmacología , Alcaloides Indólicos/aislamiento & purificación , Alcaloides Indólicos/farmacología , Streptomyces/química , Antineoplásicos/química , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Células HCT116 , Humanos , Alcaloides Indólicos/química , Biología Marina , Conformación Molecular , Estructura Molecular , EstereoisomerismoRESUMEN
Benzyl, benzoyl, and acetyl protected 1-OH and 1-SH glycoses in the glucose, glucosamine, galactose, mannose, and lactose series react with nitrobenzenes activated by one or two electron withdrawing substituents like nitro and cyano to afford the corresponding aryl glycosides in 50-100% yield. The S(N)Ar displacement of nitrite by 1-OH glycoses is reversible and gives predominantly the alpha-glycosides, whereas 1-SH glycoses do not anomerize and afford the beta-glycosides. Thus, the prepared dicyanophenyl gycosides are useful building blocks for the preparation of phthalocyanine-glycoconjugates via template synthesis.
Asunto(s)
Glicósidos/síntesis química , Nitritos/química , Nitrobencenos/química , Glicosilación , Indoles/química , IsoindolesRESUMEN
A new synthetic method providing expedient access to a wide range of polyfunctionalized N-hydroxyindoles (IV) is reported. These unique constructs are assembled by nucleophilic additions to in situ generated α,ß-unsaturated nitrones (III) through carbon-carbon and carbon-heteroatom bond formation. The new synthetic technology was applied to the synthesis of nocathiacin I (1) model systems (2 and 3a-c) containing the N-hydroxyindole structural motif.