RESUMO
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.
Assuntos
Produtos Biológicos/farmacologia , Biomarcadores Tumorais/metabolismo , Proteínas de Ligação a DNA/metabolismo , Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora)/metabolismo , Glicólise/efeitos dos fármacos , Alcaloides Indólicos/farmacologia , Fosfopiruvato Hidratase/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Sequência de Aminoácidos , Produtos Biológicos/química , Biomarcadores Tumorais/química , Proteínas de Ligação a DNA/química , Descoberta de Drogas , Células HCT116 , Humanos , Alcaloides Indólicos/química , Dados de Sequência Molecular , Terapia de Alvo Molecular , Fosfopiruvato Hidratase/química , Proteínas/química , Proteínas/metabolismo , Streptomyces/química , Proteínas Supressoras de Tumor/químicaRESUMO
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.
Assuntos
Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Alcaloides Indólicos/isolamento & purificação , Alcaloides Indólicos/farmacologia , Streptomyces/química , Antineoplásicos/química , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Alcaloides Indólicos/química , Biologia Marinha , Conformação Molecular , Estrutura Molecular , EstereoisomerismoRESUMO
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.
Assuntos
Glicosídeos/síntese química , Nitritos/química , Nitrobenzenos/química , Glicosilação , Indóis/química , IsoindóisRESUMO
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.
