RESUMO
We have shown that manassantin A downregulated the HIF-1alpha expression and inhibited the secretion of VEGF. We have also demonstrated that the 2,3-cis-3,4-trans-4,5-cis-configuration of the tetrahydrofuran is critical to the HIF-1 inhibition of manassantin A.
Assuntos
Furanos/química , Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Lignanas/química , Animais , Linhagem Celular , Fator 1 Induzível por Hipóxia/metabolismo , Lignanas/síntese química , Lignanas/farmacologia , Camundongos , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
A convergent route to the synthesis of manassantins A and B, potent inhibitors of HIF-1, is described. Central to the synthesis is a stereoselective addition of an organozinc reagent to a 2-benzenesulfonyl cyclic ether to achieve the 2,3-cis-3,4-trans-4,5-cis-tetrahydrofuran of the natural products. Preliminary structure-activity relationships suggested that the (R)-configuration at C-7 and C-7''' is not critical for HIF-1 inhibition. In addition, the hydroxyl group at C-7 and C-7''' can be replaced with a carbonyl group without loss of activity.
Assuntos
Éteres Cíclicos/química , Furanos/síntese química , Lignanas/síntese química , Compostos Organometálicos/química , Sulfonas/química , Zinco/química , Furanos/química , Furanos/farmacologia , Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Lignanas/química , Lignanas/farmacologia , Conformação Molecular , EstereoisomerismoRESUMO
A versatile route to the synthesis of 2,5-diaryl-3,4-dimethyltetrahydrofuran lignans, (-)-odoratisol C (1), (-)-futokadsurin A (2), (-)-veraguensin (3), (+)-fragransin A2 (4), (+)-galbelgin (5), and (+)-talaumidin (6), is described. Central to the synthesis of the lignans is BF(3) x OEt(2)-promoted deoxygenation/epimerization of the hemiketal 9a followed by stereoselective reduction of the oxocarbenium ion intermediates 8a,b.