RESUMEN
Potent antagonists of the integrin α(5)ß(1), which are RGD mimetics built from tyrosine are described. This letter describes the optimization of in vitro potency obtained by variation of two parts of the molecule, the basic group and the linker between the basic group and the phenyl central core.
Asunto(s)
Integrina alfa5beta1/antagonistas & inhibidores , Oligopéptidos/síntesis química , Tirosina/análogos & derivados , Tirosina/síntesis química , Adhesión Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Fibrinógeno/química , Fibronectinas/química , Humanos , Integrina alfa5beta1/metabolismo , Células K562 , Modelos Moleculares , Imitación Molecular , Oligopéptidos/farmacología , Albúmina Sérica/química , Relación Estructura-Actividad , Tirosina/farmacologíaRESUMEN
Potent antagonists of the integrin α(5)ß(1), which are RGD mimetics built from tyrosine are described. This paper describes the optimization of in vitro potency obtained by variation of two parts of the molecule, the central aromatic core and the amide moiety.
Asunto(s)
Integrina alfa5beta1/antagonistas & inhibidores , Oligopéptidos/síntesis química , Tirosina/análogos & derivados , Tirosina/síntesis química , Adhesión Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Fibrinógeno/química , Fibronectinas/química , Humanos , Integrina alfa5beta1/metabolismo , Células K562 , Modelos Moleculares , Imitación Molecular , Oligopéptidos/farmacología , Albúmina Sérica/química , Relación Estructura-Actividad , Tirosina/farmacologíaRESUMEN
Simple organocopper reagents are shown to undergo anti-stereoselective 1,4-addition to menthyloxy-substituted lactone 1 in the presence of BF3.OEt2; the Lewis acid causes partial epimerisation of the acetal centre after conjugate addition. Enolate alkylation of the adducts leads to di- and trisubstituted lactones that are converted, in favourable cases, into di- and trisubstituted cyclopentenones.