RESUMEN
A new bioactive saponin (1), together with a known saponin (polygalasaponin XXVIII) has been isolated from the callus tissue culture of Polygala amarella. Based on spectroscopic data, especially direct and long-range heteronuclear 2D NMR analysis and on chemical transformations, the structure of 1 was elucidated as 3-O-beta-D-glucopyranosyl presenegenin-28-O-beta-D-galactopyranosyl-(1 --> 3)-beta-D-xylopyranosyl-(1 --> 4)-alpha-L-rhamnopyranosyl-(1 --> 2)-[beta-D-glucopyranosyl-(1 --> 3)]-beta-D-fucopyranoside. Both saponins showed significant immunological properties based on the enhancement of granulocyte phagocytosis in vitro.
Asunto(s)
Adyuvantes Inmunológicos/aislamiento & purificación , Ácido Oleanólico/análogos & derivados , Plantas Medicinales/química , Saponinas/aislamiento & purificación , Adyuvantes Inmunológicos/farmacología , Secuencia de Carbohidratos , Cromatografía de Gases , Europa (Continente) , Granulocitos/efectos de los fármacos , Granulocitos/inmunología , Humanos , Hidrólisis , Técnicas In Vitro , Espectroscopía de Resonancia Magnética , Datos de Secuencia Molecular , Fagocitosis/efectos de los fármacos , Saponinas/farmacología , Semillas/química , Espectrometría de Masa Bombardeada por Átomos Veloces , Espectrofotometría Infrarroja , Espectrofotometría UltravioletaRESUMEN
New prodrugs consisting of a beta-D-glucuronic acid linked to a MDR reversal agent (verapamil, quinine or dipyridamole) through a self-immolative spacer were synthesized. Four of them were selected for their reduced cytoxicity and beta-glucuronidase enzymatic efficient hydrolysis. Combined use of these prodrugs with a beta-D-glucuronyl-spacer-doxorubicin (HMR1826) according to an ADEPT strategy restored in vitro the sensibility of a MDR resistant strain.
Asunto(s)
Antineoplásicos/síntesis química , Profármacos/síntesis química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Cromatografía Líquida de Alta Presión , Dipiridamol/química , Dipiridamol/farmacología , Doxorrubicina/química , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Estabilidad de Medicamentos , Escherichia coli/enzimología , Glucuronatos/química , Ácido Glucurónico , Glucuronidasa/química , Humanos , Hidrólisis , Leucemia L1210/patología , Profármacos/química , Profármacos/farmacología , Quinina/química , Quinina/farmacología , Espectrofotometría Ultravioleta , Relación Estructura-Actividad , Células Tumorales Cultivadas , Verapamilo/química , Verapamilo/farmacologíaRESUMEN
The three new hydrophilic prodrugs 2, 3 and 4 have been prepared from methyl (4-hydroxymethyl-2-nitrophenyl 2,3,4-tri-O-acetyl-beta-D-glucopyranosid)uronate (5) and doxorubicin. Their low cytotoxicity, efficient release of doxorubicin after hydrolysis by beta-D-glucuronidase, and in the cases of 2 and 3 stability at pH 7.2 fulfil the preliminary requirement for their use in antibody-directed enzyme prodrug therapy or prodrug monotherapy.
