erbB-2 oncogene inhibition by geldanamycin derivatives: synthesis, mechanism of action, and structure-activity relationships

摘要: Overexpression of the erbB-2 oncogene has been linked to poor prognosis in breast, ovarian, and gastric cancers. Naturally occurring benzoquinoid ansamycin antibiotics herbimycin A, geldanamycin (GDM), dihydrogeldanamycin were found potently deplete p185, oncoprotein, human breast cancer SKBR-3 cells culture. Chemistry efforts modify selectively ansa ring GDM afforded derivatives with greater potency vitro vivo. Analogs demonstrated inhibition p185 phosphotyrosine cell culture vivo after systemic drug administration nu/nu nude mice bearing Fisher rat embryo transfected erbB-2. Functional group modification was performed stereoselectively regiospecifically without need for protection strategies. Essential functional groups that required anti-erbB-2 activity 7-carbamate 2,3-double bond. Modification at other positions permitted. Structure-activity relationships are described 1-5-, 7-9-, 11-, 15-, 22-substituted geldanamycins.