Schnur R C, Corman M L, Gallaschun R J, Cooper B A, Dee M F, Doty J L, Muzzi M L, DiOrio C I, Barbacci E G, Miller P E
Pfizer Central Research, Groton, Connecticut 06340, USA.
J Med Chem. 1995 Sep 15;38(19):3813-20. doi: 10.1021/jm00019a011.
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), and dihydrogeldanamycin were found to potently deplete p185, the erbB-2 oncoprotein, in human breast cancer SKBR-3 cells in culture. Chemistry efforts to modify selectively the ansa ring of GDM afforded derivatives with greater potency in vitro and in vivo. Analogs demonstrated inhibition of p185 phosphotyrosine in cell culture and in vivo after systemic drug administration to nu/nu nude mice bearing Fisher rat embryo cells transfected with human erbB-2. Functional group modification in the ansa ring was performed stereoselectively and regiospecifically without the need for protection strategies. Essential functional groups that were required for anti-erbB-2 activity were the 7-carbamate and the 2,3-double bond. Modification of the functional groups at the other positions was permitted. Structure-activity relationships are described for 1-5-, 7-9-, 11-, 15-, and 22-substituted geldanamycins.
erbB-2癌基因的过表达与乳腺癌、卵巢癌和胃癌的不良预后相关。天然存在的苯醌型安莎霉素类抗生素赫比霉素A、格尔德霉素（GDM）和二氢格尔德霉素被发现能有效降低培养的人乳腺癌SKBR-3细胞中erbB-2癌蛋白p185的水平。对GDM的安莎环进行选择性修饰的化学研究得到了在体外和体内具有更高活性的衍生物。类似物在细胞培养中以及对携带转染了人erbB-2的Fisher大鼠胚胎细胞的裸鼠进行全身给药后，在体内均显示出对p185磷酸酪氨酸的抑制作用。安莎环上的官能团修饰是立体选择性和区域特异性的，无需保护策略。抗erbB-2活性所需的关键官能团是7-氨基甲酸酯和2,3-双键。允许对其他位置的官能团进行修饰。描述了1-5-、7-9-、11-、15-和22-取代格尔德霉素的构效关系。
