Murdock K C, Lee V J, Citarella R V, Durr F E, Nicolau G, Kohlbrenner M
American Cyanamid Company, Medical Research Division, Pearl River, New York 10965.
J Med Chem. 1993 Jul 23;36(15):2098-101. doi: 10.1021/jm00067a007.
The selective phosphorylation of bisantrene (1) affords bis(phosphonoguanidinic acid) 6, a prodrug with enhanced aqueous solubility (as sodium salt 7) at physiological pH. Unlike 1, in a rat tail vein model, no precipitation was observed when bis(phosphonoguanidinic acid) 6 was injected. While in rats 6 hydrolyzed to monophosphonoguanidinic acid 9 with a half-life of ca. 12 min., complete hydrolysis to bisantrene required several hours. The corresponding monophosphonoguanidinic acid 9 was synthesized from bisantrene and also showed good solubility and antitumor activity. While the antitumor activities of 6 in mice were comparable to bisantrene against B-16 melanoma and P-388 and L-1210 leukemias, it was inactive in vitro vs several tumor cell types. Thus, its activity in vivo resulted from its ability to serve as a prodrug for bisantrene.
双膦腈蒽（1）的选择性磷酸化得到双（膦酰胍基酸）6，它是一种前药，在生理pH值下具有增强的水溶性（作为钠盐7）。与1不同，在大鼠尾静脉模型中，注射双（膦酰胍基酸）6时未观察到沉淀。虽然在大鼠体内6水解为单膦酰胍基酸9，半衰期约为12分钟，但完全水解为双膦腈蒽需要数小时。相应的单膦酰胍基酸9由双膦腈蒽合成，也显示出良好的溶解性和抗肿瘤活性。虽然6在小鼠体内对B-16黑色素瘤、P-388和L-1210白血病的抗肿瘤活性与双膦腈蒽相当，但它在体外对几种肿瘤细胞类型无活性。因此，它在体内的活性源于其作为双膦腈蒽前药的能力。
