Pettit G R, Lippert J W
Cancer Research Institute and Department of Chemistry and Biochemistry, Arizona State University, Tempe 85287-2404, USA.
Anticancer Drug Des. 2000 Jun;15(3):203-16.
The original synthesis of combretastatin A-1 (1) was modified to allow an efficient scale-up procedure for obtaining this anti-neoplastic stilbene. Subsequent conversion to a useful prodrug was accomplished by diphosphorylation (to 10), with in situ formation of dibenzylchlorophosphite, followed by cleavage of the benzyl ester protecting groups with trimethyliodosilane. The phosphoric acid intermediate was treated with sodium methoxide to complete a practical route to the sodium phosphate prodrug (4). Selective hydrogenation of phosphate 10 and treatment of the product with sodium methoxide led to combretastatin B-1 prodrug (5). The phosphoric acid precursor of prodrug 4 was employed in a parallel series of reactions to produce a selection of metal and ammonium cation prodrug candidates. Each of the phosphate salts was evaluated from the perspective of relative solubility behavior and cancer cell growth inhibition. The sodium phosphate prodrug of combretastatin A-1 (4) was selected for detailed antineoplastic studies.
对康普他汀A-1（1）的原始合成方法进行了改进，以实现一种高效的放大工艺来制备这种抗肿瘤的芪类化合物。随后通过二磷酸化（生成10）将其转化为一种有用的前药，原位生成二苄基氯亚磷酸酯，然后用三甲基碘硅烷裂解苄酯保护基团。用甲醇钠处理磷酸中间体，完成了制备磷酸钠前药（4）的实用路线。对磷酸盐10进行选择性氢化，并用甲醇钠处理产物，得到康普他汀B-1前药（5）。前药4的磷酸前体用于一系列平行反应，以制备多种金属和铵阳离子前药候选物。从相对溶解行为和癌细胞生长抑制的角度对每种磷酸盐进行了评估。选择康普他汀A-1的磷酸钠前药（4）进行详细的抗肿瘤研究。
