Steinberg G, Borch R F
Department of Medicinal Chemistry and Molecular Pharmacology and the Cancer Center, Purdue University, West Lafayette, Indiana 47907, USA.
J Med Chem. 2001 Jan 4;44(1):69-73. doi: 10.1021/jm000306g.
A novel nitroheterocyclic bis(haloethyl)phosphoramidate prodrug linked through lysine to a pteroic acid has been prepared and evaluated as a potential alkylating agent to target tumor cells that overexpress the folate receptor. The prodrug exhibited IC(50) values in the micromolar range and was 10-400-fold less cytotoxic in vitro than the phosphoramidate that lacks the lysine-pteroyl moiety. The data does not support a contribution of the folate receptor to cytotoxicity. In an attempt to determine the basis for the decreased cytotoxicity in the pteroyl-lysyl analogue, compounds were prepared in which the lysine-pteroyl moiety was replaced with lysine alone or with an n-propyl group. The n-propyl and the lysyl analogues were on average 3.8- and 21-fold less potent than the unsubstituted bis(haloethyl)phosphoramidate, respectively. Chemical reduction of the prodrugs followed by (31)P NMR kinetics demonstrated that all of the phosphoramidate anions cyclized to the aziridinium ion at similar rates and gave comparable product distributions, suggesting that changes in chemical activation did not account for the differences in cytotoxicity. It is likely that folate receptor-mediated transport is not sufficient to deliver adequate intracellular concentrations of the cytotoxic phosphoramide mustard.
一种新型的通过赖氨酸连接到蝶酸的硝基杂环双（卤代乙基）磷酰胺酯前药已被制备，并被评估为一种潜在的烷基化剂，用于靶向过度表达叶酸受体的肿瘤细胞。该前药的半数抑制浓度（IC₅₀）值在微摩尔范围内，在体外其细胞毒性比缺乏赖氨酸 - 蝶酰部分的磷酰胺酯低10 - 400倍。数据不支持叶酸受体对细胞毒性有贡献。为了确定蝶酰 - 赖氨酰类似物细胞毒性降低的原因，制备了一些化合物，其中赖氨酸 - 蝶酰部分分别被单独的赖氨酸或正丙基取代。正丙基和赖氨酰类似物的效力分别比未取代的双（卤代乙基）磷酰胺酯平均低3.8倍和21倍。前药经化学还原后通过³¹P NMR动力学表明，所有磷酰胺酯阴离子以相似的速率环化形成氮丙啶离子，并给出相当的产物分布，这表明化学活化的变化不能解释细胞毒性的差异。叶酸受体介导的转运可能不足以提供足够的细胞内细胞毒性磷酰胺氮芥浓度。
