Jiang Yongying, Hu Longqin
Department of Pharmaceutical Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
Bioorg Med Chem Lett. 2007 Jan 15;17(2):517-21. doi: 10.1016/j.bmcl.2006.10.017. Epub 2006 Oct 12.
4-Aminocyclophosphamide (4-NH2-CPA, 7) was proposed as a prodrug moiety of phosphoramide mustard. Four diastereomers of phenylalanine-conjugates of 4-NH2-CPA were synthesized and their stereochemistry was assigned based on chromatographic and spectroscopic data. All diastereomers were stable in phosphate buffer but only the cis-(4R)-isomer of 15 was efficiently cleaved by alpha-chymotrypsin with a half-life of 20 min, which is much shorter than the 8.9h to >12h half-lives found for the other diastereomers. LC-MS analysis of the proteolytic products of cis-(4R)-15 indicated that 4-NH2-CPA was released upon proteolysis and further disintegrated to phosphoramide mustard. These results suggest the feasibility of using peptide-conjugated cis-(4R)-4-NH2-CPA as potential prodrugs for proteolytic activation in tumor tissues.
4-氨基环磷酰胺（4-NH2-CPA，7）被提议作为磷酰胺氮芥的前药部分。合成了4-NH2-CPA的苯丙氨酸共轭物的四种非对映异构体，并根据色谱和光谱数据确定了它们的立体化学结构。所有非对映异构体在磷酸盐缓冲液中均稳定，但只有15的顺式-（4R）-异构体能被α-胰凝乳蛋白酶有效裂解，半衰期为20分钟，这比其他非对映异构体的8.9小时至>12小时的半衰期短得多。顺式-（4R）-15蛋白水解产物的LC-MS分析表明，4-NH2-CPA在蛋白水解时释放，并进一步分解为磷酰胺氮芥。这些结果表明使用肽共轭的顺式-（4R）-4-NH2-CPA作为肿瘤组织中蛋白水解激活的潜在前药的可行性。
