Foster A B, Jarman M, Kinas R W, van Maanen J M, Taylor G N, Gaston J L, Parkin A, Richardson A C
J Med Chem. 1981 Dec;24(12):1399-403. doi: 10.1021/jm00144a006.
In seeking analogues of cyclophosphamide (1) having improved antitumor activity by virtue of accelerated formation of the cytotoxic metabolite phosphoramide mustard, cis and trans isomers of 5-fluoro- and 5-chlorocyclophosphamide (9, 10, 11 and 12, respectively) were synthesized by condensation of the appropriate 3-amino-2-halopropan-1-ol (13 or 26) with N,N-bis(2-chloroethyl)phosphoramidic dichloride (14). The metabolism of the halocyclophosphamides by rat liver microsomes was stereoselective; the cis isomers (9 and 11) were poorly metabolized, whereas the trans isomers (10 and 12) were metabolized with efficiency comparable to that of cyclophosphamide. However, there was no evidence that the yield of phosphoramide mustard produced by the trans analogues were significantly greater than that from cyclophosphamide following microsomal 4-hydroxylation. Hence, the halogen substituents did not accelerate beta-elimination of acrolein from the acyclic aldehydo tautomers. As expected, the poorly metabolized cis-5-fluoride (9) had little activity against the ADJ/PC6 tumor in mice. However, the cis-5-chloride (11) was as active as the trans isomer (12) and each had approximately half the therapeutic index of 1. The trans-5-fluoride (10) was much less active, having an ED90 value some 16-fold that of 1.
为了寻找具有改善的抗肿瘤活性的环磷酰胺（1）类似物，这些类似物通过加速细胞毒性代谢物磷酰胺氮芥的形成而起作用，5-氟环磷酰胺和5-氯环磷酰胺的顺式和反式异构体（分别为9、10、11和12）通过合适的3-氨基-2-卤代丙醇（13或26）与N,N-双（2-氯乙基）磷酰胺二氯（14）缩合而合成。大鼠肝微粒体对卤代环磷酰胺的代谢具有立体选择性；顺式异构体（9和11）代谢较差，而反式异构体（10和12）的代谢效率与环磷酰胺相当。然而，没有证据表明微粒体4-羟基化后反式类似物产生的磷酰胺氮芥产量明显高于环磷酰胺。因此，卤素取代基并未加速无环醛式互变异构体中丙烯醛的β消除。正如预期的那样，代谢较差的顺式-5-氟化物（9）对小鼠的ADJ/PC6肿瘤几乎没有活性。然而，顺式-5-氯化物（11）与反式异构体（12）活性相当，且它们的治疗指数均约为1的一半。反式-5-氟化物（10）活性低得多，其ED90值约为1的16倍。
