Szekerke M
Cancer Treat Rep. 1976 Apr;60(4):347-54.
The possibilities offered by a combination of the "latency" and "carrier" principles were studied by joining the phosphoramide mustard group with amino acids. The structures of the resulting derivatives are reminiscent of cyclophosphamide, but they provide feasibility for stereoisomeric modifications and for incorporation into synthetic peptides. Modlel peptides with a different ring system containing cyclic diesters of the N,N-bis(2-chloroethyl)phosphoramidic acid were also constructed. The relative intensities of antitumor activity, toxicity, and antitumor spectrum can be influenced by these molecular manipulations, indicating that the pharmacokinetics, and probably even the enzymatic activation, are markedly dependent upon the overall physiochemical properties and stereochemistry of the molecule. Another approach has been to use larger molecular weight materials as carriers either of the phosphoramide mustard group or the cyclic amino acid derivatives. Both noncovalent and covalent linkages were tried; based on stability properties, conjugates must be regarded as more adequate potential candidates for lysosomotropism.
通过将磷酰胺氮芥基团与氨基酸结合，研究了“潜伏”和“载体”原理相结合所带来的可能性。所得衍生物的结构让人联想到环磷酰胺，但它们为立体异构修饰以及并入合成肽提供了可行性。还构建了具有不同环系的模型肽，该环系包含N，N - 双（2 - 氯乙基）磷酰胺酸的环状二酯。这些分子操作可影响抗肿瘤活性、毒性和抗肿瘤谱的相对强度，这表明药代动力学，甚至可能还有酶促活化，都明显依赖于分子的整体物理化学性质和立体化学。另一种方法是使用更大分子量的材料作为磷酰胺氮芥基团或环状氨基酸衍生物的载体。尝试了非共价和共价连接；基于稳定性，结合物必须被视为更合适的潜在溶酶体趋向性候选物。
