Ghodrati F, Lavoie E J
Department of Pharmaceutical Chemistry, College of Pharmacy, Rutgers, State University of New Jersey, Piscataway 08855.
Drug Des Discov. 1994 Feb;11(2):135-47.
Hexamethylmelamine is in clinical use as an antineoplastic agent. Derivatives and prodrugs of two of its biologically-active metabolites were prepared in an effort to alter its solubility and to enhance bioavailability. In this study prodrugs of pentamethylmelamine and hydroxymethylpentamethylmelamine were synthesized. Among the compounds prepared were N-(methoxymethyl)pentamethylmelamine, N-(ethylthiomethyl)pentamethylmelamine, and several N'-alkyl-N'-methyl-N-(aminomethyl)pentamethylmelamine and N'-aryl-N'-methyl-N-(aminomethyl)pentamethylmelamine derivatives. The aqueous solubility of these prodrugs relative to hexamethylmelamine was compared. The half-lives of these prodrugs were also determined at pH 7.4. The more stable derivatives were assayed at pH 6.4. These prodrugs represent a novel approach for the delivery of the suspect active metabolite of hexamethylmelamine, hydroxymethylpentamethylmelamine.
六甲蜜胺作为一种抗肿瘤药物正在临床使用。为了改变其溶解度并提高生物利用度，制备了其两种生物活性代谢物的衍生物和前药。在本研究中，合成了五甲蜜胺和羟甲基五甲蜜胺的前药。所制备的化合物包括N-（甲氧基甲基）五甲蜜胺、N-（乙硫基甲基）五甲蜜胺以及几种N'-烷基-N'-甲基-N-（氨甲基）五甲蜜胺和N'-芳基-N'-甲基-N-（氨甲基）五甲蜜胺衍生物。比较了这些前药相对于六甲蜜胺的水溶性。还测定了这些前药在pH 7.4时的半衰期。对更稳定的衍生物在pH 6.4时进行了测定。这些前药代表了一种递送六甲蜜胺可疑活性代谢物羟甲基五甲蜜胺的新方法。
