Gamcsik M P, Ludeman S M, Shulman-Roskes E M, McLennan I J, Colvin M E, Colvin O M
Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
J Med Chem. 1993 Nov 12;36(23):3636-45. doi: 10.1021/jm00075a019.
The chemistry of the bifunctional alkylating agent phosphoramide mustard and model phosphoramides was probed by multinuclear NMR spectroscopy as a function of pH. Between pH 1 and 11, both the 31P and 15N resonances for phosphoramide mustard displayed a single monobasic titration curve with a pKa of 4.9. The protonation below pH 4.9 correlates with the loss in reactivity of the mustard. The 17O NMR spectrum of 17O-enriched phosphoramide mustard shows little change with pH. The data on the mustard was compared to 15N and 31P NMR data on 15N-enriched phosphoramidic acid, phosphorodiamidic acid, and phosphoric triamide. Contrary to the conclusions of previous studies, our combined 31P, 15N, and 17O NMR results are more consistent with N-protonation of phosphoramide mustard rather than an O-protonation. Theoretical calculations on the phosphoramidic acid, phosphorodiamidic acid, and phosphoric triamide show O-protonation to be more stable in the gas phase. For the latter two compounds, the calculations suggest that N-protonation may be the most stable protonated form in the aqueous phase. These findings influence our understanding of the structure-activity relationships of phosphoramide mustards.
通过多核核磁共振光谱研究了双功能烷基化剂磷酰胺芥和模型磷酰胺的化学性质与pH值的关系。在pH值1至11之间，磷酰胺芥的31P和15N共振均显示出单一的一元滴定曲线，pKa为4.9。pH值低于4.9时的质子化与芥子气反应活性的丧失相关。富含17O的磷酰胺芥的17O核磁共振谱随pH值变化不大。将芥子气的数据与富含15N的磷酰胺酸、二磷酰胺酸和磷酸三酰胺的15N和31P核磁共振数据进行了比较。与先前研究的结论相反，我们结合31P、15N和17O核磁共振的结果更符合磷酰胺芥的N-质子化而非O-质子化。对磷酰胺酸、二磷酰胺酸和磷酸三酰胺的理论计算表明，O-质子化在气相中更稳定。对于后两种化合物，计算表明N-质子化可能是水相中最稳定的质子化形式。这些发现影响了我们对磷酰胺芥结构-活性关系的理解。
