PROTONATION OF PHOSPHORAMIDE MUSTARD AND OTHER PHOSPHORAMIDES

被引:25
作者
GAMCSIK, MP
LUDEMAN, SM
SHULMANROSKES, EM
MCLENNAN, IJ
COLVIN, ME
COLVIN, OM
机构
[1] JOHNS HOPKINS UNIV,SCH MED,DEPT RADIOL,BALTIMORE,MD 21205
[2] JOHNS HOPKINS UNIV,SCH MED,CTR ONCOL,BALTIMORE,MD 21205
[3] DALHOUSIE UNIV,DEPT CHEM,HALIFAX B3H 4J3,NS,CANADA
[4] SANDIA NATL LABS,CTR COMPUTAT ENGN,LIVERMORE,CA 94551
关键词
D O I
10.1021/jm00075a019
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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 P-31 and N-15 resonances for phosphoramide mustard displayed a single monobasic titration curve with a pK(a) of 4.9. The protonation below pH 4.9 correlates with the loss in reactivity of the mustard. The O-17 NMR spectrum of O-17-enriched phosphoramide mustard shows little change with pH. The data on the mustard was compared to N-15 and P-31 NMR data on N-15-enriched phosphoramidic acid, phosphorodiamidic acid, and phosphoric triamide. Contrary to the conclusions of previous studies, our combined P-31, N-15, and O-17 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.
引用
收藏
页码:3636 / 3645
页数:10
相关论文
共 50 条
[1]   TABLES OF BOND LENGTHS DETERMINED BY X-RAY AND NEUTRON-DIFFRACTION .1. BOND LENGTHS IN ORGANIC-COMPOUNDS [J].
ALLEN, FH ;
KENNARD, O ;
WATSON, DG ;
BRAMMER, L ;
ORPEN, AG ;
TAYLOR, R .
JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 2, 1987, (12) :S1-S19
[2]   N-15 NUCLEAR MAGNETIC-RESONANCE SPECTROSCOPY - STATE OF HISTIDINE IN CATALYTIC TRIAD OF ALPHA-LYTIC PROTEASE - IMPLICATIONS FOR CHARGE-RELAY MECHANISM OF PEPTIDE-BOND CLEAVAGE BY SERINE PROTEASES [J].
BACHOVCHIN, WW ;
ROBERTS, JD .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1978, 100 (26) :8041-8047
[3]   NUCLEAR MAGNETIC-RESONANCE INVESTIGATION OF N-15-LABELED HISTIDINE IN AQUEOUS-SOLUTION [J].
BLOMBERG, F ;
MAURER, W ;
RUTERJANS, H .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1977, 99 (25) :8149-8159
[4]   P-31-NMR STUDIES OF THE KINETICS OF BISALKYLATION BY ISOPHOSPHORAMIDE MUSTARD - COMPARISONS WITH PHOSPHORAMIDE MUSTARD [J].
BOAL, JH ;
WILLIAMSON, M ;
BOYD, VL ;
LUDEMAN, SM ;
EGAN, W .
JOURNAL OF MEDICINAL CHEMISTRY, 1989, 32 (08) :1768-1773
[5]   EXPERIMENTAL AND THEORETICAL-STUDIES OF THE GAS-PHASE PROTONATION OF ALIPHATIC PHOSPHINE OXIDES AND PHOSPHORAMIDES [J].
BOLLINGER, JC ;
HOURIET, R ;
KERN, CW ;
PERRET, D ;
WEBER, J ;
YVERNAULT, T .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1985, 107 (19) :5352-5358
[6]  
BROCK N, 1977, Zeitschrift fuer Krebsforschung und Klinische Onkologie, V88, P185
[7]   REACTION KINETICS OF ALIPHATIC TERTIARY BETA-CHLOROETHYLAMINES IN DILUTE AQUEOUS SOLUTION .1. THE CYCLIZATION PROCESS [J].
COHEN, B ;
VANARTSDALEN, ER ;
HARRIS, J .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1948, 70 (01) :281-285
[8]  
COLVIN M, 1976, CANCER RES, V36, P1121
[9]  
COLVIN ME, UNPUB
[10]  
COLVIN ME, 1993, SAND938239 SAND NAT, P1