Synthesis and antitumor activity of cyclophosphamide analogues. 4. Preparation, kinetic studies, and anticancer screening of "phenylketophosphamide" and similar compounds related to the cyclophosphamide metabolite aldophosphamide.
Phenyl ketone phosphorodiamidates [C6H5C(O)CH2CH2OP(O)NHR1NR2R3] were synthesized in conjunction with an ongoing investigation into the effects of substituents on the dynamical solution chemistry of the metabolites of cyclophosphamide (1a). In contrast to aldophosphamide (3a), which readily interconverts with its cyclic isomer 4-hydroxycyclophosphamide (2a), phenylketophosphamide (14a: R1 = H, R2 = R3 = CH2CH2Cl) exhibited an apparent "resistance" toward an intramolecular addition reaction such that 4-hydroxy-4-phenylcyclophosphamide (13a) could not be detected either spectroscopically (31P or 13C NMR) or chemically (NaCN trapping experiment). Control studies that compared the relative reactivities of 14a and methylketophosphamide [20: CH3C(O)CH2CH2OP(O)NH2N-(CH2CH2Cl)2] revealed that the factors that modulate the ring closure/opening reactions were not peculiar to the phenyl group; however, differences between phenyl and methyl profoundly influenced the rates of fragmentation of 14a and 20. 31P NMR spectroscopy was used to determine the rates at which each compound generated a cytotoxic alkylating agent. Under a standard set of reaction conditions [1 M lutidine buffer with added Me2SO (8:2), pH 7.4, 37 degrees C], the half-lives of 2a/3a, 14a, phenylketoifosfamide (14b: R1 = R2 = CH2CH2Cl, R3 = H), phenylketotrofosfamide (14c: R1 = R2 = R3 = CH2CH2Cl), and 20 were 72, 66, 63, 56, and 173 min, respectively. Analogues 14a and 14b exhibited good anticancer activity against a variety of test systems.
S M
SM
Ludeman
V L
VL
Boyd
J B
JB
Regan
K A
KA
Gallo
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G
Zon
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K
Ishii
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D003486:Cyanides; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000627:therapeutic use; D006207:Half-Life; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D007939:Leukemia L1210 / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D010752:Phosphoramide Mustards / Q000138:chemical synthesis* / Q000627:therapeutic use
C025046:4-phenylcyclophosphamide; D000970:Antineoplastic Agents; D003486:Cyanides; D010752:Phosphoramide Mustards; C014668:4-methylcyclophosphamide; C006446:aldophosphamide; D003520:Cyclophosphamide