N-(2,2-Dimethyl-2-(2-nitrophenyl)acetyl)-4-aminocyclophosphamide as a potential bioreductively activated prodrug of phosphoramide mustard.
N-(2,2-Dimethyl-2-(2-nitrophenyl)acetyl)-4-aminocyclophosphamide isomers (DMNA-NH-CPA, 4) were synthesized stereospecifically from Boc-L-Hse(OBn)-OH and the degradation of the corresponding reduced amine 5a was investigated by UV/vis spectroscopy and LC/MS. The rate of cyclization of 5a was found to increase with decreasing pH, with half-lives ranging from 3.2 to 54 min at pH 4-7.4, suggesting that the cyclization is catalyzed by the hydronium ions. LC/MS analysis of the degradation products of 5a indicates that 4-aminocyclophosphamide is rapidly released from 4 upon reductive activation under acidic conditions and further decomposes into the cytotoxic phosphoramide mustard. These results validated 4-aminocyclophosphamide as a prodrug form of phosphoramide mustard and suggest that compound 4 can potentially be used as a prodrug of phosphoramide mustard for bioreductive activation.
Department of Pharmaceutical Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
Yongying
Y
Jiang
Longqin
L
Hu
D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D002384:Catalysis; D002853:Chromatography, Liquid / Q000379:methods; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000494:pharmacology*; D015195:Drug Design; D006863:Hydrogen-Ion Concentration; D007477:Ions; D007700:Kinetics; D013058:Mass Spectrometry / Q000379:methods; D008956:Models, Chemical; D009861:Onium Compounds / Q000737:chemistry; D010752:Phosphoramide Mustards / Q000737:chemistry / Q000494:pharmacology*; D020033:Protein Isoforms; D013056:Spectrophotometry, Ultraviolet / Q000379:methods; D013997:Time Factors
D018906:Antineoplastic Agents, Alkylating; D007477:Ions; C532929:N-(2,2-dimethyl-2-(2-nitrophenyl)acetyl)-4-aminocyclophosphamide; D009861:Onium Compounds; D010752:Phosphoramide Mustards; D020033:Protein Isoforms; C030090:phosphoramide mustard; C027727:hydronium ion; D003520:Cyclophosphamide