N3-methyl-mafosfamide as a chemically stable, alternative prodrug of mafosfamide.
The presence of an alkyl substituent at N3 in the oxazaphosphorine ring stabilizes N-substituted 4-(alkylthio)cyclophosphamides from spontaneous decomposition. Based on this finding, N3-methyl-mafosfamide was synthesized and examined as a chemically stable, biooxidative prodrug of mafosfamide. This prodrug was stable in aqueous buffer (pH 7.4, 37 degrees C) and underwent N-demethylation in a time dependent manner when incubated with rat hepatic microsomes. N3-Methyl-mafosfamide was 10-fold more cytotoxic in vitro than cyclophosphamide against mouse embryo Balb/c 3T3 cells (LC50 = 3.6 microM). Preliminary in vivo antitumor evaluation against L1210 leukemia in mice showed that this prodrug was active [Increase of life span (ILS) > 29%].
Moon
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KY
Department of Pharmaceutical Sciences, College of Pharmacy, St. John's University, Jamaica, New York 11439, USA. kmoon@mail.ncifcrf.gov
Kwon
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CH
D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D007939:Leukemia L1210 / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D011355:Prodrugs / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D011355:Prodrugs; C048341:mafosfamide; D003520:Cyclophosphamide