title: 1,3- vs 1,5-intramolecular alkylation reactions in isophosphoramide and phosphoramide mustards.
abstract: It is well-established that at pH 7.4, intramolecular 1,3-N-alkylation reactions in isophosphoramide mustard (IPM) and phosphoramide mustard (PM) produce electrophilic alkylating agents with aziridinyl moieties. To investigate the role of 1,5-intramolecular cyclizations in the chemistry of IPM and PM, the five-membered ring phospholidine products of these reactions were independently synthesized and characterized by (31)P NMR. In 0.33 M BisTris, pH 7.4, 37 degrees C, the intramolecular O-alkylation product of IPM [2-(2-chloroethylamino)-2-tetrahydro-2H-1,3,2-oxazaphospholidine-2-oxide (11)] had a chemical shift of delta 33.0 and a half-life of 3.3 h. The O-alkylation product of PM [2-amino-3-(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphospholidine-2-oxide (12)] displayed a chemical shift of delta 30.6 and a half-life of 26.9 h. For both IPM and PM, 1,5-N-alkylation provides the same product [1-(2-chloroethyl)-2-hydroxy-tetrahydro-2H-1,3,2-diazaphospholidine-2-oxide (13)]. Because of its instability, 13 was generated in situ and was not isolated; however, the chemical shift (delta 33.0) and reactivity (half-life 0.3 h at 25 degrees C) of the species attributed to 13 were consistent with the assigned structure. Resonances with (31)P NMR chemical shifts indicative of 11 or 12 did not appear in reaction solutions of IPM or PM. The compound assigned as 13 gave hydrolysis products that were not found in reaction solutions of IPM or PM. The collective data supported the conclusion that intramolecular 1,5-alkylations do not contribute to the chemistry of IPM or PM in aqueous solutions at pH 7.4, 37 degrees C. Conversely, 11 and 12 were found to be the major if not exclusive products formed in DMSO solutions of the respective cyclohexylammonium salts of IPM and PM. Both 11 and 12 were relatively noncytotoxic against a series of cell lines, but there were differences in mutagenicities. Chinese hamster ovary cells were exposed to 11 or 12 for one half-life of each compound; 11 was nonmutagenic up to 500 microM, while 12 (500 microM) was mutagenic with 246 mutant colonies/10(6) surviving cells.
authors.affiliation: Duke Comprehensive Cancer Center, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: James B
authors.initials: JB
authors.lastname: Springer
authors.forename: Young H
authors.initials: YH
authors.lastname: Chang
authors.forename: Kyo I
authors.initials: KI
authors.lastname: Koo
authors.forename: O Michael
authors.initials: OM
authors.lastname: Colvin
authors.forename: Michael E
authors.initials: ME
authors.lastname: Colvin
authors.forename: M Eileen
authors.initials: ME
authors.lastname: Dolan
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Delaney
authors.forename: James L
authors.initials: JL
authors.lastname: Flowers
authors.forename: Susan M
authors.initials: SM
authors.lastname: Ludeman
mesh_terms: D000478:Alkylation; D000818:Animals; D001388:Aziridines / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D006801:Humans; D009152:Mutagenicity Tests; D010752:Phosphoramide Mustards / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D018675:Toxicity Tests
chemical_list: D001388:Aziridines; D010752:Phosphoramide Mustards; C027061:isophosphamide mustard