Aldophosphamide acetal diacetate and structural analogues: synthesis and cytotoxicity studies.
The synthesis of aldophosphamide acetal diacetate and a number of structural analogues is described. These compounds are designed to undergo biotransformation to the corresponding aldehydes in the presence of carboxylate esterases, enzymes that are ubiquitous in mammalian tissue. Several of these aldehydes can theoretically exist in pseudoequilibrium with the 4-hydroxyoxazaphosphorine tautomers; others lack this capability. The half-lives of the acetals in 0.05 M phosphate buffer, pH 7.4, at 37 degrees C ranged from 1 to 2 days. In the presence of 2 unit equiv of porcine liver carboxylate esterase, all of the compounds were hydrolyzed with half-lives of less than 1 min. Although closely structurally related, the compounds exhibited a wide range of cytotoxicities to L1210 murine leukemia cells in vitro.
Wang
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Department of Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston 77030.
Farquhar
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D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D043182:Carboxylesterase; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D007939:Leukemia L1210; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D015394:Molecular Structure; D010752:Phosphoramide Mustards / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D010752:Phosphoramide Mustards; D011355:Prodrugs; C054580:acetaldophosphamide; D002265:Carboxylic Ester Hydrolases; D043182:Carboxylesterase