title: New ifosfamide analogs designed for lower associated neurotoxicity and nephrotoxicity with modified alkylating kinetics leading to enhanced in vitro anticancer activity.
abstract: Ifosfamide is a well known prodrug for cancer treatment with cytochrome P450 metabolism. It is associated with both antitumor activity and toxicities. Isophosphoramide mustard is the bisalkylating active metabolite, and acrolein is a urotoxic side product. Because acrolein toxicity is limited by coadministration of sodium mercaptoethanesulfonate, the incidence of urotoxicity has been lowered. Current evidence suggests that chloroacetaldehyde, a side-chain oxidation metabolite, is responsible for neurotoxicity and nephrotoxicity. The aim of our research is to prevent chloroacetaldehyde formation using new enantioselectively synthesized ifosfamide analogs, i.e., C7,C9-dimethyl-ifosfamide. We hypothesize that reduced toxicogenic catabolism may induce less toxicity without changing anticancer activity. Metabolite determinations of the dimethyl-ifosfamide analogs were performed using liquid chromatography and tandem mass spectrometry after in vitro biotransformation by drug-induced rat liver microsomes and human microsomes expressing the main CYP3A4 and minor CYP2B6 enzymes. Both human and rat microsomes incubations produced the same N-deschloroalkylated and 4-hydroxylated metabolites. A coculture assay of 9L rat glioblastoma cells and rat microsomes was performed to evaluate their cytotoxicity. Finally, a mechanistic study using (31)P NMR kinetics allowed estimating the alkylating activity of the modified mustards. The results showed that C7,C9-dimethyl-ifosfamide exhibited increased activities, although they were still metabolized through the same N-deschloroalkylation pathway. Analogs were 4 to 6 times more cytotoxic than ifosfamide on 9L cells, and the generated dimethylated mustards were 28 times faster alkylating agents than ifosfamide mustards. Among these new ifosfamide analogs, the 7S,9R-enantiomer will be assessed for further in vivo investigations for its anticancer activity and its toxicological profile.
authors.affiliation: Unité Mixte de Recherche 8638 Centre National de Recherche Scientifique Medicinal Chemistry Laboratory-Faculty of Pharmacy, University Paris Descartes, Paris, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Storme
authors.forename: Alain
authors.initials: A
authors.lastname: Deroussent
authors.forename: Lionel
authors.initials: L
authors.lastname: Mercier
authors.forename: Elise
authors.initials: E
authors.lastname: Prost
authors.forename: Micheline
authors.initials: M
authors.lastname: Re
authors.forename: Fabienne
authors.initials: F
authors.lastname: Munier
authors.forename: Thierry
authors.initials: T
authors.lastname: Martens
authors.forename: Philippe
authors.initials: P
authors.lastname: Bourget
authors.forename: Gilles
authors.initials: G
authors.lastname: Vassal
authors.forename: Jacques
authors.initials: J
authors.lastname: Royer
authors.forename: Angelo
authors.initials: A
authors.lastname: Paci
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects* / Q000627:therapeutic use; D001711:Biotransformation; D002478:Cells, Cultured; D006801:Humans; D007069:Ifosfamide / Q000009:adverse effects* / Q000031:analogs & derivatives / Q000627:therapeutic use; D007700:Kinetics; D008297:Male; D009404:Nephrotic Syndrome / Q000139:chemically induced*; D020258:Neurotoxicity Syndromes; D011355:Prodrugs / Q000009:adverse effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D018906:Antineoplastic Agents, Alkylating; D011355:Prodrugs; D007069:Ifosfamide