Isophosphoramide Mustard and Its Mechanism of Bisalkylation

Jb, Springer; Me, Colvin; Om, Colvin; Sm, Ludeman

doi:10.1021/jo980546s

Cited by 25 publications

(19 citation statements)

References 18 publications

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“…Thus, it was possible to obtain good estimations of IPM-Cl 2 , IPM-Cl/Alk, and IPM-Alk 2 abundances as a function of time, and hence estimations of k exp1 and k exp2 . These rate constants values are in close agreement with those described previously (Springer et al, 1998).…”

Section: P Mnr Kinetic Study Of Mustard Alkylating Activitysupporting

confidence: 81%

“…This signal has been assigned previously to IPM-Alk/Cl (Fig. 5A) (Springer et al, 1998). It has been shown that in the reaction sequence IPM-Cl 2 3 IPM-Cl/Alk 3 IPM-Alk 2 , the formation of both IPM-Alk/Cl and IPM-Alk 2 was preceded by an intramolecular cyclization of the chloroethylamido functionality, resulting in the formation of an aziridine.…”

Section: P Mnr Kinetic Study Of Mustard Alkylating Activitymentioning

confidence: 93%

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New Ifosfamide Analogs Designed for Lower Associated Neurotoxicity and Nephrotoxicity with Modified Alkylating Kinetics Leading to Enhanced in Vitro Anticancer Activity

Storme

Deroussent²,

Mercier³

et al. 2008

J Pharmacol Exp Ther

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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.The bisalkylating agent ifosfamide (IFO) was introduced into clinical trials in the 1970s, but its early use was limited by severe urotoxicity resulting in hemorrhagic cystitis. This side effect led to the development of sodium mercaptoethanesulfonate associated with hydration as a safe and effective regional uroprotection. Further studies have demonstrated IFO activity against a wide range of tumor types, from soft tissue sarcomas to lymphomas both in adult and pediatric

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Section: P Mnr Kinetic Study Of Mustard Alkylating Activitysupporting

confidence: 81%

Section: P Mnr Kinetic Study Of Mustard Alkylating Activitymentioning

confidence: 93%

New Ifosfamide Analogs Designed for Lower Associated Neurotoxicity and Nephrotoxicity with Modified Alkylating Kinetics Leading to Enhanced in Vitro Anticancer Activity

Storme

Deroussent²,

Mercier³

et al. 2008

J Pharmacol Exp Ther

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“…Phosphoramide mustard is a DNA-reactive alkylating agent that binds to the N 7 position of guanine (6,9). Phosphoramide mustard may also react with the O 6 position of guanine (6) and has been implicated in DNA cross-linking (10). Acrolein is believed to contribute to DNA damage primarily by creating abasic sites and single-strand breaks (11)(12)(13)(14).…”

mentioning

confidence: 99%

Development of a cancer DNA phenotype prior to tumor formation

Malins

Anderson

Gilman

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Using the carcinogen 3-methylcholanthrene (MCA), we demonstrate with Fourier transform-infrared spectroscopy that a cancer DNA phenotype is produced well in advance of palpable tumors. We further demonstrate that the administration of cyclophosphamide markedly inhibits the development of the cancer phenotype and concomitantly delays tumor formation. MCA, injected into the hind legs of mice, produced a variety of significant structural changes in the nucleotide bases and phosphodiester-deoxyribose backbone, as reflected in a substantial (34%) difference between the mean DNA spectra of the control and the MCA-injected mice. Strikingly, 57 days before the mean appearance of tumors, we could not distinguish the DNA structure of the histologically normal tissues of the MCA-injected mice from the DNA structure of the tumor tissues. This finding indicates the early development of a cancer phenotype. Confirmatory evidence was obtained when tissues from a group of mice injected with both MCA and cyclophosphamide did not manifest the cancer phenotype, and their mean DNA structure closely resembled that of the control mice. Accordingly, we propose that the cancer DNA phenotype, as evinced by Fourier transform-infrared spectroscopy, is a promising early indicator of tumor formation, and we postulate that agents capable of inhibiting this phenotype may delay or prevent carcinogenesis.3-methylcholanthrene ͉ antineoplastic agents ͉ cyclophosphamide ͉ cancer inhibition ͉ cancer prediction

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“…The mechanism of bisalkylation by isophosphoramide mustard was examined using the D 4 -labelled isotopomer and analysing the deuterium distribution in the product using 1 H and 13 C NMR spectroscopy [190] (Fig. 59).…”

Section: Biosynthetic Studiesmentioning

confidence: 99%