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Synthesis of 4-Hydroperoxy Derivatives of Ifosfamide and Trofosfamide by Direct Ozonation and Preliminary Antitumor Evaluation in V/Vo

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Synthesis of 4-Hydroperoxy Derivatives of Ifosfamide and Trofosfamide by Direct Ozonation and Preliminary Antitumor Evaluation in V/Vo [CANCER RESEARCH, 36, 2278-2281, July 1976] Synthesis of 4-Hydroperoxy Derivatives of Ifosfamide and Trofosfamide by Direct Ozonation and Preliminary Antitumor Evaluation in V/vo Hans-J. Hohorst, Gernot Peter, and Robert F. Struck Gustav-Embden-Zentrum der Biologischen Chemie, Abteilung KIr Zellchemie der J. W. Goethe-Universit~t, 6000 Frankfurt am Main, West Germany [H-J. H., G. P.], and Kettering-Meyer Laboratory, Southern Research Institute, Birmingham, Alabama 35205 [R. F. S.] SUMMARY reported routes (15, 17 to 19, 20), as well as to improve the yields. Two of us (11) have recently described such a syn- A one-step synthesis of 4-hydroperoxyifosfamide and 4- thesis of 4-hydroperoxycyclophosphamide, and application hydroperoxytrofosfamide is described. The method in- of this method to ifosfamide and trofosfamide and evalua- volves direct ozonation of ifosfamide and trofosfamide and tion of the products against leukemia L1210 in vivo are the offers improved yields in comparison with Fenton oxidation subjects of this report. The method is advantageous be- and greater convenience in comparison with ozonation of cause of its simplicity, its use of available starting materials, the appropriate 3-butenyl phosphorodiamidate. Evaluation the ease of isolation of products, and respectable yields. of the 4-hydroperoxy derivatives of cyclophosphamide, ifos- famide, and trofosfamide against leukemia L1210 in vivo suggests a superior effect for the ifosfamide derivative. MATERIALS AND METHODS Starting Materials. Cyclophosphamide, ifosfamide, and INTRODUCTION trofosfamide were obtained from Dr. Robert R. Engle, Drug Development Branch, National Cancer Institute, Silver Cyclophosphamide and its congeners ifosfamide and tro- Spring, Md., and from Asta Werke, 4800 Bielefeld, West fosfamide (1, 3) (Chart 1) are effective antitumor agents in Germany. [~H]Cyclophosphamide was obtained from Dr. E. clinical and experimental use. Metabolic activation of cyclo- SchaumlOffel, Radiologie-Zentrum der Phillipps-Universi- phosphamide is known to proceed by C4-hydroxylation by tat, Marburg/Lahn, Germany. the mixed-function oxidase of liver microsomes (4, 7, 9, 13), Ozonation, A solution of cyclophosphamide or one of its the resulting 4-hydroxycyclophospham~de then sponta- congeners (1 g) in aqueous acetone and 30% hydrogen neously yielding the unstable aldophosphamide and subse- peroxide was treated with ozone (25 mmoles/hr) generated quently the possible "ultimate" alkylating metabolite, phos- by a Welsbach Ozonator T-816 (Welsbach Corp., Philadel- phoramide mustard (5, 6, 14). phia, Pa.) at a flow rate of 0.3 liter/rain and 50 watts of Synthesis of 4-hydroxycyclophosphamide (10, 17, 19, 20), power by bubbling into the ice bath cooled solution through as well as the "preactivated" derivatives, 4-hydroperoxycy- a capillary tube. clophosphamide (10, 17, 19, 20) and 4-peroxycyclophos- TLC. "~ TLC was performed on Analtech (Newark, Del.) phamide (15, 16, 20), has been accomplished. In addition, precoated Silica Gel G plates (250 /~m thick) in ace- 4-hydroxy- and 4-hydroperoxyifosfamide have been pre- tone:chloroform (1:3). The plates were activated at 120 ~ for pared, and the latter is currently undergoing clinical trials in 1 hr and stored in a desiccated chamber. Japan (A. Takamizawa, personal communication). Experi- Alkylating Activity. Thin-layer chromatograms were mental or clinical use of the peroxidized derivatives of cy- sprayed with a 1% solution of 4-(p-nitrobenzyl)pyridine clophosphamide and its congeners, rather than the 4-hy- (Aldrich Chemical Co., Milwaukee, Wis.)in acetone, heated droxy derivatives, is preferred because the former are much in an oven for 15 min at 140 ~ and sprayed with a 3% solution more stable and spontaneously yield the hydroxy deriva- of potassium hydroxide in methanol. Alkylating compo- tives under physiological conditions (20, 21). nents yielded blue spots. Because of the potential importance of the peroxidized Column Chromatography. Column chromatography was derivatives of cyclophosphamide and its congeners, a direct performed on Silica Gel 40 (70 to 230 mesh; EM Laborato- synthesis of these types of preactivated derivatives was ries, Elmsford, N. Y.) in acetone:chloroform (3:1) for ozon- sought for the sake of convenience over the previously ized product of cyclophosphamide and in ace- tone:chloroform (1:3) for the ifosfamide and trofosfamide products. ' This investigation was supported by Contract NO1-CM-43762, National Cancer Institute, NIH, USPHS, Department of Health, Education, and Wel- Instrumentation. Mass spectral analysis was performed fare, and by Program SN 6025 (Arbeitsgemeinschaft Cytostatika) des Bundesministeriums f(ir Forschung und Technologie, Bonn, Federal Republic of Germany. 2The abbreviations used are: TLC, thin-layer chromatography; PMR, pro- Received January 27, 1976; accepted March 18, 1976. ton magnetic resonance; M, molecular ion. 2278 CANCER RESEARCH VOL. 36 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1976 American Association for Cancer Research. Direct Ozonation of Ifosfamide and Trofosfamide CICH2(~H2 CICH2I~H2 H 4/~--N tO 0 N(CH2CH2Cl)2 5~---S0 NHCH2CH2CI N(CHzCH2CI) 2 C yclophosphomide lfosfomide Trofosfomide (Isophosphomide) (Tri Iophosph o mi de) Chart 1. Cyclophosphamide and its congeners. with a Varian MAT Model 311A mass spectrometer and PMR ide). PMR analysis of the total product indicated a 20% yield measurements with a Varian XL-100-15 spectrometer (Var- of each product and a 35% recovery of starting material. ian, Inc., Palo Alto, Calif.). Infrared analysis was performed Column chromatography served to isolate 4-hydroperoxyi- with Perkin-Elmer Model 521 and 621 infrared spectropho- fosfamide in 11% yield; m.p. 123 to 125 ~ with explosive tometers (Perkin-Elmer Corp., Norwalk, Conn .). Radiochro- decomposition (Heizbank); mass spectrum, PMR, infrared, matograms were scanned with a Berthold-Radiochromato- and TLC data identical with the data for authentic 4-hydro- gram-scanner II, LB 2722 (Laboratory Professor Dr. Bert- peroxyifosfamide (18). hold, 7547 Wildbad/Schwarzwald, West Germany). 4-Hydroperoxytrofosfamide (NSC 260608). Ozonation of Evaluation against L1210 Leukemia. Compounds were trofosfamide under identical conditions yielded 25% of 4- administered i.p. on the 1st day of inoculation of 105 or 106 hydroperoxytrofosfamide, as indicated by PMR analysis. leukemia cells in C57BL • DBA/2 mice. Control and test Column chromatographic separation of the chloroform ex- animals were observed for days of survival. tract of the aqueous solution gave a fraction containing only the hydroperoxide. Concentration of the column eluate and RESULTS AND DISCUSSION refrigeration resulted in the isolation of 18% crystalline ma- terial (3 crops) that was homogeneous upon TLC analysis; Two synthetic routes to 4-hydroperoxycyclophosphamide m.p. 145 ~ with explosive decomposition (Heizbank); PMR,ti_ and 4-hydroperoxyifosfamide were heretofore available. m,,thyi ,u~f,,xid,,, tetramethylsilane reference: $1.70 to 2.33 (2H, Fenton oxidation was used successfully for synthesis of 4- multiplet, - CH2CH2CH -), 2.94 to 3.88 (12H, complex multi- hydroperoxycyclophosphamide (C. Benckhuysen, personal plet, CH2CH2CI), 3.88 to 4.60 (2H, multiplet, -C__H20-), 4.99 communication), as well as 4-peroxycyclophosphamide, al- (1H, doublet of triplets, -CH-OOH), 11.50 (1H, singlet, - though characterization of products generated by this route OOH)" infrared (cm-'): 3150, 3015, 2965, 2950, 2820, 1485, was not completed until after Takamizawa et al. (17, 19) 1445, 1370, 1345, 1310, 1260, 1235, 1215, 1140, 1105, 1085, reported their synthesis by ozonation of 3-butenyl N,N- 1060, 1030, 1010, 980, 955, 930, 905, 875, 805, 785, 740, bis(2-chloroethyl)phosphorodiamidate, a route used unsuc- 655, 540, 515: field desorption mass spectrum (re~e): 355 cessfully by Struck and Hill (12) for the synthesis of aldo- (3 CI, M + 1) +, 336 (3 CI, M - H20) § 320 (3 Ci, M - phosphamide. Van der Steen et al. (20) and Montgomery H202) § TLC" Rr 0.48 in acetone:chloroform (1:3) (RF of and Struck (10) were able to produce 4-hydroperoxycyclo- trofosfamide, 0.59). Elemental analysis: phosphamide in yields of 4 and 9%, respectively, by the Fenton method. Takamizawa et al. (17) synthesized this CqH,,CI3N.~O4P hydroperoxide in 44% overall yield by their procedure. Calculated" C 30.40, H 5.10, N 7.88 Preparation of 4-hydroperoxyifosfamide was also reported Found- C 30.37, H 4.94, N 7.81 by both methods (10, 18). For a larger scale preparation, ifosfamide (10 g) was Because of the availability of cyclophosphamide and its dissolved in a mixture of 70 ml acetone, 30 ml water, and10 congeners, synthesis of the corresponding hydroperoxides ml 30% hydrogen peroxide. Ozone (1 mmole/min) was bub- by use of the d rugs themselves appeared to be a potential, bled into the solution through a sintered glass disc at 0 ~ convenient route, and such a procedure was developed by over a 4.5-hr period. After evaporation of acetone under Peter and Hohorst (11) for 4-hydroperoxycyclophospham- reduced pressure, the reaction mixture, which showed an ide. The general applicability of the method is confirmed by oily bottom layer, was extracted with CH2CI2 (3 x 100 ml), this report on the synthesis of 4-hydroperoxyifosfamide and and the combined organic layers were dried over Na=SO4. -trofosfamide. After filtration, CH2CI2 was evaporated under reduced pres- 4-Hydroperoxyifosfamide (NSC 207117 and NSC sure at 15 ~ leaving a colorless oil. While
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