Synthesis of the metabolite N-hydroxy-desferrioxamine B.

Abstract

JV-Hydroxy-desferrioxamine B (5), a postulated metabolite of the microbial product desferrioxamine B (1), has been prepared by reduction of the intermediate oxime 6 with sodium cyanoborohydride. The oxime was obtained by selective oxidation of desferrioxamine B with hydrogen peroxide and a catalytic amount of sodium tungstate dihydrate. The iron complex derived from 5 enabled definite proof of the structure of one of four metabolites of desferrioxamine B found in urine samples of patients treated with this drug.The secondary metabolite desferrioxamine B (1) was originally isolated from Streptomyces pilosus in 1960 by Bickel et al.1] The iron containing siderophore ferrioxamine B plays an important role in iron transport in microbes, plants and animals.2)In the form of the methanesulfonate salt, the chelator desferrioxamine B (1) has been used as a drug to treat patients with transfusional iron overload or acute iron intoxication.3) Another important therapeutical application of desferrioxamine B is the removal of aluminum from patients suffering from impaired renal function and undergoing chronic haemodialysis treatment.4'5) Recently it has been shown that the sustained administration of desferrioxamine B slowed the clinical progression of the dementia associated with Alzheimer's disease.6) Furthermore desferrioxamine B has been proposed as a promising drug for the treatment of malaria because of its inhibitory activity against plasmodia in vitro and in Wv0.7~1O) In a recent clinical trial it was shown that the administration of desferrioxamine B reduced significantly the adverse effects of reperfusion injury. 1 1>12)Although desferrioxamine B (1) has been firmly established as a safe drug in chelation therapy, various toxic side effects have been reported, especially in patients treated with high doses.13~16) The hypothesis that the toxicity could be due to the depletion of other essential metal ions such as zinc or copper by the chelator has not been substantiated by experimental evidence.17) Since the side effcets are observed more frequently in patients with limited iron overload, it has been speculated that the toxic effects of the drug could be linked to the formation of certain metabolites.18) It is well known that ferrioxamine B, the iron complex, is quite stable towards metabolic degradation whereas the free ligand is rapidly metabolized. In view of the potentially morewidespread use of desferrioxamine B for the treatment of diseases which are not associated with chronic iron overload, such as Alzheimer's disease or malaria, it is imperative to carefully investigate the metabolism of desferrioxamine B and to evaluate the toxic potential of the metabolic products. In 1964, Keberle19) reported three metabolites in the urine of patients treated with the drug and he assigned structure (2) to the main metabolite in which the aminomethylene group of desferrioxamine B (1) is replaced by a carboxy group. The synthesis of this major metabolite (2) has been described recently by Dionis et al.20) Several high-perf...

Product Class 5: Hydroxylamines

“…[72][73][74][75][76][77][78][79][80][81][82] Whereas the reduction of ketoximes with sodium cyanoborohydride at pH 4 proceeds smoothly to give N-alkylhydroxylamines with no overreduction to the corresponding amines, [71] the reduction of aldoximes to the corresponding N-monosubstituted hydroxylamines generally requires adjustment to pH £3, because higher pH values generally favor formation of N,N-disubstituted hydroxylamines. [75] A series of N-alkylhydroxylamines 43, building blocks for bioactive compounds, are prepared by reduction of the corresponding oximes 42 with sodium cyanoborohydride at pH 3 in ethanol (Scheme 15).…”