Artificial siderophores. 1. Synthesis and microbial iron transport capabilities

Publisher Website
Google Scholar
Abstract
Several di- and trihydroxamate analogs of natural microbial iron chelators were prepared. The syntheses involved linkage of core structural units, including pyridinedicarboxylic acid, benzenetricarboxylic acid, nitrilotriacetic acid and tricarballylic acid, by amide bonds to 1-amino-.omega.-(hydroxyamino)alkanes to provide the polyhydroxamates [N,N''-bis[3-(acetylhydroxyamino)propyl]-2,6-pyridinedicarbamide, N,N'',N"-tris[3-(acetylhydroxyamino)propyl]-1,3,5-benzenetricarbamide, N,N''N"-tris[3-(acetylhydroxyamino)propyl]nitrilotriacetamide, N,N'',N"-tris[3-(acetylhydroxyamino)propyl]tricarballylamide, N,N''-bis[5-(acetylhydroxyamino)pentyl]-2,6-pyridinedicarbamide and N,N'',N"-tris[5-(acetylhydroxyamino)pentyl]-1,3,5-benzenetricarboxamide]. The required protected (hydroxyamino)alkanes, were prepared by different routes. 1-Amino-3-[(benzyloxy)amino]propane di-p-toluenesulfonate was prepared by the N-protected aminopropanol by oxidation to the aldehyde, formation of the substituted oxime and reduction with NaBH3CN followed by deprotection of the Boc group. The pentyl derivatives were made by direct alkylation with either benzyl acetohydroxamate or N-carbobenzoxy-O-benzylhydroxylamine. In Escherichia coli RW193 most of the analogs behaved nutritionally as ferrichrome. In E. coli AN193, a mutant lacking the ferrichrome receptor, capacity to use other natural siderophores was retained while responses to all analogs was lost. [Siderophores are important models of the development of drugs for the treatment of iron-overloaded patients.].