Artificial siderophores. 1. Synthesis and microbial iron transport capabilities

Abstract

Several di- and trihydroxamate analogues of natural microbial iron chelators have been 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 1-5. The required protected (hydroxyamino)alkanes 8, 16, and 21 were prepared by different routes. 1-Amino-3-[(benzyloxy)amino]propane di-p-toluenesulfonate (8) was prepared from the N-protected aminopropanol 6 by oxidation to the aldehyde, formation of the substituted oxime, and reduction with NaBH3CN followed by deprotection of the Boc group. The pentyl derivatives 16 and 21 were made by direct alkylation with either benzyl acetohydroxamate or N-carbobenzoxy-O-benzylhydroxylamine. In Escherichia coli RW193 most of the analogues behaved nutritionally as ferrichrome. However, in E. coli AN193, a mutant lacking the ferrichrome receptor, capacity to use other natural siderophores was retained while response to all analogues was lost.