Framework-Reactive Siderophore Analogs as Potential Cell-Selective Drugs. Design and Syntheses of Trimelamol-Based Iron Chelators

Currently, the role of DNA-directed alkylating agents as potential anticancer/ antimicrobial drugs is of wide interest. Most of the alkylating agents used clinically as drugs damage DNA in cells without specificity, and this can lead to undesired toxicity problems. Minimizing serum residence time by targeting the drug to select pathogens or organs might diminish the effects of nonselective reactivity. This paper describes the syntheses and preliminary studies of analogs of siderophores (microbial iron chelators) 2 and 20 that incorporate centers within the siderophore framework capable of generating potent electrophiles (iminium ions), hopefully after directed cellular recognition and uptake. Formation of N-aminals from trimelamol (3) and substituted hydroxamic acid 4 or 5was critical for the design and synthesis of the targets. In preliminary biological testing, compound 2, a trimelamol-based siderophore analog, was active against Escherichia coli X580, illustrating the therapeutic potential of this new type of siderophore-mediated drug design and delivery.