Syntheses of Desferrioxamine B Conjugates for Use in Antibiotic Delivery and Iron Overload Diseases

Many complex siderophore conjugates have been synthesized by the Miller group and others for the purpose of antibiotic delivery, the treatment of iron overload diseases and for the use of MRI contrast agents. Desferrioxamine B (DFO), a commercially available siderophore, has rarely been used to synthesize such conjugates due to the complexity of starting from a complete, non-protected siderophore. The methodology needed to allow DFO conjugates to be easily prepared without the need for standard protecting groups has been discussed here. A DFO-ferritin binding peptide conjugate was synthesized by using Fe(III) as a protecting group. Using a pH controlled EDC coupling reaction, selective reaction at the terminal serine of the ferritin binding peptide versus the internal lysine of the peptide was facilitated. The DFO-peptide conjugate was found to increase the demineralization of ferritin by 8-times. After the synthesis of the first peptide conjugate a scaled up synthesis was designed to provide enough conjugate for in vivo testing in mice. A maleimide linker containing DFO derivative was synthesized. A second DFO-ferritin binding peptide conjugate was synthesized using a thiol maleimide Michael reaction as the key conjugation step. Preliminary results indicate the DFO-peptide conjugate does not increase iron excretion.A DFO-dual action cephalosporin conjugated was designed which would also use a thiol maleimide Michael reaction for the key conjugation step. A dual action cephalosporin (DAC) releases a drug when attacked at the Ìøå¢-lactam ring. Although the final conjugation step had been worked out, the synthesis of the cephalosporin portion of the DFO-DAC conjugate had not. Work toward the cephalosporin portion of the conjugate led to the development of a method to deacetylate an acid protected cephalosporin. The final DFO-DAC conjugate was not obtained due to the inability to remove the cephalosporin protecting groups. Further development of the methodology reported, however, is anticipated to provide an opportunity for the discovery of new, selective antibiotics and diagnostic agents.