An elastic siderophore synthetase and rubbery substrates assemble multimeric linear and macrocyclic hydroxamic acid metal chelators.

The trihydroxamic acid bacterial siderophore desferrioxamine B (DFOB, 1) produced by the DesABCD biosynthetic cluster coordinates metals beyond Fe(iii), which identifies potential to modify this chelator type to broaden metal sequestration and/or delivery applications. Rather than producing discrete chelators by total chemical synthesis from native monomers including -hydroxy--succinyl-cadaverine (HSC, 2), the recombinant siderophore synthetase from CNB-440 (DesD) was used with different substrate combinations to produce biocombinatorial mixtures of hydroxamic acid chelators. The mixtures were screened with Ga(iii) or Zr(iv) as surrogates of immunological positron emission tomography (PET) imaging radiometals Ga(iii) or Zr(iv) to inform known or new coordination chemistry.

A first-in-class dual-chelator theranostic agent designed for use with imaging-therapy radiometal pairs of different elements.

A covalent adduct of DFOB and DOTA separated by a l-lysine residue (DFOB-l-Lys- -DOTA) exhibited remarkable regioselective metal binding, with {H}-C NMR spectral shifts supporting Zr(iv) coordinating to the DFOB unit, and Lu(iii) coordinating to the DOTA unit. This first-in-class, dual-chelator theranostic design could enable the use of imaging-therapy radiometal pairs of different elements, such as Zr for positron emission tomography (PET) imaging and Lu for low-energy β-particle radiation therapy. DFOB-l-Lys- -DOTA was elaborated with an amine-terminated polyethylene glycol extender unit (PEG4) to give DFOB- -(PEG4)-l-Lys- -DOTA (compound D2) to enable installation of a phenyl-isothiocyanate group (Ph-NCS) for subsequent monoclonal antibody (mAb) conjugation (mAb = HuJ591).