Low-molecular-weight organic compounds containing specifically configured metal-binding functional groups are known as ‘chelators’ (Gk ‘claw’) and are useful in environmental and biomedical metal sequestration or delivery applications. Chelators in current use are mostly synthetic and have narrow structural diversity, which prompted us to develop new approaches to expand chelator chemical space to improve and expand metal separation/delivery capabilities. We considered the structural diversity inherent to a sub-set of natural product chelators called siderophores which are produced by bacteria and fungi for iron(III) acquisition [1]. Using the archetypal bacterial hydroxamic acid chelator desferrioxamine B as a model system, we have dissected its assembly mechanisms [2] and exploited these to build chelators with new architectures, and coordination chemistry [3]. Our cross-discipline approach in blending organic synthesis [4], coordination chemistry and molecular biology, has led to the production of chelators as radiometal pharmaceutical agents [5, 6], and with potential for upstream radionuclide separation, and/or remediation/acquisition of toxic/commodity metal ions. The approaches developed in this work could be transferred to other natural product chelators as a platform for the facile expansion of chelator chemical space.
[1] R. Codd, Siderophores and iron transport, in: V.L. Pecoraro, Z. Guo (Eds.), Comprehensive Inorganic Chemistry III, vol. 2, Comprehensive Inorganic Chemistry III, Elsevier, Oxford, 2023, pp. 3–29.
[2] T.E. Markham, A. Sresutharsan, C.A. Rosser, R. Codd, Directing the chemoenzymatic assembly of desferrioxamine B as a single product using N-tert-butoxycarbonyl-protected substrates, Org. Biomol. Chem. 23 (2025) 7181–7187.
[3] K.P. Nolan, C.A. Rosser, J.L. Wood, J. Font, A. Sresutharsan, J. Wang, T.E. Markham, R.M. Ryan, R. Codd, An elastic siderophore synthetase and rubbery substrates assemble multimeric linear and macrocyclic hydroxamic acid metal chelators, Chem. Sci. 16 (2025) 2180–2190.
[4] T.E. Markham, R. Codd, A mild and modular approach to the total synthesis of desferrioxamine B, J. Org. Chem. 89 (2024) 5118–5125.
[5] J.L. Wood, S. Ghosh, Z.H. Houston, N.L. Fletcher, J. Humphries, K. Mardon, D.T. Akhter, W. Tieu, A. Ivashkevich, M.P. Wheatcroft, K.J. Thurecht, R. Codd, A first-in-class dual-chelator theranostic agent designed for use with imaging-therapy radiometal pairs of different elements, Chem. Sci. 15 (2024) 11748–11760.
[6] J.L. Wood, S. Ghosh, C.A. Rosser, S.V. Feeney, C.J.M. Brown, N.L. Fletcher, M.P. Wheatcroft, K.J. Thurecht, R. Codd, Synthesis and evaluation of D8W, an octadentate desferrioxamine analogue with enhanced water solubility designed for 89Zr-immuno-PET imaging, Mol. Pharm. (2026), ASAP.