A Mild Total Synthesis and Directed Chemo-enzymatic Assembly of Desferrioxamine B

Siderophores are a class of microbial natural products with exquisite binding affinity for ferric iron (Fe3+). Arguably, the most notable member of this class of natural product is DFOB, a hydroxamic acid bearing siderophore originally isolated from Streptomyces pilosus. DFOB has long running clinical significance with its listing on the WHO list of essential medicines, and is emerging as a chelator in radiopharmaceutical agents, an import moiety for new antibiotics, and a tool for investigating microbial metabolomes and proteomes. Current DFOB production is undertaken by fermentation which is hampered by the generation of other hydroxamic acid bearing-siderophores, resulting in rigorous purification processes. Exploring new approaches to the production of DFOB may alleviate the limitations of the current process allowing the selective production of this clinically important natural product.

Our recent work has investigated the selective production of DFOB by two distinct approaches. Firstly, DFOB was prepared by a mild and modular synthetic pathway that overcomes the safety concerns of previous total syntheses and allows for the potential synthesis of non-natural analogues of DFOB and its monomeric constituents. In conjunction, we have investigated the chemoenzymatic assembly of DFOB using the NRPS-independent siderophore synthetase DesD, the final enzyme in the biosynthetic pathway. DesD catalyses the iterative condensation of monomeric hydroxamic acids to generate linear and macrocyclic hydroxamate siderophores with the accommodation of these growing hydroxamic acid intermediates suggesting a level of elasticity in the biosynthetic machinery. We have sought to exploit this elasticity by employing chemically protected substrates to prevent higher order oligomerisation and generate DFOB as a single product.

Developing a new chelator for the rapid and stable complexation of the α-generators bismuth-212 and lead-212

Targeted alpha therapy (TAT) has been demonstrated to be a promising method of treatment for metastatic cancer. A vital component of the radiopharmaceuticals employing radiometals in TAT is the development of chelators that radiolabel under mild conditions and provide high complex stability. Lead-212 (212Pb, t1/2 = 10.2 h, Eβ− = 0.57, 2.2 and 1.8 MeV) is a β− emitter that is also the parent isotope for 212Bi. The use of 212Pb as an in vivo generator of α-particles circumvents the short half-life of 212Bi by extending the useful half-life of the radiopharmaceutical. However, at present no chelator exists that is optimal for both radionuclides.

This seminar will follow the process from the initial synthesis of the new chelator H2DOTS, characterisation of the non-radioactive metal complexes and optimisation of the radiolabelling with the therapeutic radionuclides 212Pb and 212Bi. These results showed efficient complexation and remarkable kinetic inertness of H2DOTS with both [212Bi]Bi3+ and [212Pb]Pb2+ that matched or surpasses the properties of the chelators H4DOTP and p-SCN-Bn-TCMC, respectively, demonstrating the unique potential of H2DOTS for developing theranostic radiopharmaceuticals.