Re-engineering Hydroxamic Acids in Therapeutics and Diagnostics

The bacterial natural product desferrioxamine B (DFOB) can form highly stable complexes with a range of metal ions, particularly Fe(III). The metal ion-coordinating properties of DFOB could potentially be exploited across broader clinical applications. The goal of this thesis was to develop two major methodological innovations to generate new molecules inspired by DFOB as lead compounds for broader clinical use. The first method was “reverse biosynthesis”, a new method for generating drug leads by enzyme-mediated fragmentation of natural products. DFOB was fragmented into smaller hydroxamic acids by the bacterium Niveispirillum irakense. Pools of DFOB catabolites were modified by combinatorial chemistry to generate analogues of the histone deacetylase (HDAC) inhibitor scriptaid as potential inhibitors of the metalloenzymes HDAC and 5-lipoxygenase (5-LO). The scriptaid analogue of N-(5-aminopentyl)-N-hydroxyacetamide (S2) demonstrated strong inhibition of 5-LO (IC50 = 58.9 µM), with only 3.4 times lower potency than the preclinical gold standard BWA4C (IC50 = 17.1 µM). The second method was the use of precursor-directed biosynthesis, which was initially applied using Streptomyces pilosus to generate a DFOB analogue which demonstrated 45 times greater water solubility than DFOB by logP measurements. This more water soluble analogue of DFOB was extended by one monomeric unit in a peptide coupling reaction to generate a tetrameric Zr(IV) chelator which exhibited 3.6 times greater water solubility than the current clinical gold standard 89Zr chelator used in positron emission tomography (PET) imaging. Precursor-directed biosynthesis was also applied with S. pilosus cultures to generate thioether-containing analogues of DFOB and a disulfide-containing analogue of DFOB which was reduced in situ as a proof of concept for a targeted drug delivery strategy. Overall, the work described in this thesis demonstrated the versatility of DFOB as a scaffold for drug development. The N. irakense-mediated catabolism of DFOB was used to establish a new method to source drugs from natural products. Precursor-directed biosynthesis was used to generate an improved Zr(IV) chelator for PET imaging together with sulfur-containing DFOB analogues with potential as new antibiotic drug leads