Deuteration is an expanding medicinal chemistry technique for improving drug pharmacokinetics. As carbon forms stronger bonds with deuterium than with hydrogen, deuterated drugs are often more resistant to degradation and show greater plasma protein binding, keeping them in circulation for longer.1, 2 In doing so, deuteration can facilitate the reduction of dosage requirements and thus reduce the potential for side effects.
Desferrioxamine B (DFOB) is an iron chelator used for the treatment of transfusion-induced iron overload resulting from the management of genetic conditions such as β-thalassemia.3 As humans have no active mechanism for the removal of iron, excess iron received through regular blood transfusions accumulates in the heart, liver and endocrine glands, where it catalyses the formation of hydroxyl radicals leading to organ damage.4 DFOB has poor metabolic stability (~30 min), resulting in high dosage requirements which can lead to side effects such as abdominal pain, arthritis, diarrhoea, pyrexia, nausea, vision and hearing loss.5, 6
The current study aimed to develop a precursor directed biosynthesis method to produce deuterated analogues of DFOB. 1,4-Diaminobutane-d8 was synthesised via direct hydrogen/deuterium exchange on commercial putrescine using a ruthenium on carbon catalyst and D2O as the deuterium source. A culture of the native DFOB producer Streptomyces pilosus was supplemented with this deuterated precursor, perturbing the biosynthetic pathway and successfully resulting in the production of a series of deuterated DFOB analogues.
Additional deuteration in the succinyl regions of the DFOB molecule revealed that S. pilosus could derive succinyl-CoA from putrescine, which is a biosynthetic pathway not previously reported for this species. This study has revealed a new method of tracking putrescine metabolism which is being developed in future metabolomics studies.