Synthesis, crystal structure, and protonation behaviour in solution of the recently-discovered drug metabolite, N1,N10-diacetyltriethylenetetramine

N1,N10-diacetyltriethylenetetramine (DAT) is a recently-discovered major in vivo metabolite of triethylenetetramine (TETA), a highly-selective CuII chelator currently under clinical development as a novel first-in-class therapeutic for the cardiovascular, renal and retinal complications of diabetes mellitus. Characterisation of DAT is an integral aspect of the pharmacological work-up required to support this clinical development programme and, to our knowledge, no previous synthesis for it has been published. Here we report the synthesis of DAT dihydrochloride (DAT·2 HCl); its crystal structure as determined by X-ray single-crystal (XRD) and powder diffraction (XRPD); and protonation constants and species distribution in aqueous solution, which represents the different protonation states of DAT at different pH values. The crystal structure of DAT·2 HCl reveals 3D-assemblies of alternating 2D-layers comprising di-protonated DAT strands and anionic species, which form an extensive hydrogen-bond network between amine groups, acetyl groups, and chloride anions. Potentiometric titrations show that HDAT+ is the physiologically relevant state of DAT in solution. These findings contribute to the understanding of TETA’s pharmacology and to its development for the experimental therapeutics of the diabetic complications.

► N1,N10-diacetyltriethylenetetramine (DAT) was synthesised with new synthetic route. ► Highly-selective CuII chelator as a novel first-in-class cardiovascular therapeutic. ► Crystal structure was solved with X-ray single crystal and powder diffraction. ► The crystal packing is stabilised by intermolecular hydrogen-bond interactions. ► Species distribution and protonation constants in solution were studied.