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

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• 作者：Kathrin A. Wichmann^a ; ^b ; Tilo Sö ; hnel^a ; Garth J.S. Cooper^b ; ^c ; ^d ; ^e ; ^{gjs.cooper@gmail.com} ; ^{g.cooper@auckland.ac.nz}
• 关键词：N1 ; N10-diacetyltriethylenetetramine dihydrochloride salt ; Drug metabolism ; Divalent copper chelator ; Synthesis ; Crystal structure ; Protonation constants
• 刊名：Journal of Molecular Structure
• 出版年：2012
• 期刊代码：62_00222860
• 类别：ch
• 出版时间：28 March, 2012
• 卷：1012
• 期：Complete
• 页码：37-42
• 文件大小：642 K

摘要

N¹,N¹⁰-diacetyltriethylenetetramine (DAT) is a recently-discovered major in vivo metabolite of triethylenetetramine (TETA), a highly-selective Cu^II 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路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路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鈥檚 pharmacology and to its development for the experimental therapeutics of the diabetic complications.