Impact of human serum albumin on Cu II and Zn II complexation by ATSM (diacetyl-bis( N 4-methylthiosemicarbazone)) and a water soluble analogue

• Published in: Dalton transactions : an international journal of inorganic chemistry 2023-10, Vol.52 (38), p.13758-13768
• Main Authors: Martínez-Camarena, Álvaro, Sour, Angélique, Faller, Peter
• Format: Article
• Language: English
• Subjects: Chemical Sciences
• ISSN: 1477-9226; 1477-9234
• DOI: 10.1039/D3DT02380J

The chelator diacetyl-bis( N 4-methylthiosemicarbazone) (ATSM) and its complexes with Cu II and Zn II are becoming increasingly investigated for medical applications such as PET imaging for anti-tumour therapy and the treatment of amyotrophic lateral sclerosis. However, the solubility in water of both the ligand and the complexes presents certain limitations for in vitro studies. Moreover, the stability of the Cu II and Zn II complexes and their metal exchange reaction against the potential biological competitor human serum albumin (HSA) has not been studied in depth. In this work it was observed that the ATSM with an added carboxylic group into the structure increases its solubility in aqueous solutions without altering the coordination mode and the conjugated system of the ligand. The poorly water-soluble Cu II – and Zn II –ATSM complexes were prevented from precipitating due to the binding to HSA. Both HSA and ATSM show a similar thermodynamic affinity for Zn II . Finally, the Cu II -competition experiments with EDTA and the water-soluble ATSM ligands yielded an apparent log  K d at pH 7.4 of about −19. When ATSM was added to Cu II - and Zn II -loaded HSA, withdrawing of Zn II was kinetically favoured, but this metal is slowly substituted by the Cu II afterwards taken from HSA so that this protein could be considered as a source of Cu II for ATSM.