Research objectives and work plan are organized in four Work Packages (WPs). Below a summary of the results obtained for each WP.
WP1: Within this WP, I prepared five AuI-NHC complexes and their corresponding new AuIII-NHC analogues in the cold lab. They have been fully characterized with standard techniques. All reactions have been performed and optimized in the cold chemistry using non-radioactive iodine. The most suitable compound (in terms of yield and stability in aqueous media) was then synthesized using the selected radioisotopes.
WP2: The dark stability of the synthesized compounds was investigated in buffer and in cell culture media (supplemented with fetal bovine serum). Two Au(III) compounds out of five were completely stable in buffer, while only one resulted moderately stable in biological relevant media. As a consequence, WP3 and WP4 have been focused on this lead compound, namely the Au(III) biscarbenic complex with 1-butyl-3-methyl-imidazol-2-ylidene NHC ligand (3). The photochemistry of such derivative in buffer was investigated with spectroscopic methods, however its moderate dark stability when solubilized in cell culture media, ruled out its use in advance biological studies. Therefore, the project has focused more on the Au(III) activation to Au(I) of 3 by biological agents in vitro and in vivo.
WP3: In order to investigate the behavior of the Au(III) derivative at the cellular level, a series of in vitro assays have been performed. Minor but important changes between the activity of the Au(III) and the Au(I) complexes in the different experimental conditions used have been observed indicating that the Au(III) compound can be considered as a drug per se and not a simple Au(I) prodrug. Furthermore, a clear-cut difference in their mode of action compared with the standard gold drug auranofin was observed, in contrast to recent literature where no particular divergences have been noted.
WP4: The lead Au(III) compound was synthesized using direct oxidation with radioactive I2 and its biodistribution in vivo was followed via PET imaging. Using this approach, we were able to dissect the reduction path of this compound once intravenously injected in healthy rats. The metal complex was rapidly, but not immediately, reduced to the Au(I) analogue as captured by PET imaging and ICP in comparison with [124I]KI control.
List of publications
1) F. Guarra, A. Terenzi*, C. Gabbiani, T. Biver, V. Gomez, J. Llop, C. Pirker, W. Berger, E. Zangrando, L. Salassa - “124I-radiolabeling of a Au(III)-NHC complex for in vivo biodistribution studies” - In Preparation (to be submitted to Angew. Chem. Int. Ed.)
2) G. Salassa, A. Terenzi* - Int. J. Mol. Sci. 2019, 20, 3483 DOI: 10.3390/ijms20143483
3) A. Terenzi*, H. Gattuso, A. Spinello, B.K. Keppler, C. Chipot, F. Dehez, G. Barone, A. Monari - Antioxidants 2019, 8, 472 DOI: 10.3390/antiox8100472
List of Conferences, workshops and and seminars in international institutes
1) 9th Asian Biological Inorganic Chemistry Conference (Asbic, Singapore 9-14 Dec 2018) “Award: Outstanding Oral Presentation”
2) 17th Congress of the International Union of Photobiology and 18th Congress of the European Society for Photobiology (Barcelona 25-30 Aug 2019)
3) 3rd Biennial Young Researchers Workshop on Biomaterials and Applications (bioMAPP19, Bilbao 4-5 Dec 2019)
4) Member of the organizing committee of the workshop “From Bioinorganic Chemistry to Catalysis 2019”, organized by DIPC (Donostia, 8 Nov 2019).
5) Invited lecture at Madrid Institute of Advanced Studies (IMDEA), Madrid (Spain) 15 Feb 2019
Outreach activities
1) Pint of Science 2018 (Donostia, 14-16 May 2018) -
https://pintofscience.es/events/sansebastian(öffnet in neuem Fenster)2) Eureka! Zienzia Museoa “A Life in Science” (Donostia, 5 November 2018) -
https://www.eurekamuseoa.eus/es/encuentro-de-vidas-cientificas(öffnet in neuem Fenster)3) Creativium Project (Donostia, 17 January 2019) -
https://p4k.dipc.org/en/photographic-exhibition(öffnet in neuem Fenster)
