Volume 17, Issue 13 e202200135
Research Article

A Green Synthesis of Carbene-Metal-Amides (CMAs) and Carboline-Derived CMAs with Potent in vitro and ex vivo Anticancer Activity

Nikolaos V. Tzouras

Nikolaos V. Tzouras

Department of Chemistry and Centre for Sustainable Chemistry, Ghent University, Krijgslaan 281,S-3, 9000 Ghent, Belgium

Department of Chemistry, Laboratory of Organic Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, 15771 Athens, Greece

Search for more papers by this author
Dr. Thomas Scattolin

Dr. Thomas Scattolin

Department of Molecular Sciences and Nanosystems, Università Ca' Foscari, Campus Scientifico Via Torino 155, 30174 Venezia-Mestre, Italy

Pathology Unit, Centro di Riferimento Oncologico di Aviano (C.R.O.) IRCCS, via Franco Gallini 2, 33081 Aviano, Italy

Search for more papers by this author
Alberto Gobbo

Alberto Gobbo

Department of Chemistry and Centre for Sustainable Chemistry, Ghent University, Krijgslaan 281,S-3, 9000 Ghent, Belgium

Search for more papers by this author
Dr. Subhrajyoti Bhandary

Dr. Subhrajyoti Bhandary

Department of Chemistry and Centre for Sustainable Chemistry, Ghent University, Krijgslaan 281,S-3, 9000 Ghent, Belgium

Search for more papers by this author
Prof. Flavio Rizzolio

Corresponding Author

Prof. Flavio Rizzolio

Department of Molecular Sciences and Nanosystems, Università Ca' Foscari, Campus Scientifico Via Torino 155, 30174 Venezia-Mestre, Italy

Pathology Unit, Centro di Riferimento Oncologico di Aviano (C.R.O.) IRCCS, via Franco Gallini 2, 33081 Aviano, Italy

Search for more papers by this author
Enrico Cavarzerani

Enrico Cavarzerani

Department of Molecular Sciences and Nanosystems, Università Ca' Foscari, Campus Scientifico Via Torino 155, 30174 Venezia-Mestre, Italy

Search for more papers by this author
Prof. Vincenzo Canzonieri

Prof. Vincenzo Canzonieri

Pathology Unit, Centro di Riferimento Oncologico di Aviano (C.R.O.) IRCCS, via Franco Gallini 2, 33081 Aviano, Italy

Department of Medical, Surgical and Health Sciences, Università degli Studi di Trieste, Strada di Fiume 447, 34149 Trieste, Italy

Search for more papers by this author
Prof. Kristof Van Hecke

Prof. Kristof Van Hecke

Department of Chemistry and Centre for Sustainable Chemistry, Ghent University, Krijgslaan 281,S-3, 9000 Ghent, Belgium

Search for more papers by this author
Prof. Georgios C. Vougioukalakis

Prof. Georgios C. Vougioukalakis

Department of Chemistry, Laboratory of Organic Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, 15771 Athens, Greece

Search for more papers by this author
Prof. Catherine S. J. Cazin

Prof. Catherine S. J. Cazin

Department of Chemistry and Centre for Sustainable Chemistry, Ghent University, Krijgslaan 281,S-3, 9000 Ghent, Belgium

Search for more papers by this author
Prof. Steven P. Nolan

Corresponding Author

Prof. Steven P. Nolan

Department of Chemistry and Centre for Sustainable Chemistry, Ghent University, Krijgslaan 281,S-3, 9000 Ghent, Belgium

Search for more papers by this author
First published: 21 March 2022
Citations: 3

Graphical Abstract

Copper, silver, gold and green: A range of naturally occurring carboline alkaloid-derived carbene-metal-amide (CMA) complexes of copper, silver, and gold are synthesized for the first time under mild and operationally simple conditions. A screening against cancer cell lines and tumoroids reveals excellent cytotoxicity and selectivity in certain cases. A green purification of the compounds is showcased, in light of their promising biological/pharmacological function.

Abstract

The modularity and ease of synthesis of carbene-metal-amide (CMA) complexes based on the coinage metals (Au, Ag, Cu) and N-heterocyclic carbenes (NHCs) as ancillary ligands pave the way for the expansion of their applications beyond photochemistry and catalysis. Herein, we further improve the synthesis of such compounds by circumventing the use of toxic organic solvents which were previously required for their purification, and we expand their scope to include complexes incorporating carbolines as the amido fragments. The novel complexes are screened both in vitro and ex vivo, against several cancer cell lines and high-grade serous ovarian cancer (HGSOC) tumoroids, respectively. Excellent cytotoxicity values are obtained for most complexes, while the structural variety of the CMA library screened thus far, provides promising leads for future developments. Variations of all three components (NHC, metal, amido ligand), enable the establishment of trends regarding cytotoxicity and selectivity towards cancerous over normal cells.

Conflict of interest

The authors declare no conflict of interest.

Data Availability Statement

The data that support the findings of this study are available in the supplementary material of this article.