Increasing the Cytotoxicity of Ru(II) Polypyridyl Complexes by Tuning the Electronic Structure of Dioxo Ligands

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2020
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Notaro, Anna
Jakubaszek, Marta
Maschietto, Federica
Vinck, Robin
Felder, Patrick S.
Goud, Bruno
Tharaud, Mickaël
Ciofini, Ilaria
Bedioui, Fethi
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Journal of the American Chemical Society (JACS). American Chemical Society (ACS). 2020, 142(13), pp. 6066-6084. ISSN 0002-7863. eISSN 1520-5126. Available under: doi: 10.1021/jacs.9b12464
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Due to the great potential expressed by an anticancer drug candidate previously reported by our group, namely, Ru-sq (Ru(DIP)2(sq) (DIP, 4,7-diphenyl-1,10-phenanthroline; sq, semiquinonate ligand), we describe in this work a structure–activity relationship (SAR) study that involves a broader range of derivatives resulting from the coordination of different catecholate-type dioxo ligands to the same Ru(DIP)2 core. In more detail, we chose catechols carrying either an electron-donating group (EDG) or an electron-withdrawing group (EWG) and investigated the physicochemical and biological properties of their complexes. Several pieces of experimental evidences demonstrated that the coordination of catechols bearing EDGs led to deep-red positively charged complexes 1–4 in which the preferred oxidation state of the dioxo ligand is the uninegatively charged semiquinonate. Complexes 5 and 6, on the other hand, are blue/violet neutral complexes, which carry an EWG-substituted dinegatively charged catecholate ligand. The biological investigation of complexes 1–6 led to the conclusion that the difference in their physicochemical properties has a strong impact on their biological activity. Thus, complexes 1–4 expressed much higher cytotoxicities than complexes 5 and 6. Complex 1 constitutes the most promising compound in the series and was selected for a more in depth biological investigation. Apart from its remarkably high cytotoxicity (IC50 = 0.07–0.7 μM in different cancerous cell lines), complex 1 was taken up by HeLa cells very efficiently by a passive transportation mechanism. Moreover, its moderate accumulation in several cellular compartments (i.e., nucleus, lysosomes, mitochondria, and cytoplasm) is extremely advantageous in the search for a potential drug with multiple modes of action. Further DNA metalation and metabolic studies pointed to the direct interaction of complex 1 with DNA and to the severe impairment of the mitochondrial function. Multiple targets, together with its outstanding cytotoxicity, make complex 1 a valuable candidate in the field of chemotherapy research. It is noteworthy that a preliminary biodistribution study on healthy mice demonstrated the suitability of complex 1 for further in vivo studies.

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ISO 690NOTARO, Anna, Marta JAKUBASZEK, Nils ROTTHOWE, Federica MASCHIETTO, Robin VINCK, Patrick S. FELDER, Bruno GOUD, Mickaël THARAUD, Ilaria CIOFINI, Fethi BEDIOUI, Rainer F. WINTER, Gilles GASSER, 2020. Increasing the Cytotoxicity of Ru(II) Polypyridyl Complexes by Tuning the Electronic Structure of Dioxo Ligands. In: Journal of the American Chemical Society (JACS). American Chemical Society (ACS). 2020, 142(13), pp. 6066-6084. ISSN 0002-7863. eISSN 1520-5126. Available under: doi: 10.1021/jacs.9b12464
BibTex
@article{Notaro2020-04-01Incre-49856,
  year={2020},
  doi={10.1021/jacs.9b12464},
  title={Increasing the Cytotoxicity of Ru(II) Polypyridyl Complexes by Tuning the Electronic Structure of Dioxo Ligands},
  number={13},
  volume={142},
  issn={0002-7863},
  journal={Journal of the American Chemical Society (JACS)},
  pages={6066--6084},
  author={Notaro, Anna and Jakubaszek, Marta and Rotthowe, Nils and Maschietto, Federica and Vinck, Robin and Felder, Patrick S. and Goud, Bruno and Tharaud, Mickaël and Ciofini, Ilaria and Bedioui, Fethi and Winter, Rainer F. and Gasser, Gilles}
}
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    <dcterms:abstract xml:lang="eng">Due to the great potential expressed by an anticancer drug candidate previously reported by our group, namely, Ru-sq ([Ru(DIP)&lt;sub&gt;2&lt;/sub&gt;(sq)](PF&lt;sub&gt;6&lt;/sub&gt;) (DIP, 4,7-diphenyl-1,10-phenanthroline; sq, semiquinonate ligand), we describe in this work a structure–activity relationship (SAR) study that involves a broader range of derivatives resulting from the coordination of different catecholate-type dioxo ligands to the same Ru(DIP)&lt;sub&gt;2&lt;/sub&gt; core. In more detail, we chose catechols carrying either an electron-donating group (EDG) or an electron-withdrawing group (EWG) and investigated the physicochemical and biological properties of their complexes. Several pieces of experimental evidences demonstrated that the coordination of catechols bearing EDGs led to deep-red positively charged complexes 1–4 in which the preferred oxidation state of the dioxo ligand is the uninegatively charged semiquinonate. Complexes 5 and 6, on the other hand, are blue/violet neutral complexes, which carry an EWG-substituted dinegatively charged catecholate ligand. The biological investigation of complexes 1–6 led to the conclusion that the difference in their physicochemical properties has a strong impact on their biological activity. Thus, complexes 1–4 expressed much higher cytotoxicities than complexes 5 and 6. Complex 1 constitutes the most promising compound in the series and was selected for a more in depth biological investigation. Apart from its remarkably high cytotoxicity (IC&lt;sub&gt;50&lt;/sub&gt; = 0.07–0.7 μM in different cancerous cell lines), complex 1 was taken up by HeLa cells very efficiently by a passive transportation mechanism. Moreover, its moderate accumulation in several cellular compartments (i.e., nucleus, lysosomes, mitochondria, and cytoplasm) is extremely advantageous in the search for a potential drug with multiple modes of action. Further DNA metalation and metabolic studies pointed to the direct interaction of complex 1 with DNA and to the severe impairment of the mitochondrial function. Multiple targets, together with its outstanding cytotoxicity, make complex 1 a valuable candidate in the field of chemotherapy research. It is noteworthy that a preliminary biodistribution study on healthy mice demonstrated the suitability of complex 1 for further in vivo studies.</dcterms:abstract>
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