2. Academic Validation
  3. Increasing the π-Expansive Ligands in Ruthenium(II) Polypyridyl Complexes: Synthesis, Characterization, and Biological Evaluation for Photodynamic Therapy Applications

Increasing the π-Expansive Ligands in Ruthenium(II) Polypyridyl Complexes: Synthesis, Characterization, and Biological Evaluation for Photodynamic Therapy Applications

  • Inorg Chem. 2023 Nov 13;62(45):18510-18523. doi: 10.1021/acs.inorgchem.3c02606.
Maria Dalla Pozza 1,  Pierre Mesdom 1,  Ahmad Abdullrahman 2,  Tayler D Prieto Otoya 3,  Philippe Arnoux 4,  Céline Frochot 4,  Germain Niogret 5,  Bruno Saubaméa 6,  Pierre Burckel 7,  James P Hall 2,  Marcel Hollenstein 5,  Christine J Cardin 3,  Gilles Gasser 1
Affiliations

Affiliations

  • 1 Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health, Paris 75005, France.
  • 2 Department of Pharmacy, Chemistry and Pharmacy Building, University of Reading, Whiteknights Campus, Reading, Berkshire RG6 6AD, U.K.
  • 3 Department of Chemistry, University of Reading, Whiteknights, Reading RG6 6AD, U.K.
  • 4 Université de Lorraine, CNRS, LRGP, Nancy F-54000, France.
  • 5 Institut Pasteur, Université Paris Cité, CNRS UMR3523, Departement of Structural Biology and Chemistry, Laboratory for Bioorganic Chemistry of Nucleic Acids, Paris 75015, France.
  • 6 Université Paris Cité, INSERM, CNRS, P-MIM, Plateforme d'Imagerie Cellulaire et Moléculaire (PICMO), Paris F-75006, France.
  • 7 Université de Paris, Institut de physique du globe de Paris, CNRS, Paris F-75005, France.
PMID: 37913550 DOI: 10.1021/acs.inorgchem.3c02606
Abstract

Lack of selectivity is one of the main issues with currently used chemotherapies, causing damage not only to altered cells but also to healthy cells. Over the last decades, photodynamic therapy (PDT) has increased as a promising therapeutic tool due to its potential to treat diseases like Cancer or Bacterial infections with a high spatiotemporal control. Ruthenium(II) polypyridyl compounds are gaining attention for their application as photosensitizers (PSs) since they are generally nontoxic in dark conditions, while they show remarkable toxicity after LIGHT irradiation. In this work, four Ru(II) polypyridyl compounds with sterically expansive ligands were studied as PDT agents. The Ru(II) complexes were synthesized using an alternative route to those described in the literature, which resulted in an improvement of the synthesis yields. Solid-state structures of compounds [Ru(DIP)2phen]Cl2 and [Ru(dppz)2phen](PF6)2 have also been obtained. It is well-known that compound [Ru(dppz)(phen)2]Cl2 binds to DNA by intercalation. Therefore, we used [Ru(dppz)2phen]Cl2 as a model for DNA interaction studies, showing that it stabilized two different sequences of duplex DNA. Most of the synthesized Ru(II) derivatives showed very promising singlet oxygen quantum yields, together with noteworthy photocytotoxic properties against two different Cancer cell lines, with IC50 in the micro- or even nanomolar range (0.06-7 μM). Confocal microscopy studies showed that [Ru(DIP)2phen]Cl2 and [Ru(DIP)2TAP]Cl2 accumulate preferentially in mitochondria, while no mitochondrial internalization was observed for the other compounds. Although [Ru(dppn)2phen](PF6)2 did not accumulate in mitochondria, it interestingly triggered an impairment in mitochondrial respiration after LIGHT irradiation. Among Others, [Ru(dppn)2phen](PF6)2 stands out for its very good IC50 values, correlated with a very high singlet oxygen quantum yield and mitochondrial respiration disruption.

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