Metal complexes constitute an important class of DNA binders. In particular, a few ruthenium polyazaaromatic complexes are attractive as "light switches" because of their strong luminescence enhancement upon DNA binding. In this paper, a comprehensive study on the binding modes of several mononuclear and binuclear ruthenium complexes to human telomeric sequences, made of repeats of the d(TTAGGG) fragment is reported. These DNA sequences form G-quadruplexes (G4s) at the ends of chromosomes and constitute a relevant biomolecular target in cancer research. By combining spectroscopy experiments and molecular modelling simulations, several key properties are deciphered: the binding modes, the stabilization of G4 upon binding, and the selectivity of these complexes towards G4 versus double-stranded DNA. These results are rationalized by assessing the possible deformation of G4 and the binding free energies of several binding modes via modelling approaches. Altogether, this comparative study provides fundamental insights into the molecular recognition properties and selectivity of Ru complexes towards this important class of DNA G4s.

Photoactive ruthenium-based complexes are actively studied for their biological applications as potential theragnostic agents against cancer. One major issue of these inorganic complexes is to penetrate inside cells in order to fulfil their function, either sensing the internal cell environment or exert a photocytotoxic activity. The use of lipophilic ligands allows the corresponding ruthenium complexes to passively diffuse inside cells but limits their structural and photophysical properties. Moreover, this strategy does not provide any cell selectivity. This limitation is also faced by complexes anchored on cell-penetrating peptides. In order to provide a selective cell targeting, we developed a multivalent system composed of a photoreactive ruthenium(II) complex tethered to a calix[4]arene platform bearing multiple RGD-containing cyclopentapeptides. Extensive photophysical and photochemical characterizations of this Ru(II)–calixarene conjugate as well as the study of its photoreactivity in the presence of guanosine monophosphate have been achieved. The results show that the ruthenium complex should be able to perform efficiently its photoinduced cytotoxic activity, once incorporated into targeted cancer cells thanks to the multivalent platform.

Organic transformations can broadly be classified into four categories including cationic, anionic, pericyclic and radical reactions. While the last category has been known for decades to provide remarkably efficient synthetic pathways, it has long been hampered by the need for toxic reagents, which considerably limited its impact on chemical synthesis. This situation has come to an end with the introduction of new concepts for the generation of radical species, photoredox catalysis - which simply relies on the use of a catalyst that can be activated upon visible light irradiation - certainly being the most efficient one. The state-of-the-art catalysts mostly rely on the use of ruthenium and iridium complexes and organic dyes, which still considerably limits their broad implementation in chemical processes: alternative readily available catalysts based on inexpensive, environmentally benign base metals are therefore strongly needed. Furthermore, expanding the toolbox of methods based on photoredox catalysis will facilitate the discovery of new light-mediated transformations. This article details the use of a simple copper complex which, upon activation with blue light, can initiate a broad range of radical reactions.

Polyazaaromatic ruthenium(ii) complexes have been largely studied over the last decades, particularly in the scope of the biological applications, for the development of new diagnostic and phototherapeutic agents. In this context, Ru(ii) complexes able to react with biomolecules upon excitation are of great interest. Photo-oxidizing Ru(ii) complexes based on π-deficient ligands, such as bpz (2,2'-bypyrazine) and TAP (1,4,5,8-tetraazaphenathrene), were designed to allow a photo-induced electron transfer (PET) to take place in presence of biomolecules, thanks to their highly photo-oxidizing 3MLCT state. This PET can occur from either a guanine moiety (G) or a tryptophan residue (Trp) to the excited complex and can ultimately lead to the formation of a photoadduct, i.e. the formation of a covalent bond between the Ru(ii) complex and the G or Trp moieties of a biomolecule. Here, we report the synthesis of two new photo-oxidizing Ru(ii) complexes, [Ru(TAP)2bpz]2+ and [Ru(bpz)2TAP]2+, and the study of their photophysical and electrochemical properties. The influence of the structure of the ligand bpz/TAP on the photophysical and electrochemical properties of the four resulting complexes has been precisely determined thanks to the experimental and theoretical data obtained for to these new complexes.

A broadly applicable copper catalyst for photoredox transformations of organic halides is reported. Upon visible light irradiation in the presence of catalytic amounts of [(DPEphos)(bcp)Cu]PF6 and an amine, a range of unactivated aryl and alkyl halides were shown to be smoothly activated through a rare Cu(I)/Cu(I)*/Cu(0) catalytic cycle. This complex efficiently catalyzes a series of radical processes, including reductions, cyclizations, and direct arylation of arenes.

The photoreactive [Ru(TAP)(2)(phen)](2+) (TAP = 1,4,5,8-tetraazaphenanthrene; phen = 1,10-phenanthroline) complex tethered to the cell-penetrating peptide (CPP) TAT was studied in vitro and in cellulo. The tethering of the complex does not affect its behavior under blue-light irradiation in the presence of guanine-containing oligodeoxyribonucleotides (ODNG). Thus, the luminescence is quenched in the presence of ODNG, and gel electrophoresis experiments showed the appearance of products corresponding to the irreversible attachment of the conjugate to ODNG upon illumination. The cellular uptake of the conjugate was examined by flow cytometry, inductively coupled plasma mass spectrometry (ICP-MS), and confocal imaging microscopy. These experiments showed that the [Ru(TAP)(2)(phen-TAT)] conjugate is readily taken up by HeLa cells and, despite these favorable factors, the cellular survival was 100%, as measured by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. A possible origin of the inactivity of [Ru(TAP)(2)(phen-TAT)] under irradiation is proposed on the basis of the fluorescence-activated cell sorting (FACS), ICP-MS, and confocal microscopy results.

Le laboratoire de Chimie Organique et Photochimie de l’ULB s’est intensivement implique dans la recherche portant sur le developpement et l’etude de complexes polyazaaromatiques de rutheniumII. En utilisant des ligands π-deficients tels que le 1,4,5,8-tetraazaphenanthrene (TAP) chelates au centre metallique de RuII, des proprietes d’oxydo-reduction particulieres a l’etat excite du complexe peuvent etre obtenues. Cette recherche s’est principalement focalisee sur l’etude de complexes de RuII photoreactifs dans un cadre biologique puisque ces complexes sont capables de photoreagir avec le materiel genetique ou les proteines par l’intermediaire d’un transfert d’electron photo-induit (PET). Cependant, il existe un obstacle majeur a l’utilisation therapeutique des complexes polyazaaromatiques de RuII, a savoir leur incapacite a traverser d’eux-memes la membrane des cellules vivantes. Ce projet vise a developper une strategie ciblee de vectorisation de ces complexes, ce qui pourrait permet d’administrer l’agent therapeutique uniquement aux cellules « malades ». Le ciblage de recepteurs surexprimes par les cellules endotheliales neo-formees, tels que l’integrine αvβ3, a ete envisage dans le cadre de ce travail grâce a un ligand peptidique c(RGDfK). Ce ciblage associe a l’utilisation d’un complexe photoreactif de RuII permettrait un controle du type cellulaire, par la reconnaissance des integrines αvβ3, ainsi qu’un controle temporel de l’activite therapeutique du complexe, par l’illumination. De maniere a combiner ces agents de ciblage et l’agent therapeutique (complexe de RuII), des plateformes moleculaires de deux types ont ete utilisees et comparees entre elles, a savoir le cyclodecapeptide RAFT et un calix[4]arene. La synthese des conjugues RuII-RAFT-[c-(RGDfK)]4 et le RuII-calix[4]arene-[c-(RGDfK)]4 a donc ete realisee avec succes et leurs proprietes photophysiques et photochimiques ont ete etudiees de maniere a verifier que la presence de la plateforme ne modifie pas les proprietes des complexes de RuII ancres. Enfin, la penetration des conjugues a egalement ete evaluee et ce, sur differentes lignees cellulaires, de maniere a mettre en evidence la specificite du ciblage pour les recepteurs membranaires αvβ3.