Conception, synthèse et étude photochimiques de complexes de ruthénium nitrosyle et de composés carborane-BODIPY pour des applications potentielles comme agent thérapeutique et l'imagerie cellulaire

La chimiothérapie photo-activée (PACT) est une approche thérapeutique basée sur la libération photo-induite d'une molécule toxique capable de produire la mort cellulaire. Comme la toxicité de la molécule est déclenchée localement par la lumière, la PACT offre un moyen élégant de détruire les cellules cancéreuses sans endommager les tissus sains avoisinants. Dans ce contexte, notre groupe de recherche a mis au point des complexes de ruthénium nitrosyle (RuNO) à ligands polypyridines, capables de libérer du NO• par absorption à deux photons. Ainsi, dans le Chapitre I, après avoir passé en revue l'état de l'art de ce type de thérapie, l'évaluation de l'influence de l'introduction d'un cycle thiényle dans le ligand polypyridine est décrite comme une stratégie pour améliorer la section efficace d'absorption de deux photons. Le Chapitre II se concentre sur la thérapie de capture des neutrons par le bore (BNCT), un type de radiothérapie dans laquelle l'énergie ionisante qui produit la mort cellulaire est générée par la fission des noyaux 10B après irradiation avec des neutrons de faible énergie. Comme la mort cellulaire est limitée aux cellules enrichies en bore, la BNCT permet de traiter sélectivement les tumeurs, en minimisant les dommages aux tissus sains avoisinants. En raison de en raison de sa forte teneur en bore, les carboranes (associations polyédriques bore-carbone) sont des candidats idéaux pour la BNCT. Après une analyse complète de l'état de l'art de la BNCT, nous présentons la synthèse, la caractérisation chimique et photochimique, et l'étude de l'entrée des cellules HeLa pour un groupe de carboranes fonctionnalisés avec les fluorophores BODIPY. Les résultats montrent que la lipophilie et le moment dipolaire ont une influence importante sur la facilité avec laquelle les fluorophores étudiés pénètrent dans le milieu intracellulaire, fournissant ainsi une explication à la perméabilité cellulaire divergente que ce type de composés présente habituellement.Photoactivated chemotherapy (PACT) is a therapeutic approach based on the photo-induced release of a toxic molecule capable of producing cell death; as the toxicity of the molecule is triggered locally by light, PACT provides an elegant way to destroy cancer cells without damaging nearby healthy tissues. In this context, our research group has been developing ruthenium nitrosyl complexes (RuNO) with polypyridyl ligands which are capable of releasing NO• via two-photon absorption (TPA). In Chapter I, after reviewing the state of the art of PACT, the evaluation of the influence of the introduction of a thienyl ring in the polypyridyl ligand is described as a strategy to improve the two-photon absorption cross sections of the complexes. Chapter II focuses on Boron Neutron Capture Therapy (BNCT), a type of radiation therapy in which the ionizing energy that produces cell death is generated by the fission of 10B nuclei after irradiation with low energy neutrons. Because cell death is restricted to boron-enriched cells, BNCT provides the ability to selectively treat tumors, minimizing damage to nearby healthy tissues. Due to their high boron contents, carboranes (polyhedral carbon-boron clusters) are ideal candidates for BNCT. After a comprehensive analysis of the state of the art of BNCT, we present the synthesis, chemical and photochemical characterization, and the study of cell entry on HeLa cells for a group of carboranes functionalized with BODIPY fluorophores. The results show that lipophilicity and the dipole moment have an important influence on the ease with which the fluorophores studied permeate to the intracellular media, thus providing an explanation for the divergent cellular permeability that this type of compounds usually show

Síntesis de ligantes derivados de 2,2:6,2-terpiridina para la formación de complejos Ru con posible actividad óptica no lineal

Ciencias Química

Two-photon absorption-based delivery of nitric oxide from ruthenium nitrosyl complexes

International audienceSince the discovery of the numerous physiological roles exhibited by nitric oxide (NO), ruthenium nitrosyl (RuNO) complexes have been regarded as one of the most promising NO donors, stable, well tolerated by the body and capable of releasing NO locally and quantitatively, under light irradiation. This release can be achieved by two-photon absorption (TPA) processes, which allow the irradiation to be performed in the near infrared domain, where light has its maximum depth of penetration in biological tissues. This review provides a short introduction on the biological properties of NO, on RuNO complexes with photo-releasing capabilities, and on the origin of TPA properties in molecules. Then, the RuNO complexes with TPA capabilities are thoroughly discussed either as monometallic or polymetallic species

Chemical and photochemical behavior of ruthenium nitrosyl complexes with terpyridine ligands in aqueous media

International audienceThe synthesis and behavior in water of a set of various cis(Cl,Cl)-[R-tpyRuCl2(NO)](PF6) and trans(Cl,Cl)-[R-tpyRuCl2(NO)](PF6) (R = fluorenyl, phenyl, thiophenyl; tpy = 2,2′:6′,2′′-terpyridine) complexes are presented. In any case, one chlorido ligand is substituted by a hydroxo ligand and the final species arises as a single trans(NO,OH) isomer, whatever the nature of the starting cis/trans(Cl,Cl) complexes. Six X-ray crystal structures are presented for cis(Cl,Cl)-[thiophenyl-tpyRuCl2(NO)](PF6) (cis-3a), trans(Cl,Cl)-[thiophenyl-tpyRuCl2(NO)](PF6) (trans-3a), trans(NO,OH)-[phenyl-tpyRu(Cl)(OH)(NO)](PF6) (4a), trans(NO,OH)-[thiophenyl-tpyRu(Cl)(OH)(NO)](PF6) (4b), trans(NO,OEt)-[phenyl-tpyRu(Cl)(OEt)(NO)](PF6) (5a), and trans(NO,OH)-[phenyl-tpyRu(Cl)(OEt)(NO)](PF6) (5b) compounds. The different cis/trans(Cl,Cl) complexes exhibit an intense low-lying transition in the λ = 330–390 nm range, which appears to be slightly blue-shifted after Cl → OH substitution. In water, both cis/trans(Cl,Cl) isomers are converted to a single trans(NO,OH) isomer in which one chlorido- is replaced by one hydroxo-ligand, which avoids tedious separation workout. The water stable trans(NO,OH)-species all release NO with quantum yields of 0.010 to 0.075 under irradiation at 365 nm. The properties are discussed with computational analysis performed within the framework of Density Functional Theory

Crystal structures and conformational effects in bis-fluorenyl based ligands and related ruthenium nitrosyl complexes

International audienceFour crystal structures (two ruthenium complexes and two ligands) are presented containing a bis-fluorene fragment on which alkyl chains (methyl and hexyl) are grafted. The possibility to get both cisoid and transoid conformations in the bis-fluorene units is discussed. A computational investigation using the density functional theory indicates a tendency for a gradual stabilization of the cisoid form, as the length of the chains increases. The effect of the conformation on the charge transfer electronic properties of bis-fluorene based materials is discussed computationally at one-photon absorption (OPA) level and tentatively at two-photon absorption (TPA) levels, but it is found to be modest

Acetylacetonate Ruthenium Nitrosyls: A Gateway to Nitric Oxide Release in Water Under Near-Infrared Excitation by Two-Photon Absorption

A fundamental challenge for phototriggered therapies is to obtain robust molecular frameworks that withstand biological media. Photoactivatable nitric oxide (NO) releasing molecules (photoNORMs) based on ruthenium nitrosyl (RuNO) complexes lie among the most studied systems due to several appealing features that make them attractive for therapeutic applications. Nevertheless, the propensity of the NO ligand to be attacked by nucleophiles frequently manifests as a significant instability in water for this class of photoNORMs. Our approach to overcome this limitation involved enhancing the Ru-NO π-backbonding to lower the electrophilicity at the NO by replacing the commonly employed 2,2’-bipyridine (bpy) ligand by an anionic, electron-rich, acetylacetonate (acac). A versatile and convenient synthetic route is developed and applied for the preparation of a large library of RuNO photoNORMs with the general formula [RuNO(tpy)(acac)]2+ (tpy=2,2’:6’,2’’-terpyridine). A combined theoretical and experimental analysis of the Ru-NO bonding in these complexes is presented, supported by extensive single-crystal X-Ray diffraction experiments and by topological analyses of the electron charge density by DFT. The enhanced π-backbonding, systematically evidenced by several techniques, resulted in a remarkable stability in water for these complexes, where significant NO release efficiencies were recorded. We finally demonstrate the possibility of obtaining sophisticated water-stable multipolar NO-delivery platforms that can be activated in the near-IR region by two-photon absorption (TPA), as demonstrated for an octupolar complex with a TPA cross section of 1530 GM at λ = 800 nm and for which NO photorelease was demonstrated under TPA irradiation in aqueous media

A Trojan horse approach for enhancing the cellular uptake of a ruthenium nitrosyl complex

International audienceRuthenium nitrosyl (RuNO) complexes continue to attract significant research interest due to several appealing features that make these photoactivatable nitric oxide (NO˙) donors attractive for applications in photoactivated chemotherapy. Interesting examples of molecular candidates capable of delivering cytotoxic concentrations of NO˙ in aqueous media have been discussed. Nevertheless, the question of whether most of these highly polar and relatively large molecules are efficiently incorporated by cells remains largely unanswered. In this paper, we present the synthesis and the chemical, photophysical and photochemical characterization of RuNO complexes functionalized with 17α-ethinylestradiol (EE), a semisynthetic steroidal hormone intended to act as a molecular Trojan horse for the targeted delivery of RuNO complexes. The discussion is centered around two main molecular targets, one containing EE (EE-Phtpy-RuNO) and a reference compound lacking this biological recognition fragment (Phtpy-RuNO). While both complexes displayed similar optical absorption profiles and NO˙ release efficiencies in aqueous media, important differences were found regarding their cellular uptake towards dermal fibroblasts, with EE-Phtpy-RuNO gratifyingly displaying a remarkable 10-fold increase in cellular uptake when compared to Phtpy-RuNO, thus demonstrating the potential drug-targeting capabilities of this biomimetic steroidal conjugate

Development of an antimicrobial and antioxidant hydrogel/nano-electrospun wound dressing

A nanocomposite based on an antibiotic-loaded hydrogel into a nano-electrospun fibre with antimicrobial and antioxidant capacities is investigated. The material is composed of nanofibres of enzymatic PCL grafted with poly(gallic acid) (PGAL), a recently developed enzyme-mediated hydrophilic polymer that features a multiradical and polyanionic nature in a helicoidal secondary structure. An extensive experimental–theoretical study on the molecular structure and morphological characterizations for this nanocomposite are discussed. The hydrogel network is formed by sodium carboxymethylcellulose (CMC) loaded with the broad-spectrum antibiotic clindamycin. This nano electrospun biomaterial inhibits a strain of Staphylococcus aureus, which is the main cause of nosocomial infections. The SPTT assay demonstrates that PGAL side chains also improve the release rates for this bactericide owing to the crosslinking to the CMC hydrogel matrix. The absence of hemolytic activity and the viability of epithelial cells demonstrates that this nanocomposite has no cytotoxicity.Postprint (published version