Since the 2000’s a lot of regulations for the chemical and pharmaceutical industries have appeared especially in terms of efficiency, waste management and energy input. All these issues are now addressed and termed « Green Chemistry » a multifaceted field dealing with what we call the twelve principles of P. T. Anastas and J. C. Warner. Most important of them are: atom economy, preventing the use of solvents volatile and/or toxic, minimize chemical waste and minimize energy. By focusing on the Green Chemistry reactions, the alternative energy sources that appeared and developed are: photochemistry through light excitation, microwave, sonochemistry irradiation, and mechanochemistry.

According to IUPAC, a mechanochemical reaction is a “Chemical reaction that is induced by the direct absorption of mechanical energy”. Wilhelm Ostwald (Nobel Prize in 1909), was the first who mentioned the term “Mechanochemistry” and defined it as a “branch of chemistry which is concerned with chemical and physico-chemical changes of substances of all states of aggregation due to the influence of mechanical energy”. In the two last decades, mechanochemistry has been developed considerably in a multitude of areas such as:  inorganic compounds and metal complexes synthesis, catalysis, polymers, nanomaterials, and organic synthesis used for creating carbon-carbon, carbon-heteroatom, metal-ligand coordination bonds. It is important to point out also the many efforts developed towards mechanistic level understanding of mechanochemical processes and the possible links between the mechanical effect and the action of the forces generated at the molecular level.

– 1992: NO named ‘Molecule of the Year’ by the journal Science

– 1997: Creation of the journal Nitric Oxide (impact factor = 4.4)

– 1998: Nobel Prize awarded to NO research
 

The best NO source agents are ruthenium-nitrosyl complexes (RuNO) which release NO under light irradiation, according to the following reaction:

[RuIIL5NO]n+/- + solvent → [RuIIIL5-(solvent)]n+/- + NO

The intense research activity resulting from their study is illustrated in Figure 1. There has been a fivefold increase in the annual rate of publications over the last 20 years.

There are two obstacles to the development of the application of RuNO complexes in biological media: (i) the inherent toxicity of NO which requires it to be delivered locally and quantitatively and (ii) the need to use radiation of wavelength = 300 – 500 nm, i.e. outside the relative transparency range of biological tissues ( = 600 – 1300 nm). These pitfalls can be avoided by using two-photon absorption (TPA) in which the transition (300-500 nm) is made by absorbing two photons of double wavelength (600-1000) (see Figure 3). The TPA technique has the added advantage of being localized to the focal point of the radiation, which offers the possibility of working on a targeted cell, thus avoiding collateral damage to healthy tissue.

The TPA properties of these systems are studied by Z-scan, a technique that gives access to the “molecular cross section” (σ) which quantifies the ability of the molecule to absorb two photons in a manner similar to the molar extinction coefficient used for one-photon absorption. σ is expressed in Goppert-Mayer (GM). In the case of monometallic RuNOs the values of vary between 100 and 200 GM. An even more ambitious approach is to study polynuclear RuNOs like those shown in Figure 5.

The first research on RuNOs carried out in the laboratory aimed to consider these systems only as switchable optical materials. They were then studied in a purely organic medium (acetonitrile) or in the solid state. Looking at them as biological molecules requires studying them in water

The [FTRu(bipy)(NO)]³⁺ complex is only stable in acidic conditions and transforms to [FTRu(bipy)(NO₂)]⁺ after few minutes at pH=7. However, complexes based on the [Ru(terpy)(Cl)₂(NO)]⁺ stabilize as [Ru(terpy)(OH)(Cl)(NO)]⁺ (highly stable over a long period in the dark). It is interesting to note that the final compound is the same regardless of the starting isomer, thus avoiding the need for a separation method that can be very difficult to implement. The reaction is illustrated in Figure 7. It is observed for all tridentate substituted terpyridine ligands.

Obtaining materials with an atom or molecule that can be switched into two distinct states can generate storage capacities comparable to those of the DNA molecule, i.e. of the order of a terabyte/cm³. The choice of photochromic systems was made in favor of ruthenium complexes with a nitrosyl ligand for which two metastable states (MS1, MS2) resulting from the presence of the ruthenium-nitrosyl bond can be observed. Structural studies have shown different conformations of the Ru-NO unit depending on the state concerned.

[Ru^IINO] ^hν→ [Ru^II(ON)]

Among complexes prepared in the group, [Ru(NO)Cl(py)₄](PF₆)₂.1/2H₂O exhibit remarkable quasi-complete commutation properties at the solid state (coll. M. Buron-Lecointe).

Over the past two decades, antibiotic resistance in many pathogens, including those involved in hospital-acquired diseases, has been on the rise. In 2016, Margaret Chan, Director General of the World Health Organization, called this resistance “a global crisis, now recognized as one of the most important health threats”.

Staphylococcus epidermidis strains are among the most common bacteria involved in human infections. S. epidermidis is generally the most important cause of infection, and the second most common cause of medical device infections.

These bacteria are able to accumulate in a hydrophobic biofilm that adheres to surfaces such as medical devices. Often these infections become chronic as the immune system is unable to rid itself of these microorganisms.

Given the difficulties encountered by conventional antibiotics in treating certain infections, particularly those caused by biofilms, there is an urgent need to develop new therapies to combat antimicrobial resistance.

Nitric oxide has bactericidal properties and is described as being able to induce the dispersion of bacterial biofilms.

Nitrosyl-based ruthenium complexes are therefore potential antimicrobial agents.

The controlled release of the bactericidal agent by light makes it possible to imagine new targeted and controlled therapies.