Hybrid organic-inorganic polyoxometalates with biological and optical properties – BIOOPOM

The first step of the project consisted in the synthesis of the bisphosphonate ligands, either following published procedures or developing the synthesis of new organic molecules. The M/BP (M = Mo, W, V) complexes were then synthesized by systematic variations of the pH, the metal/ligand ratio and/or the nature of the counter-ions. One difficulty lied in the formation of crystals of sufficient good quality for single-crystal X-ray diffraction. These complexes were also characterized by 31P NMR spectroscopy, which can allow to study their stability in solution. When a compound was fully characterized, it was either sent to the United States (for the biological properties) or to Nantes (for the optical properties). Structure-properties correlations have been established and have oriented the synthesis towards the most efficient molecules.

We have succeeded in synthesizing several complexes with Mo(VI), W(VI) et V(IV, V) ions and bisphosphonate ligands with the general formula [O3PC(OH)(R)PO3]4-, biologically active, such as alendronate (R=(CH2)3NH2) and zoledronate (R=C4H5N2). These complexes have been characterized by many techniques (X-ray diffraction, electrochemistry, EPR, SQUID, NMR) and their activity against 3 types of human tumor cell lines has been measured by our collaborators in the United States. This study shows that the activity of Mo(VI) complexes depends on the structure of the complex and the nature of the grafted bisphosphonate while the vanadium complexes are very active whatever their composition and structure. However, in vivo studies have evidenced their toxicity. W(VI) complexes have a low activity. Besides, we have shown that the addition of an heterometal seems to have a benefic effect. A patent has been filed on this class of molecules. Concerning photochromic materials, we have synthesized in ILV a family of hexa and dodecanuclear Mo(VI) complexes with ligands derived from alendronate. In these complexes, the ammonium groups are hydrogen-bonded with oxygen atoms of the polyoxometalate. We have also been able to evidence a new class of photochromic molecules with sulfonium groups. Furthermore, a new family of hybrid materials particularly interesting in which one or two spiropyran moieties are grafted on an Anderson type POM has been characterized, opening the way to the synthesis of multifunctional molecules associating a photochromic molecule and either another photochromic or a luminescent molecule. Finally, seven novel hybrid materials have been obtained by the supramolecular association of various POMs and cationic spiropyran molecules and it has been possible to establish structure-properties relationships.

The BIOOPOM project opens particularly interesting perspectives in the biomedical field. Indeed, we have shown the influence of the nature of the ligand, the nuclearity of the complex and the addition of an heterometal on the antitumoral properties of the hybrid polyoxomolybdates. The zoledronate is for the moment the most efficient BP in this class of molecules. We are currently working on the synthesis of hybrid POMs with lipophilic zoledronate molecules which have proved to be very active alone. Concerning the photochromic properties, this project is going on with the synthesis of supramolecular assemblies of POMs and cationic spiropyran molecules substituted by CF3 group which stabilize the open form, spironaphtoxazin (SN), diarylethene (in collaboration with V. Guerchais in Rennes) and also BODIPY. For the covalent systems, the SP-POM platform, which is formed by an Anderson type POM on which is grafted a spiropyran molecule, gives access to multifunctional molecules. Besides SP-POM-SN and SP-POM-BODIPY systems which are already published, it is possible to isolate molecules with amphiphilic C12 and C16 chains. The group of Tianbo Liu in the United States is currently studying the formation of vesicles with these POMs. Finally, we are also planning to associate luminescent Ir(III) complexes either covalently or ionically to POMs in a manner similar to what we have done on photochromic molecules.

The BIOOPOM project has been particularly productive as it has already lead to the publication of 11 papers of which 2 on biological properties, 8 on optical materials and 1 review article (4 Inorg. Chem., 2 Chem. Commun., 2 J. Mat. Chem. C, 1 Chem. Eur. J., 1 J. Clust. Sci., 1 Inorganics). 5 other manuscripts are either submitted or in preparation. The results have also been presented in 20 oral communications. Furthermore, a patent has been filed in May 2015 on the class of molecules which are the most active against breast tumors.

The BIOOPOM proposal consists in the elaboration of a new class of multifunctional molecular compounds built of polyoxometalates (abbreviated POMs and defined as discrete anionic metal-oxygen clusters built from the connection of {MOx} polyhedra (M = V(IV,V), Mo(VI), W(VI),…)) and grafted organic ligands bearing functional groups. This class of molecules offers the opportunity to target for the same family of hybrid compounds two important properties: photochromism and anti-cancer activities. This project arises from recent promising preliminary results on a Mo(VI)/bisphosphonate POM with both optical and biological activities and described in two articles published at the end of 2010 (Chem. Commun. 2010, 46, 7733 and Chem. Eur. J. 2010, 16, 13741 respectively).

First, it can be underlined that in the solid state the photochromic performances (coloration speed, color contrast) of POMs can compete with that of purely organic photo-active molecules. For POMs, the photochromism mechanism has been rationalized in terms of intra-POM electron transfer coupled to proton transfer between an organic counterion and the inorganic core. Such mechanism has been reported only in ionic hybrid systems containing organoammonium countercations (OACs). These ionic hybrid materials can then be considered as extrinsically photochromic, i.e. the photochromic property not only depends on the POM unit, but is also strongly correlated to the nature of the POM/OAC interface, this later being often unpredictable during the self-assembling processes. Here we propose to develop a family of intrinsically photochromic POMs. Our strategy will consist in covalently linking hydrogen donor groups to POM units. Such approach must enable a fine optimization of the interaction between the proton donor moiety and the inorganic fragment by playing on the nature of the grafted organic group and of the POM core. Another advantage is that it must also allow the elaboration of materials coupling photochromic POM units with functional counterions such as cationic spiropyrans, a family of photochromic organic molecules, leading to multi-photochromic systems. Derivatives of bisphosphonate (BP) ligands with the general formula [O3PC(OH)(R2)PO3]4-, where R2 is an amino derivative able to form N-H+···O-Mo hydrogen bonds, will thus be synthesized and reacted with Mo(VI) ions to form POM/BP complexes. The ultimate goal of this part of the project is to elaborate the most outstanding family of photochromic POMs with high coloration speeds and presenting an extended palette of coloration.

Secondly, POMs have been studied for a long time for their biological activities. However, there is to date no report of medical studies on POMs with covalently grafted organic ligands possessing a recognized biological activity. The second part of this project is based on the association in the same molecule of BPs, a class of drugs largely used as anti-cancer agents, and POMs, which can have on their own an anti-tumor activity. On a chemical point of view, the family of POMs to be developed for biological purposes is thus highly similar to that mentioned above for the development of photochromic POMs. The properties of these hybrid POM/BP materials (redox potentials, solubility, acido-basic properties, and cell-penetration) can be modulated via the grafted organic functions and the nature of the inorganic core. The most potent BPs described in the literature will be synthesized and reacted with Mo(VI) but also W(VI) or V(IV,V) ions. Their activity against three human tumor cell lines will be tested. One of the aims of this project will then be the evidencing and understanding of an eventual synergic effect of the POM and the BPs. The final goal is to find the best POM/BP combination with the highest activity by varying systematically both the nature of the POM and the nature of the BP. The results of each group will orient the synthesis of further ligands and hybrid POMs in a feedback manner.