Jean-Pierre Sauvage

Photoexpulsion of surface-grafted ruthenium complexes and subsequent release of cytotoxic cargos to cancer cells from mesoporous silica nanoparticles

Ruthenium(II) polypyridyl complexes have emerged both as promising probes of DNA structure and as anticancer agents because of their unique photophysical and cytotoxic properties. A key consideration in the administration of those therapeutic agents is the optimization of their chemical reactivities to allow facile attack on the target sites, yet avoid unwanted side effects. Here, we present a drug delivery platform technology, obtained by grafting the surface of mesoporous silica nanoparticles (MSNPs) with ruthenium(II) dipyridophenazine (dppz) complexes. This hybrid nanomaterial displays enhanced luminescent properties relative to that of the ruthenium(II) dppz complex in a homogeneous phase. Since the coordination between the ruthenium(II) complex and a monodentate ligand linked covalently to the nanoparticles can be cleaved under irradiation with visible light, the ruthenium complex can be released from the surface of the nanoparticles by selective substitution of this ligand with a water molecule. Indeed, the modified MSNPs undergo rapid cellular uptake, and after activation with light, the release of an aqua ruthenium(II) complex is observed. We have delivered, in combination, the ruthenium(II) complex and paclitaxel, loaded in the mesoporous structure, to breast cancer cells. This hybrid material represents a promising candidate as one of the so-called theranostic agents that possess both diagnostic and therapeutic functions.

From Chemical Topology to Molecular Machines (Nobel Lecture)

To a large extent, the field of molecular machines started after several groups were able to prepare, reasonably easily, interlocking ring compounds (named catenanes for compounds consisting of interlocking rings and rotaxanes for rings threaded by molecular filaments or axes). Important families of molecular machines not belonging to the interlocking world were also designed, prepared, and studied but, for most of them, their elaboration was more recent than that of catenanes or rotaxanes. Since the creation of interlocking ring molecules is so important in relation to the molecular machinery area, we will start with this aspect of our work. The second part will naturally be devoted to the dynamic properties of such systems and to the compounds for which motions can be directed in a controlled manner from the outside, that is, molecular machines. We will restrict our discussion to a very limited number of examples which we consider as particularly representative of the field.

Metal-Organic Frameworks Incorporating Copper-Complexed Rotaxanes

MOFs on the move: A copper-coordinated [2]pseudorotaxanate which reacts with zinc nitrate to form threefold interpenetrated networks retains most of its solution-state chemistry, including its ability to undergo electronic switching of some of the copper(I) ions under redox control.

A Rapidly Shuttling Copper-Complexed [2]Rotaxane with Three Different Chelating Groups in Its Axis†

Molecular machines are particularly promising in relation to potential applications in the fields of information storage and processing, imaging, and nanoscale electroor photochemically driven mechanical devices, as illustrated by recent spectacular results. Catenanes and rotaxanes constitute an important subclass of such systems, and our research group has been particularly interested in transition-metalcomplexed interlocking compounds. Most of these previously reported systems were two-geometry compounds, which were able to switch between a stable five-coordinate copper(II) complex where the copper(II) center is coordinated to a bidentate and a tridentate chelate and a second form, which is a four-coordinate copper(I) complex. In the latter form, the copper(I) center is coordinated to two bidentate ligands. A rare example of a three-geometry system was reported in 1996, and was based on a [2]catenane that consisted of two identical rings, each ring incorporating two different chelating units (a biand a tridentate ligand). The copper center could thus be four-, five-, or six-coordinate. Molecular “shuttles” represent the archetype of molecular machines and, equally importantly, they are often used in the fabrication of real devices. The shuttle-like [2]rotaxanes reported to date are two-station systems. These rotaxanes consist of a mobile ring threaded by an axis that incorporates two distinct functional groups, which are able to interact with the ring. To the best of our knowledge, no molecular shuttles with three distinct stations have been reported to date. However, catenanes have been described in which one or two rings (considered as mobile) are threaded through a larger ring that incorporates three different functional groups, which are able to interact with the mobile ring(s). A particularly elegant compound that belongs to this family of catenane-based molecular machines was reported in 2003. This molecule was the first example of a catenane-based rotary motor, that is, a machine that displays controlled directionality during the dynamic process. Incidentally, non-interlocking rotary machines had already been reported by other research groups, 33] and continue to attract much attention. 35] Herein, we describe the synthesis and electrochemical behavior of a rotaxane that acts as an electrochemically driven molecular shuttle over a long distance. The rotaxane consists of a coordinating ring threaded by an axis that incorporates three different chelates. It was expected that by introducing an intermediate “station” between the two terminal chelating groups, the gliding motion of the metalcomplexed ring would be much faster than the analogous motion without the intermediate chelating group, as the distance between the terminal stations is the same for the two systems. In the present system, the distance between the two terminal coordination sites is approximately 23 . Without a relay between the two end-chelates of the axis, the shuttling motion between these two stations would be expected to be very slow. It has already been shown that the presence of an aromatic spacer between the end-stations slows the shuttling motion significantly. The two forms of the rotaxane are shown in Scheme 1. As discussed below, the introduction of a 2,2’-bipyridine (bipy) between the two end-chelates of the thread facilitates the gliding process. The translational motion over 23 is as fast as the related motion in a two-station rotaxane that incorporates a 2,9-diphenyl-1,10-phenanthroline (dpp) unit and a 2,2’,6’,2’’-terpyridine (terpy) chelate, that is, the same groups as the terminal chelates of the present system, but over a distance of less than 10 . The coordinating units on the axis are 1) a dpp chelate, 2) a bipy chelate and 3) terpy, which is a tridentate ligand. The ring incorporates an 8,8’-diphenyl-3,3’biisoquinoline (dpbiiq) bidentate ligand. This endocyclic but nonsterically hindering chelate is a key component, which favors fast translational or rotational motions within shuttlelike rotaxanes or pirouetting systems, respectively. 30] The principle of the electrochemically driven motion relies on the relative stabilities of the various copper(I) and copper(II) complexes formed with the various ligands. Within the following sequence, the thermodynamic stability of the copper(I) complexes increases from [Cu(terpy)(dpbiiq)] to [Cu(dpp)(dpbiiq)]: [Cu(terpy)(dpbiiq)]< [Cu(bipy)(dpbiiq)]< [Cu(dpp)(dpbiiq)]. The stability sequence is reversed for Cu complexes: [Cu(dpp)(dpbiiq)]< [Cu(bipy)(dpbiiq)]< [Cu(terpy)(dpbiiq)]. These relative stabilities of the complexes within these two sequences reflect the electrochemical properties of the models listed above and, in particular, their redox potentials. The Cu/Cu redox potentials of the threaded model complexes (see the Supporting Information) and those of the two-station shuttle 5(4) + as well as their chemical structures, [*] Prof. J.-P. Collin, Dr. F. Durola, J. Lux, Prof. J.-P. Sauvage Laboratoire de Chimie Organo-Min rale, Institut de Chimie, LC3 UMR 7177 du CNRS Universit de Strasbourg 4 rue Blaise Pascal, 67070 Strasbourg Cedex (France) Fax: (+ 33)3-9024-1368 E-mail: sauvage@chimie.u-strasbg.fr Homepage: http://www-chimie.u-strasbg.fr/~ lcom/

Cyclometalated RuII complexes with improved octahedral geometry: Synthesis and photophysical properties

Cyclometalated bis-tridentate ruthenium(II) complexes incorporating 2,6-diquinolin-8-ylpyridine ligands and exhibiting broad visible absorptions are described. A [Ru(N(wedge)N(wedge)N)(N(wedge)C(wedge)N)](+) complex based only on ligands with expanded bite angles has a metal-to-ligand charge-transfer excited-state lifetime of 16 ns, which is attributed to a strong ligand field and therefore reduced deactivation via metal-centered states.

Topologically complex molecules obtained by transition metal templation: it is the presentation that determines the synthesis strategy

Topological constructions made from closed curves range from simple links to intricate knots and started to capture the chemists attention in the early sixties. These mathematical objects result from particular embeddings of a single or a set of closed curves in the three-dimensional space that show an infinite variety of presentations. Simple catenanes, higher order interlocked macrocycles, and molecular knots can be synthesized via the metal template approach, just as simple macrocycles. However, this requires that rigid presentations with appropriate geometrical characteristics be identified prior to molecular design, and those selected for the metal-templated synthesis of some of these fascinating molecules are reviewed here.

A Cyclic (4)rotaxane that Behaves as a Switchable Molecular Receptor: Formation of a Rigid Scaffold from a Collapsed Structure by Complexation with Copper(I) Ions**

The most efficient molecular receptors are usually rigid edifices with a hollow part that is able to accommodate the complexed species through an electronic and geometrical complementarity between the substrate and the complexing parts of the host. By analogy with biological processes related to induced fit, other host–guest processes are based on flexible hosts that are able to adapt their geometry to that of the species to be recognized. In the very active field of catenanes, rotaxanes, and molecular machines, very few systems have been considered as interesting receptors for molecular guests. One of the main contributions to this subfield of research is that of anion recognition by various interlocking compounds. Our research group has also recently described a [3]rotaxane that is able to act as an adjustable receptor. The system consists of two rings threaded by an axis on which the rings can move freely. The complexing units are zinc porphyrins that are firmly attached to the rotaxane rings and are able to interact with given substrates that consist of doubly end functionalized compounds bearing 4-pyridyl groups. It was shown that the marked geometrical adaptability of the host in its metal-free form allows interaction with guests of very different sizes. Herein we report the properties of a related compound, namely a cyclic bisporphyrin [4]rotaxane, the behavior of which is totally different from that of a previously studied linear [3]rotaxane. Contrary to the latter compound, the metal-free [4]rotaxane collapses completely and does not show any complexation properties, whereas the copper(I)complexed compound is a good and selective receptor for diamine and dipyridyl substrates because of the scaffolding effect of the four metal centers (Figure 1). The recognition process can thus be switched on and off by complexing the free ligand to four Cu ions or demetalating the metalcomplexed species, respectively. The synthesis of rotaxane 1 [7] as well as that of its related [4]pseudorotaxane have already been reported. 1 was demetalated using a large excess of KCN (ca. 50 equivalents) at room temperature. The reaction mixture was stirred for 2.5 hours, and the crude product was then purified by chromatography on silica gel to afford the demetalated rotaxane 2 in 88% yield (Scheme 1). Rotaxane 2 was characterized by H NMR spectroscopy (COSY, ROESY, DOSY), electrospray mass spectrometry and UV/Vis spectroscopy. Very surprisingly, the H NMR spectrum of rotaxane 2 shows considerable loss of symmetry compared to the metalated system 1, in which all the Cu centers as well as the four stoppers were chemically equivalent. A quarter of the rotaxane 1 only had thus to be considered for complete NMR assignment. By contrast, the H NMR signals of 2 were doubled compared to those of rotaxane 1. Two distinct stoppers with significantly different H NMR signals and thus markedly different environments can be identified. NOE interactions between some parts of 2 were clearly detected, whereas these fragments were too far away from one another in 1 to show any interaction. For instance, some protons of the tBu groups of one type of stopper (H-re’; r= “rod”) correlate to protons H-b4’ and Hb7’ (b=bismacrocycle) of the 1,10-phenanthroline unit in 2, thus indicating that this stopper and a given 1,10-phenanthroline unit are located very close to one another. As the bismacrocycles and the axles are both rigid, the proximity between two such fragments tends to indicate that the topography of 2 is markedly different from that of 1, and that 2 has a totally collapsed structure. This hypothesis was confirmed by additional observations. For instance, one proton of the (CH2)3 linker (H-r9) is strongly shielded upon decomplexation; the corresponding signal moves from Figure 1. Principle of the recognition process that is switched on and off by metalation or demetalation. Small gray dots: Cu ions; gray squares: porphyrins; black double arrow: guest compound. The chemical structures of 1 and 2 are shown in Scheme 1.

Synthesis of [5]Rotaxanes Containing Bi- and Tridentate Coordination Sites in the Axis

A new example of a linear [5]rotaxane has been synthesized by using the traditional gathering-and-threading approach but based on an unusual axle incorporating a symmetrical bis(bidentate) chelating fragment built on a 4,7-phenanthroline core. The stoppering reaction is particularly noteworthy since, instead of using a trivial bulky stopper as precursor to the blocking group, two semistoppered copper-complexed [2]pseudorotaxanes (namely [2]semirotaxanes) are used, which leads to the desired [5]rotaxane in good yield. The efficiency of the method relies on the use of click chemistry, with its very mild conditions, and on the protection by a transition-metal (copper(I)) of the various coordinating groups present in the fragments to be interconnected (terpy and bidentate chelating groups), thus inhibiting potential detrimental side reactions during the copper-catalyzed stoppering reaction. Since the external fragments and the central core of the system contain tri- and bidentate chelating units, respectively, the axle of the final [5]rotaxane incorporates two types of coordinating units: two external terpy groups (terpy: 2,2:6,2-terpyridine) and two central bidentate ligands. Such a situation enables the system to tidy two different metals centers, and to localize them in a priori well-defined positions. This is what was observed when mixing the free ligand with a mixture of Zn(2+) and Li(+) : the zinc(II) ions were unambiguously shown to occupy the external sites, whereas the Li(+) cations were found in the central part of the [5]rotaxane. An X-ray diffraction study carried out on a [3]pseudorotaxane, the axis of which is similar to the central part of the [5]rotaxane axle, demonstrates that Zn(2+) is clearly five-coordinate, the fifth ligand being a counterion, even when the coordination site of the pseudorotaxane is designed for four-coordinate metals, which is in marked contrast with copper(I) or Li(+) .

[2]Catenanes Built Around Octahedral Transition-Metal Complexes that Contain Two Intertwined Endocyclic but Non-sterically Hindering Tridentate Ligands

Sterically hindering bidentate chelates, such as 2,9-diphenyl-1,10-phenanthroline, form entwined complexes with copper(I) and other tetrahedrally coordinated transition-metal centres. To prepare octahedral complexes containing two entwined tridentate ligands and thus apply a strategy similar to that used for making catenanes with tetrahedral metal centres, the use of the classical terpy ligand (terpy=2,2:6,2-terpyridine) appears to be attractive. In fact, 6,6-diphenyl-2,2:6,2-terpyridine (dp-terpy) is not appropriate due to strong pinching of the organic backbone by coordination to the metal and thus stable entwined complexes with this ligand cannot be obtained. Herein, we report the synthesis and coordination properties of a new family of tridentate ligands, the main features of which are their endocyclic nature and non-sterically hindering character. The coordinating fragment consists of two 8-phenylisoquinolin-3-yl groups attached at the 2 and 6 positions of a pyridine nucleus. Octahedral complexes containing two such entangled ligands around an octahedral metal centre, such as Fe(II) , Ru(II) or Co(III) , are highly stable, with no steric congestion around the metal. By using functionalised ligands bearing terminal olefins, double ring-closing metathesis leads to [2]catenanes in good yield with Fe(II) or Co(III) as the templating metal centre. The X-ray crystallography structures of the Fe(II) precursor and the Fe(II) catenane are also reported. These show that although significant pinching of the ligand is observed in both Fe(II) complexes, the system is very open and no steric constraints can be detected.

Donor–acceptor molecular figures-of-eight

The intermolecular template-directed synthesis, separation and characterisation of two constitutional isomers that are self-complexing donor-acceptor [1]rotaxanes has been achieved by click chemistry, starting from a π-electron deficient tetracationic cyclophane containing two azide functions and a π-electron rich 1,5-dioxynaphthalene-containing polyether chain terminated by propargyl groups.