Self-Assembled Bis-Acridinium Tweezer Equilibria Controlled by Multi-Responsive Properties.

Protonated and methylated bis-acridinium tweezers built around a 2,6-diphenylpyridyl and an electron enriched 2,6-di(p-anisyl)pyridyl spacer have been synthesized. These tweezers can self-assemble in their corresponding homodimers and the associated thermodynamic parameters have been probed in organic solvents. The switching properties of the tweezers have been exploited in biphasic transfer experiments showing the shift of the equilibria towards the homodimers. Moreover, the thermodynamic parameters of the formation of the reduced methylated homodimers investigated by electrochemical experiments revealed the dissociation of the dimers. Thus, in addition to solvent and temperature, the pH and redox responsiveness of the acridinium units of the tweezers make it possible to modulate to a larger extent the monomer-dimer equilibria.

Multi-Responsive Eight-State Bis(acridinium-Zn(II) porphyrin) Receptor.

A multi-responsive receptor consisting of two (acridinium-Zn(II) porphyrin) conjugates has been designed. The binding constant between this receptor and a ditopic guest has been modulated (i) upon addition of nucleophiles converting acridinium moieties into the non-aromatic acridane derivatives and (ii) upon oxidation of the porphyrin units. A total of eight states has been probed for this receptor resulting from the cascade of the recognition and responsive events. Moreover, the acridinium/acridane conversion leads to a significant change of the photophysical properties, switching from electron to energy transfer processes. Interestingly, for the bis(acridinium-Zn(II) porphyrin) receptor, charge-transfer luminescence in the near-infrared has been observed.

Allosterically Driven Assembly of a Multisite Cage-Based [2]Semirotaxane.

The assembly of a [2]semirotaxane from a half-dumbbell endowed with a pyrazine coordination site and a bis-Zn(II) porphyrin cage as a multisite ring is reported. The threading is allosterically driven by the coordination of silver(I) ions to the multiple binding sites of the cage linkers, as shown by NMR studies. Addition of chloride ions destabilizes [2]semirotaxane, leading to its disassembly into its cage and half-dumbbell components.

Dual-Readout of the Mechanical Response of a Bis-acridinium [2]Rotaxane.

A [2]rotaxane built around a multi-responsive bis-acridinium macrocycle has been synthesized. Structural investigation has confirmed the interlocked nature of the molecule, and MD simulations illuminated its conformational dynamics with atomic resolution. Both halochromic and redox-switching properties were explored to shed light on the mechanical response and electronic changes that occur in the bis-acridinium [2]rotaxane. The topology of the rotaxane led to different mechanical behaviors upon addition of hydroxide ions or reduction that were easily detected by UV/Vis spectroscopy and electrochemistry.

Allosteric Control of Naphthalene Diimide Encapsulation and Electron Transfer in Porphyrin Containers: Photophysical Studies and Molecular Dynamics Simulation.

The complexation processes of N,N'-dibutyl-1,4,5,8-naphthalene diimide (NDI) into two types of π-electron-rich molecular containers consisting of two Zn(II)-porphyrins connected by four flexible linkers of two different lengths, were characterized by means of absorption and emission spectroscopies and molecular dynamics simulation. Notably, the addition of NDI leads to a strong quenching of the fluorescence of both cages only when they are in an open conformation suitable for guest encapsulation, a situation triggered by silver(I) ions binding to the lateral triazoles. Molecular dynamics simulations confirm the fast binding of NDI, likely assisted by NDI-silver(I) interactions. Upon NDI complexation, the two porphyrin macrocycles get closer, with an optimized face to face orientation, suggesting an induced-fit mechanism through π-π interactions with the NDI aromatic cycle. Ultrafast transient absorption experiments allowed to identify the process of quenching of the Zn-porphyrin fluorescence as an efficient photoinduced electron transfer reaction between the cage porphyrin and the included NDI guest. The process occurs on fast and ultrafast time scales in the two complexes (1.5 ps and ≤300 fs) leading to a short-lived charge separated state (charge recombination lifetimes in the order of 30-40 ps). The combined computational and experimental approach used here is able to furnish a reliable model of the NDI-cage complexation mechanism and of the corresponding electron transfer reaction, attesting the allosteric control of both processes by the silver(I) ions.

Multifunctional cubic liquid crystalline nanoparticles for chemo- and photodynamic synergistic cancer therapy.

With the aim of engineering multifunctional nanoparticles useful for cancer therapy, a diketopyrrolopyrrole-porphyrin based photosensitizer was here conjugated to a block copolymer (Pluronic F108), and used to stabilize in water lipidic cubic liquid crystalline nanoparticles (cubosomes), also loaded with the antineoplastic agent docetaxel. The physicochemical characterization by SAXS, DLS, and cryo-TEM demonstrated that the formulation consisted of cubosomes, about 150 nm in size, possessing a bicontinuous cubic structure (space group Pn3m). The cellular imaging experiments proved that these nanoparticles localized in lysosomes and mitochondria, while cytotoxicity tests evidenced a slight but significant synergistic effect which, after irradiation, increased the toxicity induced by docetaxel alone, allowing further reduction of cell viability.

Synthesis and In Vitro Studies of a Gd(DOTA)-Porphyrin Conjugate for Combined MRI and Photodynamic Treatment.

With the aim of developing new molecular theranostic agents, a π-extended Zn(II) porphyrin as photosensitizer for photodynamic therapy (PDT) linked to two GdDOTA-type complexes for magnetic resonance imaging (MRI) detection was synthesized. The relaxivity studies revealed a much higher relaxivity value per Gd ion for this medium sized molecule (19.32 mM-1 s-1 at 20 MHz and 298 K) compared to clinical contrast agents-a value which strongly increases in the presence of bovine serum albumin, reaching 25.22 mM-1 s-1. Moreover, the photophysical studies showed the strong ability of the molecule to absorb light in the deep red (670 nm, ε ≈ 60000 M-1 cm-1) and in the near-infrared following two-photon excitation (920 nm, σ2 ≈ 650 GM). The conjugate is also able to generate singlet oxygen, with a quantum yield of 0.58 in DMSO. Promising results were obtained in cellular studies, demonstrating that the conjugate is internalized in HeLa cells at micromolar concentration and leads to 70% of cell death following 30 min irradiation at 660 nm. These results confirm the potential of the designed molecule as an imaging and therapeutic agent.

A Bis-Acridinium Macrocycle as Multi-Responsive Receptor and Selective Phase-Transfer Agent of Perylene.

A bis-acridinium cyclophane incorporating switchable acridinium moieties linked by a 3,5-dipyridylanisole spacer was studied as a multi-responsive host for polycyclic aromatic hydrocarbon guests. Complexation of perylene was shown to be the most effective and was characterized in particular by a charge-transfer band as signal output. Effective catch and release of the guest was triggered by both chemical (proton/hydroxide) and redox stimuli. Moreover, the dicationic host was also easily switched between organic and perfluorocarbon phases for applications related to the enrichment of perylene from a mixture of polycyclic aromatic hydrocarbons.

Positive Allosteric Control of Guests Encapsulation by Metal Binding to Covalent Porphyrin Cages.

The allosteric control of the receptor properties of two flexible covalent cages is reported. These receptors consist of two zinc(II) porphyrins connected by four linkers of two different sizes, each incorporating two 1,2,3-triazolyl ligands. Silver(I) ions act as effectors, responsible for an on/off encapsulation mechanism of neutral guest molecules. Binding silver(I) ions to the triazoles opens the cages and triggers the coordination of pyrazine or the encapsulation of N,N'-dibutyl-1,4,5,8-naphthalene diimide. The X-ray structure of the silver(I)-complexed receptor with short connectors is reported, revealing the hollow structure with a cavity well-defined by two eclipsed porphyrins. Rather unexpectedly, the crystallographic structure of this receptor with pyrazine as a guest molecule showed that the cavity is occupied by two pyrazines, each binding to the zinc(II) porphyrin in a monotopic fashion.

Tumour-targeting photosensitisers for one- and two-photon activated photodynamic therapy.

Despite the advantages of photodynamic therapy (PDT) over chemotherapy or radiotherapy such as low side effects, lack of treatment resistance and spatial selectivity inherent to light activation of the drug, several limitations especially related to the photosensitiser (PS) prevent PDT from becoming widespread in oncology. Herein, new folic acid- and biotin-conjugated PSs for tumour-targeting PDT are reported, with promising properties related to PDT such as intense absorption following one-photon excitation in the red or two-photon excitation in the near-infrared, and also high singlet oxygen quantum yield (close to 70% in DMSO). Cellular studies demonstrated that both targeted PSs induced phototoxicity, the folate-targeted PS being the most effective one with 80% of cell death following 30 min of irradiation and a phototoxicity four times higher than that of the non-targeted PS. This result is in accordance with the uptake of the folate-targeted PS in HeLa cells, mediated by the folate receptors. Moreover, this folate-targeted PS was also phototoxic following two-photon excitation at 920 nm, opening new perspectives for highly selective PDT treatment of small and deep tumours.

A Porphyrin Dimer-GdDOTA Conjugate as a Theranostic Agent for One- and Two-Photon Photodynamic Therapy and MRI.

A molecular theranostic agent designed for photodynamic therapy (PDT) treatment in the near-infrared and for imaging tissue tumors with magnetic resonance imaging (MRI) is reported. It consists of a linear π-conjugated Zn(II) porphyrin dimer linked at each extremity to a GdDOTA-type complex. This agent has shown very promising potential for PDT applications with good singlet oxygen generation in DMSO and high linear absorption in the near-infrared (λmax = 746 nm, ε ≈ 105 M-1 cm-1). Moreover, this molecule has a propensity for two-photon excited PDT with high two-photon cross sections (∼8000 GM in 880-930 nm range), which should allow for deeper tumor treatments and higher spatial precision as compared to conventional one-photon PDT. Regarding the MRI contrast agent properties, the molecule has shown superior relaxivity (14.4 mM-1 s-1 at 40 MHz, 298 K) in comparison to clinical contrast agents and the ability to be internalized in cells, thanks to its amphiphilic character. Irradiation of HeLa cells using either one-photon (740 nm) or two-photon excitation (910 nm) has led in both cases to important cell death.

Chemically Induced Breathing of Flexible Porphyrinic Covalent Cages.

The synthesis of two flexible bis-porphyrin cages 3 and 4, incorporating respectively Zn(II) porphyrins and free-base porphyrins, is reported. In both cages, the four covalent linkers that bind the two porphyrins are functionalized with two 1,2,3-triazolyl ligands. These cages were characterized by NMR and HRMS, and for cage 3 incorporating 1,4-diazabicyclo[2.2.2]octane (DABCO), an X-ray crystallographic structure was obtained. Chemically induced conformational changes are studied and compared to those of two related cages with longer flexible linkers. Binding of four silver(I) ions to the peripheral ligands opens the flattened structures in solution and locks the two porphyrins in a face-to-face disposition. Addition of an excess of acid fully expands the cages due to electrostatic repulsion between the positively charged sites. These two reversible processes allow for a chemically induced breathing of the flexible structures.

A Theranostic Agent Combining a Two-Photon-Absorbing Photosensitizer for Photodynamic Therapy and a Gadolinium(III) Complex for MRI Detection.

The convergent synthesis and characterization of a potential theranostic agent, [DPP-ZnP-GdDOTA](-), which combines a diketopyrrolopyrrole-porphyrin component DPP-ZnP as a two-photon photosensitizer for photodynamic therapy (PDT) with a gadolinium(III) DOTA complex as a magnetic resonance imaging probe, is presented. [DPP-ZnP-GdDOTA](-) has a remarkably high longitudinal water proton relaxivity (19.94 mm(-1) s(-1) at 20 MHz and 25 °C) for a monohydrated molecular system of this size. The Nuclear Magnetic Relaxation Dispersion (NMRD) profile is characteristic of slow rotation, related to the extended and rigid aromatic units integrated in the molecule and to self-aggregation occurring in aqueous solution. The two-photon properties were examined and large two-photon absorption cross-sections around 1000 GM were determined between 910 and 940 nm in DCM with 1 % pyridine and in DMSO. Furthermore, the new conjugate was able to generate singlet oxygen, with quantum yield of 0.42 and 0.68 in DCM with 1 % pyridine and DMSO, respectively. Cellular studies were also performed. The [DPP-ZnP-GdDOTA](-) conjugate demonstrated low dark toxicity and was able to induce high one-photon and moderate two-photon phototoxicity on cancer cells.

Four Gadolinium(III) Complexes Appended to a Porphyrin: A Water-Soluble Molecular Theranostic Agent with Remarkable Relaxivity Suited for MRI Tracking of the Photosensitizer.

A molecular theranostic agent for magnetic resonance imaging (MRI) and photodynamic therapy (PDT) consisting of four [GdDTTA](-) complexes (DTTA(4-) = diethylenetriamine-N,N,N″,N″-tetraacetate) linked to a meso-tetraphenylporphyrin core, as well as its yttrium(III) analogue, was synthesized. A variety of physicochemical methods were used to characterize the gadolinium(III) conjugate 1 both as an MRI contrast agent and as a photosensitizer. The proton relaxivity measured in H2O at 20 MHz and 25 °C, r1 = 43.7 mmol(-1) s(-1) per gadolinium center, is the highest reported for a bishydrated gadolinium(III)-based contrast agent of medium size and can be related to the rigidity of the molecule. The complex displays also a remarkable singlet oxygen quantum yield of Ï•Δ = 0.45 in H2O, similar to that of a meso-tetrasulfonated porphyrin. We also evidenced the ability of the gadolinium(III) conjugate to penetrate in cancer cells with low cytotoxicity. Its phototoxicity on Hela cells was evaluated following incubation at low micromolar concentration and moderate light irradiation (21 J cm(-2)) induced 50% of cell death. Altogether, these results demonstrate the high potential of this conjugate as a theranostic agent for MRI and PDT.

Cyclic [4]rotaxanes containing two parallel porphyrinic plates: toward switchable molecular receptors and compressors.

Twenty years ago, researchers considered the synthesis of simple rotaxanes a challenging task, but with the rapid development of this field, chemists now view these interlocking molecules as accessible synthetic targets. In a major advance for the field, researchers have developed transition metals or organic molecules as templating structures, making it easier to construct these molecular systems. In addition, chemists have found ways to introduce new functional groups, which have given these compounds new properties. Today researchers can also construct multirotaxanes consisting of several individual components, but the synthesis of the most complex structures remains challenging. This Account primarily discusses the cyclic [4]rotaxanes incorporating porphyrins that the Strasbourg group has synthesized and studied during the past few years. These cyclic [4]rotaxanes consist of two rigid rods threaded through the four rings of two molecules of a bis-macrocycle, and the synthetic strategy used for making them relies on the copper(I)-driven "gathering-and-threading" reaction. The formation of the threaded precursors was mostly quantitative, and the quadruple stoppering reaction leading to the target compound produces high yields because of the efficient copper-catalyzed azide-alkyne cycloaddition (CuAAC) or click chemistry reaction. These rotaxanes behave as receptors for various ditopic guests. We prepared and studied two types of molecules: (i) a rigid compound whose copper(I) complex has a well-defined shape, with high selectivity for the guest geometry and (ii) a much more flexible [4]rotaxane host that could act as a distensible receptor. The rigid [4]rotaxane was crystallized, affording a spectacular X-ray structure that matched the expected chemical structure. In addition, metalation or demetalation of the rigid [4]rotaxane induces a drastic geometric rearrangement. The metal-free compound is flat without a binding pocket, while the copper-complexed species forms a rectangle-like structure. The removal of copper(I) also expels any complexed guest molecule, and this process is reversible, making the rigid porphyrinic [4]rotaxane a switchable receptor. The rigid [4]rotaxane was highly selective for short, ditopic guests in its copper(I)-complexed form, but the flexible copper(I)-complexed [4]rotaxane proved to be a versatile receptor. Its conformation can adjust to the size of the guest molecule similar to the induced fit mechanism that some enzymes employ with substrates.

A Porphyrin Coordination Cage Assembled from Four Silver(I) Triazolyl-Pyridine Complexes.

The synthesis of a zinc(II) porphyrin 1 with four appended triazolyl-pyridine chelates is reported. Complexation of the porphyrin peripheral ligands with Ag(I) ions in a 1:2 binding stoichiometry afforded quantitatively the coordination cage [Ag4 (1)2 ](4+) . The assembly and disassembly processes of the cage were investigated in solution using UV/Vis spectroscopy. The mathematical analysis of the data obtained in the UV/Vis titration of 1 with Ag(I) confirmed the assembly in CH2 Cl2 /MeOH (90:10) solution of a species having a 1:2 porphyrin/silver stoichiometry and assigned to it an overall stability constant of 5.0×10(26) M(-5) . The use of a model system allowed an independent assessment of a microscopic binding constant value (Km ) for the interaction between the triazolyl-pyridine ligand and Ag(I) . The coincidence that existed between the Km values extracted from the model system and the titration of 1 provided an indication of the quality and fit of the data analysis. It also allowed the calculation of the average effective molarity (EM) value for the three intramolecular processes that led to the cage assembly as 2.6 mM. Simulated speciation profiles supported the conclusion that at millimolar concentration and working under strict stoichiometric control of the silver/porphyrin ratio, the cage [Ag4 (1)2 ](4+) was the species exclusively assembled in solution. On the other hand, when the concentration of added Ag(I) was approximately 2.6 mM, 50 % of the coordination cage disassembled into open aggregates.

Diketopyrrolopyrrole-porphyrin conjugates with high two-photon absorption and singlet oxygen generation for two-photon photodynamic therapy.

Two-photon photodynamic therapy is a promising therapeutic method which requires the development of sensitizers with efficient two-photon absorption and singlet-oxygen generation. Reported here are two new diketopyrrolopyrrole-porphyrin conjugates as robust two-photon absorbing dyes with high two-photon absorption cross-sections within the therapeutic window. Furthermore, for the first time the singlet-oxygen generation efficiency of diketopyrrolopyrrole-containing systems is investigated. A preliminary study on cell culture showed efficient two-photon induced phototoxicity.

Transition-metal-complexed catenanes and rotaxanes: from dynamic systems to functional molecular machines.

Transition metal-based catenanes and rotaxanes constitute a specific class of mechanically interlocked molecules whose metal centers are essential both as templates in the construction of the compounds and for their ability to induce large-amplitude motions. In the present chapter we will first present a historical perspective of the field of interlocking compounds in general, in relation to molecular machines, starting with old work dating back to the 1980s and 1990s. Copper was shown many years ago to be the metal of choice for synthesizing the compounds via a template approach and for setting the molecules in motion using a redox signal (Cu(II)/Cu(I)). In a second paragraph, we will discuss various rotaxanes able to undergo a pirouetting motion of the axis within the threaded ring. Two families of such molecules will be mentioned: (1) a porphyrin-containing [2]rotaxane whose pirouetting motion is induced by a chemical reaction and (2) electrochemically driven systems. In this second category of [2]rotaxanes, the rate of motion could be dramatically increased by gradually modifying structural parameters and, in particular, by making the metal center less and less hindered by its surrounding ligands. The third section will be devoted to molecular shuttles and muscles, both families of compounds being reminiscent of linear machines such as biological muscles. By replacing the classical 2,9-diaryl-1,10-phenanthroline chelate (highly shielding and hindering) used by our group since the 1980s by an endocyclic but non-sterically hindering 3,3'-biisoquinoline derivative, the shuttling rate was increased in spectacular fashion, demonstrating the importance of steric factors in transition metal-based molecular machines. The same 3,3'-biisoquinoline motif was also used in the elaboration of a three-station shuttle, leading to long-distance (>20 Å) transport of a ring along the axis on which it is threaded. Finally, porphyrin-containing [3]rotaxanes and [4]rotaxanes, the latter displaying an overall cyclic structure, will be discussed and shown to behave as adjustable and switchable receptors. The synthesis of such compounds is a particularly challenging task in itself. In addition, the new receptors display fascinating properties such as, in particular, their ability to compress various guests and to expel them from their binding site using a chemical signal.

Synthesis and solution studies of silver(I)-assembled porphyrin coordination cages.

The synthesis and the characterization of two porphyrin coordination cages are reported. The design of the cage formation is based on the coordination of silver(I) ions to the pyridyl units of 3-pyridyl appended porphyrins. (1)H/(109)Ag NMR spectroscopy, and diffusion-ordered spectroscopy (DOSY) experiments demonstrate that both the free base porphyrin 2H-TPyP and the Zn-porphyrin Zn-TPyP form the closed cages, [Ag4(2H-TPyP)2](4+) and [Ag4(Zn-TPyP)2](4+), respectively, upon addition of two equivalents of Ag(+). The complexation processes are characterized in details by means of absorption and emission spectroscopy in diluted CH2Cl2 solutions. The data are discussed in the frame of the point-dipole exciton coupling theory; the two porphyrin monomers, in fact, experience a rigid face-to-face geometry in the cages and a weak inter-porphyrin exciton coupling. An intermediate species is observed, for Zn-TPyP, in a porphyrin/Ag(+) stoichiometric ratio of about 1:0.5 and is tentatively ascribed to an oblique open form. The occurrence of a photoinduced electron-transfer reaction within the cages is excluded on the basis of the experimental outcomes and thermodynamic evaluations. Photophysical experiments evidence different reactivities of singlet and triplet excited states in the assemblies. A lower fluorescence quantum yield and triplet formation is discussed in relation to the constrained geometry of the complexes. Unusually long triplet excited state lifetimes are measured for the assemblies.

NIR dual luminescence from an extended porphyrin. Spectroscopy, photophysics and theory.

Spectroscopic and photophysical properties of an extended Zn porphyrin with fused bis(tetraazaanthracene) arms including a 2,9-diphenyl-1,10-phenanthroline incorporated in a polyether macrocycle are investigated in solvents of different polarity pointing to the presence of two emitting singlet excited states. The absorption and emission features are identified and ascribed, on the basis of solvent polarity dependence, to a π-π* and to a charge transfer (CT) state, respectively. Whereas the intraligand π-π* transition is assigned to the intense absorption observed at 442-455 nm, the CT states contribute to the bands at 521-525 nm and 472-481 nm. The theoretical analysis of the absorption spectrum confirms the presence of two strong bands centered at 536 and 437 nm corresponding to CT and π-π* states, respectively. Weak CT transitions are calculated at 657 and 486 nm. Two emission maxima are observed in toluene at 724 nm from a (1)π-π* state and at 800 nm from a (1)CT state, respectively. (1)CT bands shift bathochromically by increasing the solvent polarity whereas the energy of the (1)π-π band is less affected. Likewise, the emission yield and lifetime associated with the low energy (1)CT band are strongly affected by solvent polarity. This is rationalized by a (1)π-π* → (1)CT internal conversion driven by solvent polarity, this process being competitive with the (1)π-π* to ground state deactivation channel. Time resolved absorption spectra indicate the presence of two triplet states, a short-lived one (nanoseconds range) and a longer lived one (hundreds of microsecond range) ascribed to a (3)π-π* and a (3)CT, respectively. For them, a conversion mechanism similar to that of the singlet excited states is suggested.