Remote electrochemical modulation of pKa in a rotaxane by co-conformational allostery

Allosteric control, one of Nature’s most effective ways to regulate functions in biomolecular machinery, involves the transfer of information between distant sites. The mechanistic details of such a transfer are still object of intensive investigation and debate, and the idea that the intramolecular communication could be enabled by dynamic processes is gaining attention as a complement to traditional explanations. Mechanically interlocked molecules, owing to the particular kind of connection between their components and the resulting dynamic behavior, are attractive systems to investigate allosteric mechanisms and exploit them to develop functionalities with artificial species. We show that the pKa of an ammonium site located on the axle component of a [2]rotaxane can be reversibly modulated by changing the affinity of a remote recognition site for the interlocked crown ether ring through electrochemical stimulation. The use of a reversible ternary redox switch enables us to set the pKa to three different values, encompassing more than 7 units. Our results demonstrate that in the axle the two sites do not communicate, and that in the rotaxane the transfer of information between them is made possible by the shuttling of the ring, that is, by a dynamic intramolecular process. The investigated coupling of electron- and proton-transfer reactions is reminiscent of the operation of the protein complex I of the respiratory chain

8p22 MTUS1 Gene Product ATIP3 Is a Novel Anti-Mitotic Protein Underexpressed in Invasive Breast Carcinoma of Poor Prognosis

BACKGROUND: Breast cancer is a heterogeneous disease that is not totally eradicated by current therapies. The classification of breast tumors into distinct molecular subtypes by gene profiling and immunodetection of surrogate markers has proven useful for tumor prognosis and prediction of effective targeted treatments. The challenge now is to identify molecular biomarkers that may be of functional relevance for personalized therapy of breast tumors with poor outcome that do not respond to available treatments. The Mitochondrial Tumor Suppressor (MTUS1) gene is an interesting candidate whose expression is reduced in colon, pancreas, ovary and oral cancers. The present study investigates the expression and functional effects of MTUS1 gene products in breast cancer. METHODS AND FINDINGS: By means of gene array analysis, real-time RT-PCR and immunohistochemistry, we show here that MTUS1/ATIP3 is significantly down-regulated in a series of 151 infiltrating breast cancer carcinomas as compared to normal breast tissue. Low levels of ATIP3 correlate with high grade of the tumor and the occurrence of distant metastasis. ATIP3 levels are also significantly reduced in triple negative (ER- PR- HER2-) breast carcinomas, a subgroup of highly proliferative tumors with poor outcome and no available targeted therapy. Functional studies indicate that silencing ATIP3 expression by siRNA increases breast cancer cell proliferation. Conversely, restoring endogenous levels of ATIP3 expression leads to reduced cancer cell proliferation, clonogenicity, anchorage-independent growth, and reduces the incidence and size of xenografts grown in vivo. We provide evidence that ATIP3 associates with the microtubule cytoskeleton and localizes at the centrosomes, mitotic spindle and intercellular bridge during cell division. Accordingly, live cell imaging indicates that ATIP3 expression alters the progression of cell division by promoting prolonged metaphase, thereby leading to a reduced number of cells ungergoing active mitosis. CONCLUSIONS: Our results identify for the first time ATIP3 as a novel microtubule-associated protein whose expression is significantly reduced in highly proliferative breast carcinomas of poor clinical outcome. ATIP3 re-expression limits tumor cell proliferation in vitro and in vivo, suggesting that this protein may represent a novel useful biomarker and an interesting candidate for future targeted therapies of aggressive breast cancer

Electrochemically and Chemically Induced Redox Processes in Molecular Machines

International audienceThe controlled motion of ions, molecules, or supramolecular entities has inspired scientists for more than 25 years, and the concept remains of great interest for the development of moveable nanoscale objects for applications in electronics, medicine, and materials chemistry. Artificial molecular machines that involve electron exchange processes induced by electrical, chemical, or photochemical energy, have been widely developed. More specifically, machines that are stimulated by electrochemical means have been the focus of particular attention because such systems can allow the change of states to be followed and can enable access to mechanistic pathways through direct monitoring. Furthermore, these devices have the ability to connect the nanoscale machine to the macroscopic world, for instance by surface immobilization. In this review, we report recent examples of redox-based molecular machines in both fluid solution and in organized or controllable environments such as modified electrodes, nanoparticles, polymers, gels, and liquid crystals. Basic concepts of molecular machinery and general applications are also discussed

Thermodynamic Insights on a Bistable Acid–Base Switchable Molecular Shuttle with Strongly Shifted Co-conformational Equilibria

3Bistable [2]rotaxanes in which the affinities of the two stations can be reversed form the basis of molecular shuttles. Gaining quantitative information on such rotaxanes in which the ring distribution between the two stations is largely nonsymmetric has proven to be very challenging. Herein, we report on two independent experimental methodologies, based on luminescence lifetime measurements and acid–base titrations, to determine the relative populations of the two co‐conformations of a [2]rotaxane. The assays yield convergent results and are sensitive enough to measure an equilibrium constant (K≈4000) out of reach for NMR spectroscopy. We also estimate the ring distribution constant in the switched (deprotonated) state (K′99.92 %). Finally, our results show that the pKa of the pH‐responsive station depends on the ring affinity of the pH‐insensitive station, an observation that paves the way for the design of new artificial allosteric systems.reservedmixedRAGAZZON, GIULIO; CREDI, ALBERTO; COLASSON, BENOIT XAVIERRagazzon, Giulio; Credi, Alberto; Colasson, BENOIT XAVIE

Photoinduced Electron Transfer Involving a Naphthalimide Chromophore in Switchable and Flexible [2]Rotaxanes

The interlocking of ring and axle molecular components in rotaxanes provides a way to combine chromophoric, electron-donor and electron-acceptor moieties in the same molecular entity, in order to reproduce the features of photosynthetic reaction centers. To this aim, the photoinduced electron transfer processes involving a 1,8-naphthalimide chromophore embedded in several rotaxane-based dyads were investigated by steady-state and time-resolved absorption and luminescence spectroscopic experiments in the 300 fs-10 ns time window. Different rotaxanes built around the dialkylammonium / dibenzo[24]crown-8 ether supramolecular motif were designed and synthesized to decipher the relevance of key structural factors, such as the chemical deactivation of the ammonium-crown ether recognition, the presence of a secondary site for the ring along the axle, and the covalent functionalization of the macrocycle with a phenothiazine electron donor. Indeed, the conformational freedom of these compounds gives rise to a rich dynamic behavior induced by light, and may provide opportunities for investigating and understanding phenomena that take place in complex (bio)molecular architectures

An Artificial Molecular Transporter

6The transport of substrates is one of the main tasks of biomolecular machines in living organisms. We report a synthetic small‐molecule system designed to catch, displace, and release molecular cargo in solution under external control. The system consists of a bistable rotaxane that behaves as an acid–base controlled molecular shuttle, whose ring component bears a tether ending with a nitrile group. The latter can be coordinated to a ruthenium complex that acts as the load, and dissociated upon irradiation with visible light. The cargo loading/unloading and ring transfer/return processes are reversible and can be controlled independently. The robust coordination bond ensures that the cargo remains attached to the device while the transport takes place.openopenSchäfer, Christian; RAGAZZON, GIULIO; Colasson, Benoit; LA ROSA, MARCELLO; SILVI, SERENA; CREDI, ALBERTOSchäfer, Christian; Ragazzon, Giulio; Colasson, Benoit; LA ROSA, Marcello; Silvi, Serena; Credi, Albert

Light-driven molecular machines based on ruthenium(II) polypyridine complexes: Strategies and recent advances

Multicomponent molecular systems that exhibit large amplitude movements controlled by external inputs \u2013 namely, molecular machines \u2013 are extensively investigated both for their basic science interest and for their potential applications in technology and medicine. Light is a convenient stimulus to operate molecular machines because it can provide both an energy supply to feed their motion and an analytical signal to monitor their state. Research in the past two decades has shown that the unique and highly tunable structural, photophysical, photochemical and redox properties of Ru(II) polypyridine complexes are advantageous tools for implementing a light-induced response in molecular devices and machines. Here we describe the latest progresses in the realization of artificial nanoscale machines that use such metal complexes to process light signals. We will show the level of creativity and sophistication reached in this research area by describing a few selected examples

The template synthesis of dimetallic complexes

The FeII ion acts as a template to generate a dinuclear triple-stranded complex, in which two tris-diimine compartments are separated by rigid diphenylurea spacers. The template reaction involves the combination of 11 particles and leads to the formation of a single highly symmetrical product, as shown by X-ray diffraction studies. The diiron(II) complex undergoes reversible oxidation to the FeIII derivative. On the other hand, the CuI centre promotes the template formation of a double stranded dinuclear complex, which shows a total and unique resistance to the oxidation to CuII. Such an intriguing feature results (i) from the bulkiness of the substituents, which hinders the planarization of the donor set, and (ii) from the rigidity of the diphenylurea spacers, which prevent disassembling of the double stranded complex and formation of two mononuclear chelated CuI species

Metal-Controlled Assembly and Selectivity of a Urea-Based Anion Receptor

The terdentate ligand 3 (LH, 2-formylpyridine 4-thiosemicarbazone) forms with FeII and NiII 2:1 complexes of octahedral geometry of formula [MII(LH)2]2+. X-ray diffraction studies have shown that in both complexes the thiourea moieties of the coordinated thiosemicarbazones are exposed to the outside and are prone to establish hydrogen-bonding bifurcate interactions with oxoanions. However, spectrophotometric studies in CHCl3 soln. have shown that only the poorly basic NO3- ion is able to form authentic hydrogen-bond complexes with thiourea subunits, whereas all the other investigated anions (CH3COO-, NO2-, F-) induce deprotonation of the N-H fragment. The extreme enhancement of the thiourea acidity is based on the coordinative interaction of the sulfur atom with the metal, which stabilizes the thiolate form, and it is much higher than that exerted by any other covalently linked electron-withdrawing substituent, for example, -NO2

Electrochemically Triggered Double Translocation of Two Different Metal Ions with a Ditopic Calix[6]arene Ligand

International audienceA ditopic ligand based on a calix[6]arene with three imidazoles (Im) appended at the small rim and three triazoles (Tria) at the large one is able to form selectively two stable heterodinuclear complexes with Zn(Im)(II)/Cu(Tria)(I) and Cu(Im)(II)/Zn(Tria)(II). In the Cu(I) case, the zinc cation is preferentially coordinated at the Im site while the copper is bound at the Tria site. The situation is the opposite when Cu(II) is used. The position of the two cations within the complex can be electrochemically switched via the oxidation reduction of the copper cation between oxidation states +I and +II. The presence of the zinc cation is crucial (i) to control the bistability of the system by an allosteric structuring role and (ii) to promote the metal switch since the monocopper complex exhibits reversible behavior with Cu located at the imidazole site in both oxidation states. This represents the first example of a double translocation of two different metal cations