Portrait of a Family of Highly Stabilizing and Selective Guanine Quadruplex Platinum(II)-Based Binders.

The long-standing history of platinum coordination complexes in nucleic acid recognition attests to the unique suitability of such species for therapeutic applications. Here, we report the synthetic exploration and development of a family of di-imine ligands, and their platinum(II) complexes, elaborated on a 3-(2-pyridyl)-[1,2,4]triazolo[4,3-a]pyridine platform which, in its unsubstituted form, has recently been shown to display exceptional capabilities for guanine quadruplex (G4) targeting. The identification of facile, high-yielding synthetic methods for the derivatization of this platform for the incorporation of additional sites of interactions with guanine quadruplex loops and grooves, along with the optimization of platinum(II) complexation methods, are discussed. Gratifyingly, preliminary biophysical screening of this novel family of binders validates all but one family members as robust G4 binders and highlights enhanced selectivity for quadruplex versus duplex DNA compared to the parent compound. These results bear promise for practical developments based on this platform.

Going Platinum to the Tune of a Remarkable Guanine Quadruplex Binder: Solution- and Solid-State Investigations.

Guanine quadruplex recognition has gained increasing attention, inspired by the growing awareness of the key roles played by these non-canonical nucleic acid architectures in cellular regulatory processes. We report here the solution and solid-state studies of a novel planar platinum(II) complex that is easily assembled from a simple ligand, and exhibits notable binding affinity for guanine quadruplex structures, while maintaining good selectivity for guanine quadruplex over duplex structures. A crystal structure of this ligand complexed with a telomeric quadruplex confirms double end-capping, with dimerization at the 5' interface.

Closing the Loop: Triazolylpyridine Coordination Drives the Self-Assembly of Metallomacrocycles with Tunable Topologies for Small-Molecule and Guanine-Quadruplex Recognition.

The 2-(1,2,3-triazol-4-yl)pyridine motif, with its facile "click" synthesis and remarkable coordinative properties, is an attractive chelate for applications in the metal-directed self-assembly of intricate three-dimensional structures. Organic ligands that bear two such chelates bridged by flexible hinge moieties readily undergo self-assembly with metal ions of different coordination geometries to generate a series of topologically diverse metallomacrocycles that can be used for numerous applications. Herein, the synthesis and self-assembly of one such ligand with zinc(II), copper(II), and palladium(II) ions is reported, and the stability of the resulting metallomacrocycles described. An investigation into the use of these metallomacrocycles for the recognition of both small-molecule substrates, such as deoxyguanosine monophosphate, and larger biological assemblies, such as DNA and RNA guanine quadruplexes, is also described.

To Loop or Not to Loop: Influence of Hinge Flexibility on Self-Assembly Outcomes for Acridine-Based Triazolylpyridine Chelates with Zinc(II), Iron(II), and Copper(II).

Coordination-driven self-assembly has been established as an effective strategy for the efficient construction of intricate architectures in both natural and artificial systems, for applications ranging from gene regulation to metal-organic frameworks. Central to these systems is the need for carefully designed organic ligands, generally with rigid components, that can undergo self-assembly with metal ions in a predictable manner. Herein, we report the synthesis and study of three novel organic ligands that feature 3,6-disubstituted acridine as a rigid spacer connected to two 2-(1,2,3-triazol-4-yl)pyridine "click" chelates through hinges of the same length but differing flexibility. The flexibility of these "three-atom" hinges was modulated by i) moving from secondary to tertiary amide functional groups and ii) replacing an sp2 amide carbon with an sp3 methylene carbon. In an effort to understand the role of hinge flexibility in directing self-assembly into mononuclear loops or dinuclear cylinders, the impact of these changes on self-assembly outcomes with zinc(II), iron(II), and copper(II) ions is described.

Reprogramming the assembly of unmodified DNA with a small molecule.

The ability of DNA to store and encode information arises from base pairing of the four-letter nucleobase code to form a double helix. Expanding this DNA 'alphabet' by synthetic incorporation of new bases can introduce new functionalities and enable the formation of novel nucleic acid structures. However, reprogramming the self-assembly of existing nucleobases presents an alternative route to expand the structural space and functionality of nucleic acids. Here we report the discovery that a small molecule, cyanuric acid, with three thymine-like faces, reprogrammes the assembly of unmodified poly(adenine) (poly(A)) into stable, long and abundant fibres with a unique internal structure. Poly(A) DNA, RNA and peptide nucleic acid (PNA) all form these assemblies. Our studies are consistent with the association of adenine and cyanuric acid units into a hexameric rosette, which brings together poly(A) triplexes with a subsequent cooperative polymerization. Fundamentally, this study shows that small hydrogen-bonding molecules can be used to induce the assembly of nucleic acids in water, which leads to new structures from inexpensive and readily available materials.

Systematic study of the synthesis and coordination of 2-(1,2,3-triazol-4-yl)-pyridine to Fe(II), Ni(II) and Zn(II); ion-induced folding into helicates, mesocates and larger architectures, and application to magnetism and self-selection.

With its facile synthesis, the pyridine-1,2,3-triazole chelate is an attractive building block for coordination-driven self-assembly. When two such chelates are bridged by a spacer and exposed to cations of octahedral geometrical preference, they generally self-assemble into dinuclear triple-stranded structures in the solid state and in solution in the presence of non-coordinating counter-ions. In solution, a wider range of architectures may nevertheless form, depending on the nature of the spacer. A systematic study of the spacer and substitution pattern is therefore presented, which allows assessing the various factors affecting self-assembly around the pyridine-1,2,3-triazole chelate, as well as the stereochemical control in these architectures. Applications to chirality, magnetism and system selection are discussed, and involve Fe(ii), Ni(ii), Zn(ii) and Cu(i) cations.

Sugar recognition: designing artificial receptors for applications in biological diagnostics and imaging.

At the cellular level, numerous processes ranging from protein folding to disease development are mediated by a sugar-based molecular information system that is much less well known than its DNA- or protein-based counterparts. The subtle structural diversity of such sugar tags nevertheless offers an excellent, if challenging, opportunity to design receptors for the selective recognition of biorelevant sugars. Over the past 40 years, growing interest in the field of sugar recognition has led to the development of several promising artificial receptors, which could soon find widespread use in medical diagnostics and cell imaging.

Controlled synthesis and alkaline earth ion binding of switchable formamidoxime-based crown ether analogs.

The partial positive charge of amide protons is used to promote macrocyclization and form crown-ether analogs. Their deprotonation generates very selective pH-switchable alkaline earth ion receptors only in the presence of an appropriate substrate.

Telomere targeting with a new G4 ligand enhances radiation-induced killing of human glioblastoma cells.

The aim of this study was to test in vitro the efficacy of TAC, an original G-quadruplex ligand, as a potential radiosensitizing agent for glioblastoma multiforme (GBM). Two human radioresistant telomerase-positive GBM cell lines (SF763 and SF767) were analyzed, with and without TAC treatment, for telomere length, cell proliferation, apoptosis, cell-cycle distribution, gene expression, cytogenetic aberrations, clonogenic survival assay, 53BP1 immunofluorescence staining, and γH2AX phosphorylation. We found that low concentrations of TAC (0.5 and 1 µmol/L) inhibited the proliferation of GBM cells in a concentration-dependent manner after only 1 week of treatment, with minimal effects on cell cycle and apoptosis. TAC treatment had no visible effect on average telomere length but modified expression levels of telomere-related genes (hTERT, TRF1, and TRF2) and induced concentration-dependent DNA damage response and dicentric chromosomes. Survival curves analysis showed that exposure to nontoxic, subapoptotic concentrations of TAC enhanced radiation-induced killing of GBM cells. Analysis of DNA repair after irradiation revealed delayed repair kinetics in GBM cells treated with TAC. Furthermore, the combined treatment (TAC and radiation) significantly increased the frequency of chromosomal aberrations as compared with radiation alone. These findings provide the first evidence that exposure to a G4 ligand radiosensitizes human glioblastoma cells and suggest the prospect of future therapeutic applications.

Z-formamidoximes in molecular folding and macrocycles.

The formamidoxime configurational Z isomer coupled with the pyridylbiscarboxamide conformational codon were used to fold planar, curved structures. When embedded into macrocycles, this folded motif promotes dimerization through π-π stacking and hydrogen-bonding and the formation of tubules akin to molecular channels in the solid state.

Alkoxyamine-derived formamidines: configurational control and molecular folding.

N,N'-Disubstituted formamidines, and amidines in general, have very rich configurational, conformational, and tautomeric diversities. As part of an effort to incorporate alkoxyamine-derived formamidine units into foldamers, the first evidence for the isolation of the up-to-now unknown E isomer, the conditions for its exclusive formation, its stability and self-assembly properties, and its configurational isomerization to its much more common Z counterpart are reported. Considering the distinctly different H-bonding patterns displayed by both E and Z isomers, such configurational control may find applications in self-assembly, molecular recognition, and biomimetic systems.

New pharmaceutical applications for macromolecular binders.

Macromolecular binders consist of polymers, dendrimers, and oligomers with binding properties for endogenous or exogenous substrates. This field, at the frontier of host/guest chemistry and pharmacology, has met a renewed interest in the past decade due to the clinical success of several sequestrants, like sevelamer hydrochloride (Renagel®) or sugammadex (Bridion®). In many instances, multivalent binding by the macromolecular drugs can modify the properties of the substrate, and may prevent it from reaching its site of action and/or trigger a biological response. From small (e.g., ions) to larger substrates (e.g., bacteria and cells), this review presents the state-of-the-art of macromolecular binders and provides detailed illustrative examples of recent developments bearing much promise for future pharmaceutical applications.

Molecular tweezers: concepts and applications.

Taken to the molecular level, the concept of "tweezers" opens a rich and fascinating field at the convergence of molecular recognition, biomimetic chemistry and nanomachines. Composed of a spacer bridging two interaction sites, the behaviour of molecular tweezers is strongly influenced by the flexibility of their spacer. Operating through an "induced-fit" recognition mechanism, flexible molecular tweezers select the conformation(s) most appropriate for substrate binding. Their adaptability allows them to be used in a variety of binding modes and they have found applications in chirality signalling. Rigid spacers, on the contrary, display a limited number of binding states, which lead to selective and strong substrate binding following a "lock and key" model. Exquisite selectivity may be expressed with substrates as varied as C(60) , nanotubes and natural cofactors, and applications to molecular electronics and enzyme inhibition are emerging. At the crossroad between flexible and rigid spacers, stimulus-responsive molecular tweezers controlled by ionic, redox or light triggers belong to the realm of molecular machines, and, applied to molecular tweezing, open doors to the selective binding, transport and release of their cargo. Applications to controlled drug delivery are already appearing. The past 30 years have seen the birth of molecular tweezers; the next many years to come will surely see them blooming in exciting applications.

Amine exchange in formamidines: an experimental and theoretical study.

N-H-containing formamidines combine a reasonably strong association to carboxylic acids to form complexes of well-defined geometries with a simultaneous proton-induced electrophilicity enhancement that allows for the exchange of their amine portion. The N=C(H)-NH fragment, therefore, undergoes "imine-like" exchange with N-containing nucleophiles. Because of the prototropic equilibrium, the N=C(H)-NH fragment may behave as a "bisimine" centred on the same carbon, in which both N-containing fragments can be exchanged. Considering the proton-induced sensitisation of both C-N units and the well-defined formamidine-carboxylic acid complex geometry, it should be possible to use carboxylic acids as templates for the synthesis of defined architectures by dynamic amine exchange within formamidines. This study highlights three exchange regimes based on the nature of the incoming amine (aliphatic amines, aromatic amines and alkoxyamines), as well as exchange rules based on the amine leaving groups. Following this analysis, a proof of concept for carboxylic acid templated macrocycle formation through dynamic exchange is provided.

Click-triazole: coordination of 2-(1,2,3-triazol-4-yl)-pyridine to cations of traditional tetrahedral geometry (Cu(I), Ag(I)).

Coordination studies of the pyridine-triazole diad to copper(i) and silver(i) reveal the potential and conditions for the solution- and solid-state self-assembly of supramolecular architectures based on this motif.

pH-Responsive molecular tweezers.

Molecular tweezers are dynamic devices that are able to switch from one conformation to another upon stimulation by an external trigger. In this work, we report a new water-soluble macromolecular carrier bearing a pH-responsive molecular tweezer, whose affinity for a substrate depends on the external pH. The conformational change of the switching unit was evidenced by (1)H NMR spectroscopy, and fluorescence studies conducted in aqueous media demonstrated the ability of the carrier to bind to substrates in a pH-dependent fashion.

Stereochemical and conformational exchanges in N,N'-di(2-pyridyl)formamidines: An X-ray and (1)H NMR study.

The solid state structure of N,N'-di(2-pyridyl)formamidine displays a four-hydrogen-bonded dimer. In solution, two isomers are observed, one of which is selected and amplified either by crystallization or by adding protons. Solution state analysis of N,N'-di(2-pyridyl)formamidines reveals the presence of the uncommon Z formamidine isomer, which equilibrates with the E-isomer with an activation energy of 90 kJ mol(-1) in CDCl(3).

STM insight into hydrogen-bonded bicomponent 1D supramolecular polymers with controlled geometries at the liquid-solid interface.

Bicomponent supramolecular polymers, consisting of two alternating molecules bridged through six H-bonds, are observed by STM at the solid-liquid interface. Control of the geometry of the 1D architecture was obtained by using two different connecting molecules with different conformational rigidity, affording either linear (see picture, left) or zigzag (right) motifs.

Naphthyridine-based helical foldamers and macrocycles: synthesis, cation binding, and supramolecular assemblies.

Unraveling the factors that control the conformation of molecular chains is of great interest both for understanding the shape of biological molecular strands and for designing artificial ones that adopt desired forms. Thus, a variety of artificial folding codons have been identified that enforce the formation, among others, of helices, strands, and loops, the major emphasis being on the shape of the foldamer. We report herein the synthesis and study of a family of foldamers and macrocycles based on the 1,8-naphthyridine and pyrimidine units, whose internal cavity is large enough to accommodate ionic substrates, and focus on the impact of guest binding within a cylindrical environment. Interestingly, the binding event within these large oligomers is translated to the outside of the receptors and affects the interaction of the overall complexes with the outside world. For instance, alkali cations bind to the one-turn helices and macrocycles to promote fibril formation and aggregation. Also, polyammonium substrates are able to tune the length of the overall helix assemblies and the rigidity of long oligomers. The reported data on one-turn, two-turn helices and macrocycles not only allows one to devise a model for the ion-controlled supramolecular assembly of such systems but also provides evidence that such controlled scaffolds bear promise in the design of complex systems.