Designing a New Class of Bases for Nucleic Acid Quadruplexes and Quadruplex‐Active Ligands

A new class of quadruplex nucleobases, derived from 3‐deazaguanine, has been designed for various applications as smart quadruplex ligands as well as quadruplex‐based aptamers, receptors, and sensors. An efficient strategy for modifying the guanine quadruplex core has been developed and tested by using quantum chemistry methods. Several potential guanine derivatives modified at the 3‐ or 8‐position or both are analyzed, and the results compared to reference systems containing natural guanine. Analysis of the formation energies (BLYP‐D3(BJ)/def2‐TZVPP level of theory, in combination with the COSMO model for water) in model systems consisting of two and three stacked tetrads with Na⁺/K⁺ ion(s) inside the internal channel indicates that the formation of structures with 3‐halo‐3‐deazaguanine bases leads to a substantial gain in energy, as compared to the corresponding reference guanine complexes. The results cast light on changes in the noncovalent interactions (hydrogen bonding, stacking, and ion coordination) in a quadruplex stem upon modification of the guanine core. In particular, the enhanced stability of the modified quadruplexes was shown to originate mainly from increased π–π stacking. Our study suggests the 3‐halo‐3‐deazaguanine skeleton as a potential building unit for quadruplex systems and smart G‐quadruplex ligands.     

Polymorphism of methyl 4‐amino‐3‐phenylisothiazole‐5‐carboxylate: an experimental and theoretical study

Being a close analogue of amflutizole, methyl 4‐amino‐3‐phenylisothiazole‐5‐carboxylate (C₁₁H₁₀N₂O₂S) was assumed to be capable of forming polymorphic structures. Noncentrosymmetric and centrosymmetric polymorphs have been obtained by crystallization from a series of more volatile solvents and from denser tetrachloromethane, respectively. Identical conformations of the molecule are found in both structures. The two polymorphs differ mainly in the intermolecular interactions formed by the amino group and in the type of stacking interactions between the π‐systems. The most effective method for revealing packing motifs in structures with intermolecular interactions of different types (hydrogen bonding, stacking, dispersion, etc.) is to study the pairwise interaction energies using quantum chemical calculations. Molecules form a column as the primary basic structural motif due to stacking interactions in both polymorphic structures under study. The character of a column (straight or zigzag) is determined by the orientations of the stacked molecules (in a `head‐to‐head' or `head‐to‐tail' manner). Columns bound by intermolecular N—H…O and N—H…N hydrogen bonds form a double column as the main structural motif in the noncentrosymmetric structure. Double columns in the noncentrosymmetric structure and columns in the centrosymmetric structure interact strongly within the ab crystallographic plane, forming a layer as a secondary basic structural motif. The noncentrosymmetric structure has a lower density and a lower (by 0.59 kJ mol^?1) lattice energy, calculated using periodic calculations, compared to the centrosymmetric structure.     

Hydrogen‐bonding versusπ–π stacking interactions in dipyrido[f,h]quinoxaline‐6,7‐dicarbonitrile and 6,7‐dicyanodipyrido[f,h]quinoxalin‐1‐ium chloride dihydrate

The solvent‐free title compound, C₁₆H₆N₆, is an aromatic derivative of phenanthroline with an extended π system. It exhibits a remarkable π–π columnar stacking in the crystal structure, with interplanar distances of 3.229 (3) and 3.380 (3) Å, the shorter spacing being between the two molecules within the asymmetric unit. Adjacent units along the stacked arrays are rotated in‐plane with respect to one another by approximately 120°. The hydrochloride derivative, C₁₆H₇N₆⁺·Cl⁻·2H₂O, in which one of the phenanthroline N atoms has been protonated, crystallized as a dihydrate. The supramolecular organization in this compound is characterized by continuous hydrogen bonding between the component species, yielding two‐dimensional hydrogen‐bonded networks. This study demonstrates the high significance of the π–π stacking interactions in the solvent‐free aromatic system and how they can be undermined by introducing hydrogen‐bonding capacity into the ligand.     

Influence of π-stacking on the N7 and O6 proton affinity of guanine

The influence of π-stacking interactions between guanine (G) and the side chain of tyrosine (Tyr) on the N7 and O6 proton affinities of guanine and on the capability of these sites to act as hydrogen bond acceptors is analyzed at the B3LYP-D, M05-2X and MP2 levels of theory. With all methods, results from full geometry optimizations indicate that stacking interactions increase the N7 and O6 proton affinities by about 5–6 kcal mol^?1, the increase being slightly larger for N7. Consistently with these results, hydrogen bond distances between guanine and one water molecule decrease in the stacked system. Moreover, interaction energy between H₂O and (G-Tyr) is found to be 2–3 kcal mol^?1 larger than in G···H₂O. This strengthening arises from the additional Tyr–H₂O stabilizing interactions and from a cooperative interplay between stacking and hydrogen bond forces.     

Density functional study of guanine and uracil quartets and of guanine quartet/metal ion complexes

The structures and interaction energies of guanine and uracil quartets have been determined by B3LYP hybrid density‐functional calculations. The total interaction energy ΔE^T of the C_4h‐symmetric guanine quartet consisting of Hoogsteen‐type base pairs with two hydrogen bonds between two neighbor bases is −66.07 kcal/mol at the highest level. The uracil quartet with C6 H6O4 interactions between the individual bases has only a small interaction energy of −20.92 kcal mol⁻¹, and the interaction energy of −24.63 kcal/mol for the alternative structure with N3 H3O4 hydrogen bonds is only slightly more negative. Cooperative effects contribute between 10 and 25% to all interaction energies. Complexes of metal ions with G‐quartets can be classified into different structure types. The one with Ca²⁺ in the central cavity adopts a C_4h‐symmetric structure with coplanar bases, whereas the energies of the planar and nonplanar Na⁺ complexes are almost identical. The small ions Li⁺, Be²⁺, Cu⁺, and Zn²⁺ prefer a nonplanar S₄‐symmetric structure. The lack of coplanarity prevents probably a stacking of these base quartets. The central cavity is too small for K⁺ ions and, therefore, this ion favors in contrast to all other investigated ions a C₄‐symmetric complex, which is 4.73 kcal/mol more stable than the C_4h‐symmetric one. The distance 1.665 Å between K⁺ and the root‐mean‐square plane of the guanine bases is approximately half of the distance between two stacked G‐quartets. The total interaction energy of alkaline earth ion complexes exceeds those with alkali ions. Within both groups of ions the interaction energy decreases with an increasing row position in the periodic table. The B3LYP and BLYP methods lead to similar structures and energies. Both methods are suitable for hydrogen‐bonded biological systems. Compared with the before‐mentioned methods, the HCTH functional leads to longer hydrogen bonds and different relative energies for two U‐quartets. Finally, we calculated also structures and relative energies with the MMFF94 forcefield. Contrary to all DFT methods, MMFF94 predicts bifurcated C HO contacts in the uracil quartet. In the G‐quartet, the MMFF94 hydrogen bond distances N2 H22N7 are shorter than the DFT distances, whereas the N1 H1O6 distances are longer. © 2000 John Wiley & Sons, Inc. J Comput Chem 22: 109–124, 2001     

A post‐SCF quantum chemistry study on local minima of 8‐oxo‐guanine stacked with all four nucleic acid bases in B‐DNA conformations

The post SCF MP2/6‐31G*(d=0.25) method was applied to obtain potential energy surface of 8‐oxoguanine stacked with all four canonical DNA bases. The spatial neighbourhood was scanned of stacked complexes found in the native B‐DNA. The presented results suggest that the hydroxyl radical modification of guanine at C₈ position has significant impact on structural, energetic, orbital and electrostatic properties of stacked complexes with canonical DNA bases. The pair stabilization energy, including electron correlation terms, suggests that the 5′‐A/GA‐3′ pair is the most stable among all of the studied complexes. The 8‐oxo‐guanine has been found as a source of significant changes in electroaccepting properties compared to stacked pairs formed by canonical guanine since both electron affinities and localization of HOMO orbital were altered. However, electro‐donation abilities are not modified after replacement of guanine with 8‐oxo‐guanine irrespectively on the context of B‐DNA bases.     

Adenine versus guanine quartets in aqueous solution: dispersion-corrected DFT study on the differences in π-stacking and hydrogen-bonding behavior

We have investigated the performance of the dispersion-corrected density functionals (BLYP-D, BP86-D and PBE-D) and the widely used B3LYP functional for describing the hydrogen bonds and the stacking interactions in DNA base dimers. For the gas-phase situation, the bonding energies have been compared to the best ab initio results available in the literature. All dispersion-corrected functionals reproduce well the ab initio results, whereas B3LYP fails completely for the stacked systems. The use of the proper functional leads us to find minima for the adenine quartets, which are energetically and structurally very different from the C_4h structures, and might explain why adenine has to be sandwiched between guanine quartets to form planar adenine quartets.     

A novel one‐dimensional metal–organic framework with a μ‐cyanido‐argentate group: catena‐poly[[(5,5′‐dimethyl‐2,2′‐bipyridyl‐κ2N,N′)silver(I)]‐μ‐cyanido‐κ2N:C]

The design and synthesis of metal coordination and supramolecular frameworks containing N‐donor ligands and dicyanidoargentate units is of interest due to their potential applications in the fields of molecular magnetism, catalysis, nonlinear optics and luminescence. In the design and synthesis of extended frameworks, supramolecular interactions, such as hydrogen bonding, π–π stacking and van der Waals interactions, have been exploited for molecular recognition associated with biological activity and for the engineering of molecular solids.The title compound, [Ag(CN)(C₁₂H₁₂N₂)]_n, crystallizes with the Ag^I cation on a twofold axis, half a cyanide ligand disordered about a centre of inversion and half a twofold‐symmetric 5,5′‐dimethyl‐2,2′‐bipyridine (5,5′‐dmbpy) ligand in the asymmetric unit. Each Ag^I cation exhibits a distorted tetrahedral geometry; the coordination environment comprises one C(N) atom and one N(C) atom from substitutionally disordered cyanide bridging ligands, and two N atoms from a bidentate chelating 5,5′‐dmbpy ligand. The cyanide ligand links adjacent Ag^I cations to generate a one‐dimensional zigzag chain. These chains are linked together via weak nonclassical intermolecular interactions, generating a two‐dimensional supramolecular network.     

[2‐(2‐Pyridyl)‐1H‐benzimidazole‐κ2N2,N3]bis(p‐toluato‐κ2O,O′)manganese(II)

In the title compound, [Mn(C₈H₇O₂)₂(C₁₂H₉N₃)], the manganese(II) centre is surrounded by three bidentate chelating ligands, namely, one 2‐(2‐pyridyl)benzimidazole ligand [Mn—N = 2.1954 (13) and 2.2595 (14) Å] and two p‐toluate ligands [Mn—O = 2.1559 (13)–2.2748 (14) Å]. It displays a severely distorted octahedral geometry, with cis angles ranging from 58.87 (4) to 106.49 (5)°. Intermolecular C—H...O hydrogen bonds between the p‐toluate ligands link the molecules into infinite chains, and every two neighbouring chains are further coupled by N—H...O and C—H...O hydrogen bonds between the 2‐(2‐pyridyl)benzimidazole and p‐toluate ligands, leading to an infinite ribbon‐like double‐chain packing mode. The complete solid‐state structure can be described as a three‐dimensional supramolecular framework, stabilized by these intermolecular hydrogen‐bonding interactions and possible C—H...π interactions, as well as stacking interactions involving the 2‐(2‐pyridyl)benzimidazole ligands.     

Unconventional hydrogen bonding and π‐stacking in two substituted pyridine carboxamides

The crystal structures of two para‐substituted aryl derivatives of pyridine‐2‐carboxamide, namely N‐(4‐fluorophenyl)pyridine‐2‐carboxamide, C₁₂H₉FN₂O, (I), and N‐(4‐nitrophenyl)pyridine‐2‐carboxamide, C₁₂H₉N₃O₃, (II), have been studied. Compound (I) exhibits unconventional aryl–carbonyl C—H...O and pyridine–fluorine C—H...F hydrogen bonding in two dimensions and well defined π‐stacking involving pyridine rings in the third dimension. The conformation of (II) is more nearly planar than that of (I) and the intermolecular interactions comprise one‐dimensional aryl–carbonyl C—H...O hydrogen bonds leading to a stepped or staircase‐like progression of loosely π‐stacked molecules. The close‐packed layers of planar π‐stacked molecules are related by inversion symmetry. Two alternating interplanar separations of 3.439 (1) and 3.476 (1) Å are observed in the crystal lattice and are consistent with a repetitive packing sequence, ABA′B′AB…, for the π‐stacked inversion pairs of (II).     

A new three‐dimensional CdII supramolecular framework constructed from the 1‐[(1H‐tetrazol‐5‐yl)methyl]‐1,4‐diazoniabicyclo[2.2.2]octane ligand

A new tetrazole–metal supramolecular compound, di‐μ‐chlorido‐bis(trichlorido{1‐[(1H‐tetrazol‐5‐yl‐κN²)methyl]‐1,4‐diazoniabicyclo[2.2.2]octane}cadmium(II)), [Cd₂(C₈H₁₆N₆)₂Cl₈], has been synthesized and structurally characterized by single‐crystal X‐ray diffraction. In the structure, each Cd^II cation is coordinated by five Cl atoms (two bridging and three terminal) and by one N atom from the 1‐[(1H‐tetrazol‐5‐yl)methyl]‐1,4‐diazoniabicyclo[2.2.2]octane ligand, adopting a slightly distorted octahedral coordination geometry. The bridging bicyclo[2.2.2]octane and chloride ligands link the Cd^II cations into one‐dimensional ribbon‐like N—H...Cl hydrogen‐bonded chains along the b axis. An extensive hydrogen‐bonding network formed by N—H...Cl and C—H...Cl hydrogen bonds, and interchain π–π stacking interactions between adjacent tetrazole rings, consolidate the crystal packing, linking the poymeric chains into a three‐dimensional supramolecular network.     

Violuric acid monohydrate: a second polymorph with more extensive hydrogen bonding

Crystals of a second polymorph of violuric acid monohydrate [systematic name: pyrimidine‐2,4,5,6(1H,3H)‐tetrone monohydrate], C₄H₃N₃O₄·H₂O, have higher density and a more extensive hydrogen‐bonding arrangement than the previously reported polymorph. Violuric acid and water molecules form essentially planar hydrogen‐bonded sheets, which are stacked in an offset …ABCABC… repeat pattern involving no ring‐stacking interactions.     

Stacking Interactions: A Supramolecular Approach to Upgrade Weak Halogen Bond Donors

The co-crystallization of tetracyanobenzene (TCB) with haloarenes ArX provided six new co-crystals TCB ⋅ ArX (ArX=PhCl, PhBr, 4-MeC₆H₄Cl, 4-MeC₆H₄Br, 4-MeOC₆H₄Cl, 1,2-Br₂C₆H₄) which were studied by X-ray diffraction. In these systems, the strong collective effect of π⋅⋅⋅π stacking interactions and lone pair-(X)⋅⋅⋅π-hole-(C) bondings between TCB and ArX promote the strength of X⋅⋅⋅N_cyano halogen bonding (HaB). Theoretical studies showed that the stacking interactions affect the σ-hole depth of the haloarenes, thus significantly boosting their ability to function as HaB donors. According to the molecular electrostatic potential calculations, the σ- hole-(Cl) value (1.5 kcal/mol) in the haloarene 4-MeOC₆H₄Cl (featuring an electron-rich arene moiety and exhibiting very poor σ-hole-(Cl) ability) increases significantly in the stacked trimer (TCB)₂ ⋅ 4-MeOC₆H₄Cl (12.5 kcal/mol). Theoretical DFT calculations demonstrate the dramatic increase of X⋅⋅⋅N_cyano HaB strength for stacked trimers in comparison with parent unstacked haloarenes.     

Hydrogen‐Bonding‐Mediated Vesicular Assembly of Functionalized Naphthalene–Diimide‐Based Bolaamphiphile and Guest‐Induced Gelation in Water

This paper describes the spontaneous vesicular assembly of a naphthalene–diimide (NDI)‐based non‐ionic bolaamphiphile in aqueous medium by using the synergistic effects of π‐stacking and hydrogen bonding. Site isolation of the hydrogen‐bonding functionality (hydrazide), a strategy that has been adopted so elegantly in nature, has been executed in this system to protect these moieties from the bulk water so that the distinct role of hydrogen bonding in the self‐assembly of hydrazide‐functionalized NDI building blocks could be realized, even in aqueous solution. Furthermore, the electron‐deficient NDI‐based bolaamphiphile could engage in donor–acceptor (D–A) charge‐transfer (CT) interactions with a water‐insoluble electron‐rich pyrene donor by virtue of intercalation of the latter chromophore in between two NDI building blocks. Remarkably, even when pyrene was located between two NDI blocks, intermolecular hydrogen‐bonding networks between the NDI‐linked hydrazide groups could be retained. However, time‐dependent AFM studies revealed that the radius of curvature of the alternately stacked D–A assembly increased significantly, thereby leading to intervesicular fusion, which eventually resulted in rupturing of the membrane to form 1D fibers. Such 2D‐to‐1D morphological transition produced CT‐mediated hydrogels at relatively higher concentrations. Instead of pyrene, when a water‐soluble carboxylate‐functionalized pyrene derivative was used as the intercalator, non‐covalent tunable in‐situ surface‐functionalization could be achieved, as evidenced by the zeta‐potential measurements.     

An analytic potential energy function for the amide–amide and amide–water intermolecular hydrogen bonds in peptides

An analytic potential energy function is proposed and applied to evaluate the amide–amide and amide–water hydrogen‐bonding interaction energies in peptides. The parameters in the analytic function are derived from fitting to the potential energy curves of 10 hydrogen‐bonded training dimers. The analytic potential energy function is then employed to calculate the N? H…O?C, C? H…O?C, N? H…OH₂, and C?O…HOH hydrogen‐bonding interaction energies in amide–amide and amide–water dimers containing N‐methylacetamide, acetamide, glycine dipeptide, alanine dipeptide, N‐methylformamide, N‐methylpropanamide, N‐ethylacetamide and/or water molecules. The potential energy curves of these systems are therefore obtained, including the equilibrium hydrogen bond distances R(O…H) and the hydrogen‐bonding energies. The function is also applied to calculate the binding energies in models of β‐sheets. The calculation results show that the potential energy curves obtained from the analytic function are in good agreement with those obtained from MP2/6‐31+G** calculations by including the BSSE correction, which demonstrate that the analytic function proposed in this work can be used to predict the hydrogen‐bonding interaction energies in peptides quickly and accurately. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2009     

A Supramolecular Sorting Hat: Stereocontrol in Metal–Ligand Self‐Assembly by Complementary Hydrogen Bonding

A combination of self‐complementary hydrogen bonding and metal–ligand interactions allows stereocontrol in the self‐assembly of prochiral ligand scaffolds. A unique, non‐tetrahedral M₄L₆ structure is observed upon multicomponent self‐assembly of 2,7‐diaminofluorenol with 2‐formylpyridine and Fe(ClO₄)₂. The stereochemical outcome of the assembly is controlled by self‐complementary hydrogen bonding between both individual ligands and a suitably sized counterion as template. This hydrogen‐bonding‐mediated stereoselective metal–ligand assembly allows the controlled formation of nonsymmetric discrete cage structures from previously unexploited ligand scaffolds.     

Syntheses,Structure Analyses and Thermal Stabilities of Two Schiff Base Metal Complexes

A Schiff base ligand 1‐salicylideneamino‐1,3,4‐triazole (L) was prepared. Two new complexes with Schiff base, [Zn(L)₂(SCN)₂] ( 1 ) and [Co₂(L)₅(SCN)₄]·H₂O ( 2 ) have been synthesized and structurally characterized. Complex 1 takes a mononuclear zinc structure and the coordination geometry of zinc atom exhibits a distorted tetrahedron, in which a zig‐zag chain is constructed through hydrogen bonding interactions. A 2D supramolecular network is formed through Π‐Π stacking between triazole planes and phenyl planes of adjacent chains, and a 3D supramolecular network is further constructed by these non‐covalent Π‐Π stacking interactions between the triazole planes of neighboring layers. Complex 2 takes a dinuclear structure with the bidentate‐bridging Schiff base ligands, and cobalt site exhibits a distorted octahedron. The lattice water molecules and neutral complex 2 units form a dimer with hydrogen bonding interactions. In addition, IR and thermal gravimetric analysis are presented.     

Two tautomeric polymorphs of 2,6‐dichloropurine

Two polymorphs of 2,6‐dichloropurine, C₅H₂Cl₂N₄, have been crystallized and identified as the 9H‐ and 7H‐tautomers. Despite differences in the space group and number of symmetry‐independent molecules, they exhibit similar hydrogen‐bonding motifs. Both crystal structures are stabilized by intermolecular N—H...N interactions that link adjacent molecules into linear chains, and by some nonbonding contacts of the C—Cl...π type and by π–π stacking interactions, giving rise to a crossed two‐dimensional herringbone packing motif. The main structural difference between the two polymorphs is the different role of the molecules in the π–π stacking interactions.     

4‐Amino‐3‐methyl‐6‐phenyl‐1,2,4‐triazin‐5(4H)‐one (metamitron) and 4‐amino‐6‐methyl‐3‐phenyl‐1,2,4‐triazin‐5(4H)‐one (isometamitron)

The title structures, both C₁₀H₁₀N₄O, are substitutional isomers. The N—N bond lengths are longer and the C=N bond lengths are shorter by ca 0.025 Å than the respective average values in the C=N—N=C group of asymmetric triazines; the assessed respective bond orders are 1.3 and 1.7. There are N—H⋯O and N—H⋯N hydrogen bonds in both structures, with 4‐­amino‐3‐methyl‐6‐phenyl‐1,2,4‐triazin‐5(4H)‐one containing a rare bifurcated N—H⋯N,N hydrogen bond. The structures differ in their mol­ecular stacking and the hydrogen‐bonding patterns.     

Si?H and C?H Activation by Transition Metal Complexes: A Step Towards Isolable Alkane Complexes?

The recognition of the fundamental contributions by G. A. Olah on the elucidation of the structure of nonclassical carbocations, in the form of the award of the Nobel prize for chemistry, has recently emphasized the importance of electron-deficient bonds in the understanding of chemical bonding in organic chemistry. In the field of coordination chemistry, the formulation of electron-deficient bonds has been used for some time to describe nonclassical interactions between atoms. Traditional ligands in coordination chemistry such as amines and phosphanes bond to metal centers through their lone pair of electrons. Synergistic bonding effects dominate in the coordination of π-bonded ligands such as alkenes. In the mid-1980s the discovery of dihydrogen complexes having side-on coordination of H₂ gave fresh impetus to transition metal chemistry as well as to the understanding of the interaction of σ-coordinating ligands with transition metals. In the meantime, transiton metal complexes can be obtained with a variety of σ-coordinated X-H fragments, and their mode of bonding can be understood by a common and quite general model. The chemistry of σ-bound silane ligands is particularly varied and well-investigated. These silane ligands enable the investigation of a large range of σ-coordinated metal complex fragments up to complete oxidative addition with cleavage of the Si? H bond and formation of silyl(hydrido) complexes, which has thus also widened our general understanding of the bonding of other σ-bound ligands. Whilst there is a large range of isolable and stable H₂ and SiR₄ complexes available, there are no such alkane analogues known at present. Only when the C? H bond is part of a ligand that is already directly bonded to the transition metal center will the resulting chelate effect stabilize this agostic C-H-M interaction. The complexation of SiH₄, the simplest heavier homologue of CH₄, was achieved recently. This is a further step towards the understanding of the factors which govern σ-complexation of ligands at transition metal centers.