An ab initio quantum mechanics calculation that correlates with ligand orientation and DNA cleavage site selectivity in camptothecin-DNA-topoisomerase I ternary cleavage complexes

Camptothecin (CPT), a cytotoxic natural alkaloid isolated from Camptotheca acuminata, and its derivatives represent an important class of cancer chemotherapeutic drugs that act by inhibiting topoisomerase I (top1). The mechanism of top1 inhibition by CPT has been determined by X-ray crystallography. Biochemical studies carried out both in vitro and in vivo indicated that CPT has strict DNA sequence preference for -1 T and strong preference for +1 G at the cleavage site. To understand the molecular determinants for the CPT binding orientation and DNA sequence selectivity, we present a quantum mechanics calculation where only pi-pi stacking interactions were included to shed some light on the mechanism of this sequence selectivity. This ab initio calculation can not only reproduce the experimental binding orientation of CPT at the cleavage site but also shows very good correlation between the binding energy for different sequences and the observed frequency of CPT-stabilized sites in the SV40 viral genome. Therefore, it can be concluded that hydrogen bonding of the ligand to the surrounding amino acid residues of the protein is of minor significance. The present method should be applicable to other polycyclic top1 inhibitors.     

Synthesis, characterization, and adsorption behavior of aniline modified polystyrene resin for phenol in hexane and in aqueous solution

Macroporous crosslinked poly(p-vinylbenzylaniline) (PVBA) was synthesized and its adsorption isotherms for phenol in hexane and in aqueous solution were comparatively measured. It was shown that the adsorption isotherms in hexane were straight lines and passed through the origin, whereas those in aqueous solution could be simulated by Freundlich isotherms. Adsorption enthalpies of phenol onto PVBA were calculated, and the results indicated that the adsorption was an exothermic process. Comparison of the adsorption behaviors of PVBA, poly(p-vinylbenzylmethylamine) (PVBMA), and poly(p-vinylbenzyl-p-nitroaniline) (PVBNA) for phenol in hexane suggested that hydrogen bonding and pi-pi stacking were primarily responsible for the adsorption, the nitrogen atom and benzene ring of PVBA acted as hydrogen bonding acceptors and formed hydrogen bonding with the hydrogen atom of hydroxyl group of phenol. Investigation of the adsorption mechanism in aqueous solution revealed that hydrogen bonding and hydrophobic interaction were the main driving forces.     

Structures and properties of ruthenium(II) complexes of pyridylamine ligands with oxygen-bound amide moieties: regulation of structures and proton-coupled electron transfer

Tris(2-pyridylemthyl)amine (TPA) derivatives having two amide moieties at the 6-positions of the two pyridine rings of TPA and their Ru(II) complexes were synthesized and characterized by spectroscopic methods, X-ray crystallography, and electrochemical measurements. The complexes prepared were [RuCl(L)]PF(6) (L = N,N-bis(6-(1-naphthoylamide)-2-pyridylmethyl)-N-(2-pyridylmethyl)amine (1), N,N-bis(6-(2-naphthoylamide)-2-pyridylmethyl)-N-(2-pyridylmethyl)amine (2), N,N-bis(6-(isobutyrylamide)-2-pyridylmethyl)-N-(2-pyridylmethyl)amine (3)); the crystal structures of the three compounds were established by X-ray crystallography. In variable-temperature (1)H NMR spectra of 1 and 2 in CD(3)CN solutions, the pi-pi stacking in 1 was too rigid to exhibit any fluxional motions in NMR measurements; however, the pi-pi stacking of 2 was weaker and showed fluxional behavior in nearly T-shaped pi-pi interaction for the 2-naphthly groups (DeltaH degrees = -2.3 kJ mol(-1); DeltaG degrees = -0.9 kJ mol(-1) and DeltaS degrees = -7.7 J mol(-1) K(-1) at 233 K in CD(3)CN). For each of these three complexes, one of the amide moieties coordinated to the Ru(II) center through an amide oxygen. The other uncoordinated amide N-H formed intramolecular hydrogen bonding which remained intact even in aqueous media, indicating the intramolecular hydrogen bonding was geometrically compelled to form. The amide coordination is also stabilized and strengthened by the hydrogen bonding, so that the structure of each compound is maintained in solution. It is suggested that this hydrogen bonding lowers the redox potentials of the Ru(II) centers due to polarization of the coordinated amide C=O bond, in which the oxygen atom becomes more electrostatically negative and its electron-donating ability is strengthened. The N-H protons in the coordinated amide moieties were found to undergo a reversible deprotonation-protonation process, and the redox potentials of the Ru(II) centers could be regulated in the range of 500 mV in CH(3)CN solutions. The Pourbaix diagram for 1 clearly showed that this proton-coupled redox behavior is a one-electron/one-proton process, and the pK(a) value was estimated to be approximately 6.     

Synthesis of functionalized porphyrins as oxygen ligand receptors

Oxophilic synthetic receptors were designed and synthesized using a porphyrin scaffold, with the aim of constructing a preorganized complementary binding site for phenols and carbohydrates. We pursued three strategies for phenol recognition: (1) Lewis acid/Lewis base combinations serving as a hydrogen bond donor and acceptor for the OH group, (2) Lewis base/pi-pi stacking, targeting both the OH group and the aromatic moiety of phenols, and (3) exchange of the axial hydroxyl ligand on a trivalent and oxophilic metal center of aluminum porphyrin. For the recognition of acidic phenols, the most promising recognition motif was Lewis base/pi-pi stacking, which can bind to phenols with a hydrogen bond and pi-pi stacking interactions. [5-(8-Quinolyl)-10,15,20-triphenylporphyrinato]zinc binds to p-nitrophenol with a binding constant of 540 M(-)(1) in CHCl(3) at 25 degrees C. For carbohydrate recognition, we designed the metalloporphyrin receptor having 8-quinolyl groups and o-carbomethoxymethoxyphenyl groups, where these Lewis basic parts serve as the cooperative hydrogen bonding sites for the hydroxyl groups of glucoside. The receptor binds to beta-octyl glucoside with a binding constant of 7.35 x 10(4) M(-)(1) in CHCl(3) at 15 degrees C, demonstrating importance of formation of a highly ordered hydrogen bonding network between the receptor and the guest. These binding features have significant implications for the rational design of oxophilic artificial receptors.     

Silver(I) coordination polymers containing heteroditopic ureidopyridine ligands: the role of ligand isomerism, hydrogen bonding, and stacking interactions

New silver (I) coordination polymers has been successfully designed and synthesized using heteroditopic ureidopyridine ligands 1 and 2 via a combination of coordinations bonds, hydrogen bonding, and pi-pi stacking interactions. This study shows an example of the orientation of the pyridine nitrogen relative to the urea moiety (4-substituted, 1, or 3-substituted, 2), used to control the packing of resulting crystalline coordination polymers. The ureidopyridine ligands present some flexibility because of the conformational rotation around the central urea moiety. The co-complexation of the silver(I) cation by two pyridine moieties and of the PF(6)(-) counteranion by the urea moiety results in the formation of discrete [1(2)Ag](+)PF(6)(-), (3) and [2(2)Ag](+)PF(6)(-), (4) complexes presenting restricted rotation around the central urea functionality. The geometrical information contained in the structures of ligands 1 and 2 and the heteroditopic complexation of silver hexafluorophosphate are fully exploited in an independent manner resulting in the emergence of quasi-rigidly preorganized linear and angular building blocks of 3 and 4, respectively. Additional pi-pi stacking contacts involving interactions between the pi-donor benzene and the pi-acceptor pyridine systems reinforce and direct the self-assembly of the above-described combined structural motifs in the solid state. Accordingly, linear and tubular arrays of pi-pi stacked architectures are generated in the solid state by synergistic and sequential metal ion complexation, hydrogen bonding, and pi-pi stacking interactions.     

Binding ability and assembly behavior of beta-cyclodextrin complexes with 2,2'-dipyridine and 4,4'-dipyridine

Two channel-type supramolecular aggregations 1 and 2 were prepared by the inclusion complex of beta-cyclodextrin with 2,2'-dipyridine and 4,4'-dipyridine, respectively, and their binding ability and assembly behavior were investigated comprehensively by X-ray crystallography, (1)H NMR, circular dichroism spectra, and microcalorimetric titration in solution and the solid state. The obtained results revealed that the hydrogen bonds and pi-pi stacking interactions are crucial factors for the formation of the molecular aggregations containing beta-cyclodextrin and dipyridines. The disparity of nitrogen atom position in dipyridines leads not only to the distinct crystal system and space group, i.e., monoclinic system (C2) for 1 and triclinic system (P-1) for 2, but also different binding modes and thermodynamical parameters upon complexation of 2,2'-dipyridine and 4,4'-dipyridine with beta-cyclodextrin in aqueous solution.     

Synthesis, spectroscopic and structural studies of new Schiff bases prepared from 3,5-Bu2t-salicylaldehyde and heterocyclic amines: X-ray structure of N-(3,5-di-tert-butylsalicylidene)-1-ethylcarboxylato-4-aminopiperidine

Two new sterically hindered salicylaldimines, N-(2,2,6,6-tetramethyl-piperidine-4)-3,5-Bu2t-salicylaldimine (I) and N-(1-carboxyethyl piperidine-4)-3,5-Bu2t-salicylaldimine (II), have been prepared and characterized by IR, UV-vis, 1H NMR, 13C NMR techniques and the structure of II has been examined by X-ray crystallography. No intermolecular H-bonding, pi-pi stacking or C--H...pi interactions are observed in the structure. The crystal structure the was mainly governed by intermolecular steric repulsions, due to bulky tert-butyl groups and the tendency of salicylaldimine rings to pack in parallel mode forms one-dimensional columns.     

The influence of hydrogen bonding and pi-pi stacking interactions on the self-assembly properties of C3-symmetrical oligo(p-phenylenevinylene) discs

Three C3-symmetrical discotics containing a 1,3,5-benzenetricarboxamide unit functionalized with pi-conjugated oligo(p-phenylenevinylene)s (OPV)s have been synthesized and fully characterized. For the two amide OPV discs a two-step transition from helical stacks to molecularly dissolved species was observed and surprisingly, the topology of the amide determines the stability and helicity of the fibers in solution and the length of the fibrils at a surface. In case of the bipyridine disc, aggregates were formed that show little chiral ordering while the stacks remain present over a large temperature range. At a surface, completely disordered structures exist probably as a result of competing types of pi-pi stacking interactions that differ in strength and orientation. The results show that the design of functional self-assembled architectures based on hydrogen bonding and pi-pi stacking interactions is an extremely delicate matter and reveal that special demands have to be taken into account to balance the topology, directionality and strength of multiple secondary interactions.     

Chiral aggregation and spontaneous resolution of thiosemicarbazone metal complexes

Chiral aggregation and spontaneous resolution of thiosemicarbazone metal complexes MnL2 (1 and 1') (HL = acetylpyrazine thiosemicarbazone) were achieved through cooperation of hydrogen bonding and pi-pi stacking interactions. Compound 1 crystallized in a chiral space group P4(1)2(1)2 and the molecules exhibited lambda-configuration. Head-to-tail pyrazine-amino hydrogen bonding linked the molecules together presenting a two-dimensional homochiral sheet. The interlayer pi-pi stacking interactions linked the layers in a homochiral array and extended the 2D homochirality to a three-dimensional network. Compound 1 crystallized in space group P4(3)2(1)2, the opposite handedness of P4(1)2(1)2. The molecules, the two-dimensional hydrogen-bonded sheets and the three-dimensional network all exhibited the opposite chiralities to those of 1. Solid state CD spectra measurements confirmed the occurrence of spontaneous resolution of MnL2 and demonstrated that one of the enantiomers of the compound was always in excess. The zinc complexes (2 and 3) and nickel complex 4 crystallized in the chiral space group P4(3)2(1)2. Similar two-dimensional pyrazine-amine hydrogen bonded chiral sheets and three-dimensional networks were found in the crystal packing patterns. The cadmium complex 5 crystallized in a chiral space group P2(1)2(1)2(1), however, it exhibited a similar chiral packing pattern. The only difference was that enlarged Cd-S and Cd-N bond lengths induced the potential 4(1) symmetry. All results indicated that the supramolecular synthon, the cooperation of the pyrazine-amino hydrogen bonding and the pi-pi stacking interactions, were robust enough so that the orientation of the molecules in the solid state could be predicted to a reasonable degree of accuracy.     

Structure of the jet-cooled 1-naphthol dimer studied by IR dip spectroscopy: cooperation between the pi-pi interaction and the hydrogen bonding

The structure of a jet-cooled 1-naphthol (1-NpOH) dimer was investigated by using resonant-enhanced two-photon ionization (R2PI) and ion-detected infrared (IR) dip spectroscopy. A geometrical optimization and a frequency calculation in (1-NpOH)2 were also performed at the MP2/cc-pVDZ level. Stable isomers in the MP2/cc-pVDZ calculation were classified into a structure dominated only by the pi-pi interaction and structures formed by cooperation between the pi-pi interaction and hydrogen bonding. On the basis of a comparison between the observed and calculated IR spectra, the geometry of (1-NpOH)2 was concluded to be a pi-pi stacking structure supported by hydrogen bonding.     

Engineering the structure and magnetic properties of crystalline solids via the metal-directed self-assembly of a versatile molecular building unit

We report the supramolecular chemistry of several metal complexes of N-(4-pyridyl)benzamide (NPBA) with the general formula [Ma(NPBA)2AbSc], where M = Co2+, Ni2+, Zn2+, Mn2+, Cu2+, Ag+; A = NO3-, OAc-; S = MeOH, H2O; a = 0, 1, 2; b = 0, 1, 2, 4; and c = 0, 2. NPBA contains structural features that can engage in three modes of intermolecular interactions: (1) metal-ligand coordination, (2) hydrogen bonding, and (3) pi-pi stacking. NPBA forms one-dimensional (1-D) chains governed by hydrogen bonding, but when reacted with metal ions, it generates a wide variety of supramolecular scaffolds that control the arrangement of periodic nanostructures and form 1- (2-4), 2- (5), or 3-D (6-10) solid-state networks of hydrogen bonding and pi-pi stacking interactions in the crystal. Isostructural 7-9 exhibit a 2-D hydrogen bonding network that promotes topotaxial growth of single crystals of their isostructural family and generates crystal composites with two (11) and three (12) different components. Furthermore, 7-9 can also form crystalline solid solutions (M,M')(NPBA)2(NO3)2(MeOH)2 (M, M' = Co2+, Ni2+, or Zn2+, 13-16), where mixtures of Co2+, Ni2+, and Zn2+ share the same crystal lattice in different proportions to allow the formation of materials with modulated magnetic moments. Finally, we report the effects that multidimensional noncovalent networks exert on the magnetic moments between 2 and 300 K of 1-D (4), 2-D (5), and 3-D (7, 8, 10, and 13-16) paramagnetic networks.     

Sterically controlled recognition of macromolecular sequence information by molecular tweezers

Sequence-specific binding is demonstrated between pyrene-based tweezer molecules and soluble, high molar mass copolyimides. The binding involves complementary pi-pi stacking interactions, polymer chain-folding, and hydrogen bonding and is extremely sensitive to the steric environment around the pyromellitimide binding-site. A detailed picture of the intermolecular interactions involved has been obtained through single-crystal X-ray studies of tweezer complexes with model diimides. Ring-current magnetic shielding of polyimide protons by the pyrene "arms" of the tweezer molecule induces large complexation shifts of the corresponding 1H NMR resonances, enabling specific triplet sequences to be identified by their complexation shifts. Extended comonomer sequences (triplets of triplets in which the monomer residues differ only by the presence or absence of a methyl group) can be "read" by a mechanism which involves multiple binding of tweezer molecules to adjacent diimide residues within the copolymer chain. The adjacent-binding model for sequence recognition has been validated by two conceptually different sets of tweezer binding experiments. One approach compares sequence-recognition events for copolyimides having either restricted or unrestricted triple-triplet sequences, and the other makes use of copolymers containing both strongly binding and completely nonbinding diimide residues. In all cases the nature and relative proportions of triple-triplet sequences predicted by the adjacent-binding model are fully consistent with the observed 1H NMR data.     

Noncovalent interactions between modified cytosine and guanine DNA base pair mimics investigated by terahertz spectroscopy and solid-state density functional theory

Modified cytosine and guanine nucleobases cocrystallize in a hydrogen bonding configuration similar to that observed in native DNA. The noncovalent interactions binding these base pairs in the crystalline solid were investigated using terahertz (THz) spectroscopy and solid-state density functional theory (DFT). While stronger hydrogen bonding interactions are responsible for the general molecular orientations in the crystalline state, it is the weaker dipole-dipole and dispersion forces that determine the overall packing arrangement. The inclusion of dispersion interactions in the DFT calculations was found to be necessary to accurately simulate the unit cell structure and THz vibrational spectrum. Using properly modeled intermolecular potentials, the lattice vibrational motions of the cytosine and guanine derivatives were calculated. The vibrational characters of the modes exhibited by the DNA base pair mimic in the THz region were primarily rotational motions and are indicative of the energies and the nature of vibrations that would likely be observed between similar base pairs in DNA molecules.     

The CH–π Interaction in Protein–Carbohydrate Binding: Bioinformatics and In Vitro Quantification

The molecular recognition of carbohydrates by proteins plays a key role in many biological processes including immune response, pathogen entry into a cell, and cell–cell adhesion (e.g., in cancer metastasis). Carbohydrates interact with proteins mainly through hydrogen bonding, metal-ion-mediated interaction, and non-polar dispersion interactions. The role of dispersion-driven CH–π interactions (stacking) in protein–carbohydrate recognition has been underestimated for a long time considering the polar interactions to be the main forces for saccharide interactions. However, over the last few years it turns out that non-polar interactions are equally important. In this study, we analyzed the CH–π interactions employing bioinformatics (data mining, structural analysis), several experimental (isothermal titration calorimetry (ITC), X-ray crystallography), and computational techniques. The Protein Data Bank (PDB) has been used as a source of structural data. The PDB contains over 12 000 protein complexes with carbohydrates. Stacking interactions are very frequently present in such complexes (about 39 % of identified structures). The calculations and the ITC measurement results suggest that the CH–π stacking contribution to the overall binding energy ranges from 4 up to 8 kcal mol⁻¹. All the results show that the stacking CH–π interactions in protein–carbohydrate complexes can be considered to be a driving force of the binding in such complexes.     

Metallosupramolecular zippers generated by self-organization of self-complementary molecular clefts

The binding of Co(2+) and Pb(2+) ions to the terpyridine and pyridine subunits of the ligand 1 leads to the self-complementary molecular clefts 2-6, which result from the crossover combination of orthogonal-terpyridine and linear-pyridine metal-coordination subprograms and are stabilized by strong pi-pi stacking interactions. Four different cleft-type entities, [Co(2+) (2)(1)(2)] (3), [Pb(2+) (2)(1)(2)] (4), [Co(2+) (4)(1)(2)] (5), [Pb(2+) (4)(1)(2)] (6), are generated in both solution and the solid state, and may be interconverted as a function of metal/ligand stoichiometry. One- and two-dimensional metallosupramolecular zipper architectures result from self-assembly in the solid state driven by a combination of different pi-pi stacking subprograms. The U-shaped geometry of the ligand influences the possibility of zipping and thus, in turn, the generation of different zipper architectures. The structures of 2-5 have been confirmed by X-ray crystallography; that of 6 is based on NMR spectral data.     

Crystalline-state guest-exchange and gas-adsorption phenomenon for a "soft" supramolecular porous framework stacking by a rigid linear coordination polymer

A 1D rigid, linear coordination polymer, (4,4'-bipyridine)(2-pyridylsulfonate)copper, has been applied for the controlled-assembly of a new porous host that generates 1D channels by an interdigitated packing through the recognition of hydrogen bonding and pi-pi stacking interactions. The porous structure is architecturally robust when it reversibly uptakes water molecules and exchanges guest small molecules (MeOH, i-PrOH) from solution as determined by single-crystal-to-single-crystal transformation studies. Moreover, the open-channel solid displays irreversible benzene and toluene vapor sorption behaviors attributed to a widening of the channel cross-section that fetters the larger guest molecules, resulting from the dynamic, "soft" supramolecular framework.     

Selective product amplification of thymine photodimer by recognition-directed supramolecular assistance

Two symmetric ditopic supramolecular templates (1 and 2) each presenting two hydrogen bonding recognition subunits were synthesized. Each such subunit comprises the same donor and acceptor pattern, capable of binding a substrate molecule with complementary hydrogen bonding groups to form a supramolecular complex. Substrate molecules, such as thymine or uracil derivatives, yield 2 : 1 complexes with the acceptors involving two hydrogen bonds to each subunit with ideal orientation for subsequent [2 + 2] dimerization upon photoirradiation. Selective syn photoproduct formation and concomitant suppression of the trans isomer are favored by orientation of the two guest nucleobases within the template cleft. Complementary donor and acceptor hydrogen bonding induced positioning of the two substrates and steric hindrance within the template clefts are responsible for the selective product formation.     

A convenient protocol for the synthesis of ligands from a 4-methyl-3,5-diacylaminophenyl platform

The synthesis of stable and highly organized phenanthroline, terpyridine, and pyridino-oxazoline ligands bearing one or two 4-methyl-3,5-diacylaminophenyl modules equipped with two lateral dialkoxyphenyl groups has been performed using EDC.HCl and DMAP reagents in the final coupling reaction. Evidently, in the final ligands and in the solid state intermolecular hydrogen bonding maintains the coherence of the tridimensional structure as clearly evidenced by FT-IR and X-ray diffraction spectroscopy in the cases of the methoxy ligands. The supramolecular packing is also maintained by additional pi-pi stacking interactions.     

类晶加合物(M=Co,Cu, Ni)的晶体结构及分子间相互作用的理论研究

合成了3种化合物 [2-ClPyH]2CoCl4(1), [2-ClPyH]2NiCl4(2)和[2-ClPyH]2CuCl4(3), 单晶X射线衍射法晶体结构测定结果表明, 这3种化合物是同形加合物, 在它们的结构中, [2-ClPyH]+离子呈平面状, 而[MCl4]2-离子为变形的四面体. 晶体结构分析发现晶体中存在N—H…Cl和C—H…Cl氢键, 以及Cl…Cl分子间相互作用和π-π堆积作用. 对自由状态下独立的配位离子进行的几何构型优化, 以及三维周期性条件下几何结构优化的量子化学计算结果表明, 标题化合物中具有方向性和选择性的氢键决定延伸性结构的方向, 而相对较弱的卤素…卤素作用在最终晶体结构的确定中扮演很重要的角色.     

Molecular recognition and fluorescent sensing of urethane in water

Molecular recognition and fluorescent sensing of Group 2A carcinogen-urethane was achieved in aqueous solution with endo-functionalized molecular tubes. The syn-configured molecular tube was found to be a good fluorescent sensor for urethane in water (concentration range:6.2-60 μmol/L) and in beer (concentration range:22.9-60 μmol/L).