Influence of terminal substituents on the halide anion binding of foldamer-based receptors

Foldamers 1–4 incorporating different terminal substituents have been designed and synthesized for binding halide anions.~1H NMR titration experiments carried out in DMSO-d_6/CDCl_3(15/85, v/v)demonstrated that the short oligo (aryltriazole)s backbone 1 could not bind halide anions unless that amide H-bond donors were incorporated at the termini of the oligomer. Terminal substituents on oligo(aryltriazoleamide)s foldamers 2–4 display a considerable influence on the binding affinities of the foldamers for halide anions. Large steric hindrance of the terminal substituents was found to be unfavorable for binding halide anions, but aromatic π-π interactions between two terminal substituents are capable of stabilizing the conformation of foldamers thus giving rise to an enhancement in the binding strengths. However, the terminal substituents were found to hardly affect the binding selectivity in the studied cases.     

Toxicity study of allelochemical-like pesticides by a combination of 3D-QSAR, docking, Local Binding Energy (LBE) and GRID approaches

3D-QSAR, Docking, Local Binding Energy (LBE) and GRID methods were integrated as a tool for predicting toxicity and studying mechanisms of action. The method was tested on a set of 73 allelochemical-like pesticides, for which acute toxicity (LD(50)) for the rat was available. 3D-QSAR gave a model with high predictive ability and the regression maps indicated the important toxic chemical substituents. Significant ligand-protein residue interactions and oxidation positions in the binding site were found by docking analysis using CYP1A2 homology modelling. The binding energies of the compounds and the important substituents (Local Binding Energy, LBE) were calculated in order to demonstrate quantitatively the substituent contributions in the metabolism and toxicity. The GRID examination identified the CYP1A2 binding pocket feature. Finally, a 3D-QSAR map was compared to the GRID map, showing good overlaps and confirming the important role of CYP1A2 in allelochemical-like compounds toxicity.     

Strong, size-selective, and electronically tunable C-H...halide binding with steric control over aggregation from synthetically modular, shape-persistent [34]triazolophanes

A series of shape-persistent [3(4)]triazolophanes bearing t-butyl or triethylene glycol (OTg) substituents on the phenylene linkers have been prepared in a modular manner from simple building blocks. Triazolophane-halide binding affinities were determined using UV titrations in order to help in understanding the driving forces behind the large receptor-anion binding strengths supported solely by CH hydrogen-bond donors. The fixed size of the central cavity provides a means for selective recognition of Cl(-) and Br(-) anions with large binding strengths (Ka > 1,000,000 M(-1); DeltaG > -8.5 kcal mol(-1)). The smaller F(-) and larger I(-) anions are bound less tightly by approximately 1 and approximately 3 orders of magnitude, respectively. The four triazole-based H-bond donors are believed to be of primary importance, while the four phenylene CH H-bond donors take on a secondary role. Consistent with this idea, the binding affinity can be tuned by as much as 1 kcal mol(-1) by changing the character of the four phenylene-based substituents from more (OTg) to less (t-butyl) electron-donating. Preorganization was also found to play a central role, on the basis of comparisons with a foldamer analogue that shows much-reduced binding. Aggregation was facilitated as the substituents were changed from t-butyl to OTg, increasing the degree of self-association from K(E) approximately = 0 to 230 M(-1) in CD2Cl2. Diffusion NMR experiments established aggregation as opposed to dimerization. These findings indicate the importance of the cavity size for selective anion recognition as well as the role of the phenylene linkers in tuning the binding strengths and modulating the aggregation of the [3(4)]triazolophanes.     

Sugar-poly(para-phenylene ethynylene) conjugates as sensory materials: efficient quenching by Hg2+ and Pb2+ ions

Three polar poly(para-phenylene ethynylene)s (PPE) were synthesized by utilizing the Heck-Sonogashira protocol. Two of the PPEs carry beta-glucopyranose substituents. Depending upon the linker used between the glycol units and the backbone, the fluorescence of these PPEs can be quenched by Hg2+ and Pb2+ to a varying degree. Monomeric model compounds that are substituted with only one glucose unit are not efficiently quenched. The presence of many glucose substituents in one PPE assembly led to a large increase in the binding constant to Hg2+ and quenching of the fluorescence was amplified.     

Long-range assemblies on poly(dG-dC)2 and poly(dA-dT)2: phosphonium cationic porphyrins and the importance of the charge

The present paper describes synthesis and spectroscopic properties of novel cationic meso-tetraphenylporphyrins bearing two (trans) (P2) or three (P3) triphenylphosphonium substituents. The porphyrin aggregation in aqueous solutions is discussed in detail. Porphyrin binding to and self-organization onto long-range assemblies on poly(dA-dT)2 or poly(dG-dC)2 were probed by combination of absorption, fluorescence, circular dichroism (CD), transient and resonance light-scattering (RLS) techniques. The higher hydrophobicity of P2 is manifested by more extensive self-organization. Induced CD and intensive RLS indicate binding to the chiral environment on the nucleic acids exterior and exciton coupling between adjacent porphyrin moieties. The CD spectra of P2 on poly(dG-dC), and poly(dA-dT)2 suggest that the binding geometry is essentially independent of the base sequence. The fluorescence lifetime of about 4 ns was attributed to the long-range assembly. In the case of P3 the distinctly different CD spectra induced by GC or AT base-pair regions reveal that the number of the substituents determines how closely the porphyrin can approach the specific electronic environment on the nucleic acid exterior. The fluorescence lifetime of the P3 assembly is about 2 ns.     

配体形状对多吡啶铜(Ⅱ)配合物与DNA作用的影响

合成了一系列含有平面配体的Cu(Ⅱ)多吡啶配合物[Cu(IP)₂]²⁺、[Cu(PIP)₂]²⁺、[Cu(DPPZ)₂]²⁺和[Cu(HPIP)₂]²⁺，用吸收光谱、CD光谱和粘度等方法研究了这些配合物与小牛胸腺DNA的作用。结果表明配体上的取代基及配体的平面性对这些四面体配合物与DNA的结合强弱产生一定的影响。[Cu(DPPZ)₂]²⁺与DNA的结合较强，而[Cu(HPIP)₂]²⁺与DNA的结合较弱。CD光谱显示配合物[Cu(DPPZ)₂]²⁺、[Cu(PIP)₂]²⁺和[Cu(HPIP)₂]²⁺的加入会导致DNA的CD光谱减弱。而[Cu(IP)₂]²⁺的加入则会使DNA的CD光谱增强。同时，[Cu(IP)₂]²⁺与DNA结合后，还会引起一定程度的DNA构型转换，即DNA从B型转换成Z型。     

Spectacular induced-fit process for guest binding by a calix[6]arene Zn(II) funnel complex

The host properties of a calix[6]arene cone capped by a Zn(II) tris-imidazole core at the small rim and decorated by three NH(2) substituents at the large rim are described and compared to the hexa-tBu parent complex. It is shown that the replacement of three bulky tBu substituents by three hydrophilic and small NH(2) groups has three major impacts: the receptor is now soluble in aqueous media, it accepts large guests such as dimethyldopamine and, most interestingly, undergoes a spectacular induced-fit behavior for guest binding.     

Distribution of Chlorophyll- and Bacteriochlorophyll-derived Photosensitizers in Human Blood Plasma

Chlorophyll a and, in particular, bacteriochlorophyll a derivatives are promising candidates for photosensitizers in photodynamic therapy. The distribution of 21 (bacterio)chlorophyll derivatives among human blood plasma fractions was studied by iodixanol gradient ultracentrifugation and in situ absorption spectroscopy. Modifications of the natural pigments involved the central metal (Mg²⁺, Zn²⁺, Pd²⁺, none), the isocyclic ring (closed, open and taurinated), substituents at C-3 (vinyl, acetyl, 1-hydroxyethyl) and C-17³ (phytyl ester, free acid). Cellular blood components bound only a small fraction of the pigments. Distribution among low-density lipoproteins (LDL), high-density lipoproteins (HDL) and high-density proteins (HDP) of the plasma was influenced as follows: (1) application in Cremophor^® EL slightly altered pigment distribution by lipoprotein modification, (2) only very polar pigments with multiple hydrophilic substituents showed substantial HDP binding, (3) the presence of the esterifying alcohol at C-17³ caused enrichment in LDL, this was more pronounced with bacteriochlorophylls than with chlorophylls, (4) substituents at C-3 had only little influence on the distribution, (5) Zn²⁺-complexes were enriched in HDL compared to Mg²⁺ and Pd²⁺ complexes, indicating specific binding of the former. Equilibration of pigments among the different fractions was largely complete within 3 h.     

Structure–Activity Studies on the Fluorescent Indicator in a Displacement Assay for the Screening of Small Molecules Binding to RNA

A series of xanthone and thioxanthone derivatives with aminoalkoxy substituents were synthesized as fluorescent indicators for a displacement assay in the study of small‐molecule–RNA interactions. The RNA‐binding properties of these molecules were investigated in terms of the improved binding selectivity to the loop region in the RNA secondary structure relative to 2,7‐bis(2‐aminoethoxy)xanthone (X2S) by fluorimetric titration and displacement assay. An 11‐mer double‐stranded RNA and a hairpin RNA mimicking the stem loop IIB of Rev response element (RRE) RNA of HIV‐1 mRNA were used. The X2S derivatives with longer aminoalkyl substituents showed a higher affinity to the double‐stranded RNA than the parent molecule. Introduction of a methyl group on the aminoethoxy moiety of X2S effectively modulated the selectivity to the RNA secondary structure. Methyl group substitution at the C1′ position suppressed the binding to the loop regions. Substitution with two methyl groups on the amino nitrogen atom resulted in reducing the affinity to the double‐stranded region by a factor of 40 %. The effect of methyl substitution on the amino nitrogen atom was also observed for a thioxanthone derivative. Titration experiments, however, suggested that thioxanthone derivatives showed a more prominent tendency of multiple binding to RNA than xanthone derivatives. The selectivity index calculated from the affinity to the double‐stranded and loop regions suggested that the N,N‐dimethyl derivative of X2S would be suitable for the screening of small molecules binding to RRE.     

Structure-activity studies on the fluorescent indicator in a displacement assay for the screening of small molecules binding to RNA

A series of xanthone and thioxanthone derivatives with aminoalkoxy substituents were synthesized as fluorescent indicators for a displacement assay in the study of small-molecule-RNA interactions. The RNA-binding properties of these molecules were investigated in terms of the improved binding selectivity to the loop region in the RNA secondary structure relative to 2,7-bis(2-aminoethoxy)xanthone (X2S) by fluorimetric titration and displacement assay. An 11-mer double-stranded RNA and a hairpin RNA mimicking the stem loop IIB of Rev response element (RRE) RNA of HIV-1 mRNA were used. The X2S derivatives with longer aminoalkyl substituents showed a higher affinity to the double-stranded RNA than the parent molecule. Introduction of a methyl group on the aminoethoxy moiety of X2S effectively modulated the selectivity to the RNA secondary structure. Methyl group substitution at the C1' position suppressed the binding to the loop regions. Substitution with two methyl groups on the amino nitrogen atom resulted in reducing the affinity to the double-stranded region by a factor of 40%. The effect of methyl substitution on the amino nitrogen atom was also observed for a thioxanthone derivative. Titration experiments, however, suggested that thioxanthone derivatives showed a more prominent tendency of multiple binding to RNA than xanthone derivatives. The selectivity index calculated from the affinity to the double-stranded and loop regions suggested that the N,N-dimethyl derivative of X2S would be suitable for the screening of small molecules binding to RRE.     

Substituent-dependent fluorescent sensors for zinc ions based on carboxamidoquinoline

A series of carboxamidoquinoline-based fluorescent sensors (the AQZ family) were synthesized and characterized. The AQZ family members were highly soluble in water and showed good selectivity for Zn(2+)via enhanced fluorescence in aqueous buffer solution. Fluorescence signals could be tuned from dual-wavelength ratiometric changes to changes in the intensity of a single wavelength upon binding Zn(2+) through the introduction of different substituents onto the quinoline ring. Concentrations of free Zn(2+) of 10(-5)-10(-6) M could be detected using the sensors. Changes of substituents and their positions on the quinoline ring influenced the sensitivity for Zn(2+), but had little effect on Zn(2+) affinities.     

Synthesis and pharmacology of glutamate receptor ligands: new isothiazole analogues of ibotenic acid

The naturally occurring heterocyclic amino acid ibotenic acid (Ibo) and the synthetic analogue thioibotenic acid (Thio-Ibo) possess interesting but dissimilar pharmacological activity at ionotropic and metabotropic glutamate receptors (iGluRs and mGluRs). Therefore, a series of Thio-Ibo analogues was synthesized. The synthesis included introduction of substituents by Suzuki and Grignard reactions on 4-halogenated 3-benzyloxyisothiazolols, reduction of the obtained alcohols, followed by introduction of the amino acid moiety by use of 2-(N-tert-butoxycarbonylimino)malonic acid diethyl ester. The obtained Thio-Ibo analogues (1, 2a-g) were characterized in functional assays on recombinant mGluRs and in receptor binding assays on native iGluRs. At mGluRs, the activity at Group II was retained for compounds with small substituents (2a-2d), whereas the Group I and Group III receptor activities for all new compounds were lost. Detection of NMDA receptor affinity prompted further characterization, and two-electrode voltage-clamp recordings at recombinant NMDA receptor subtypes NR1/NR2A-D expressed in Xenopus oocytes were carried out for compounds with small substituents (chloro, bromo, methyl or ethyl, compounds 2a-d). This series of Thio-Ibo analogues defines a structural threshold for NMDA receptor activation and reveals that the individual subtypes have different steric requirements for receptor activation. The compounds 2a and 2c are the first examples of agonists discriminating individual NMDA subtypes.     

The binding energy of nitrogen 1<Emphasis Type="Italic">s</Emphasis> electrons in pyridine derivatives: Substituent effects in N-centered radical cations

The effect of substituents on the binding energy of nitrogen 1s electrons in 2-, 3-, and 4-substituted pyridine derivatives, as measured by X-ray photoelectron spectroscopy and calculated by quantum chemistry methods, was analyzed. It has been first shown that the binding energy depends not only on the inductive and resonance effects, but also on the polarization effect of the substituents.     

QSAR analyses of 3-(4-benzylpiperidin-1-yl)-N-phenylpropylamine derivatives as potent CCR5 antagonists

CCR5 receptor binding affinity of a series of 3-(4-benzylpiperidin-1-yl)propylamine congeners was subjected to QSAR study using the linear free energy related (LFER) model of Hansch. Appropriate indicator variables encoding different group contributions and different physicochemical variables such as hydrophobicity (pi), electronic (Hammett sigma), and steric (molar refractivity, STERIMOL values) parameters of phenyl ring substituents of the compounds were used as predictor variables. The Hansch analysis explores the importance of the lipophilicity and electron-donating substituents for the binding affinity. However, this method could not give more insight into the structure-activity relationships because of the diverse molecular features in the data set. 3D-QSAR analyses of the same data set using Molecular Shape Analysis (MSA), Receptor Surface Analysis (RSA), and Molecular Field Analysis (MFA) techniques were also performed. The best model with acceptable statistical quality was derived from the MSA, which showed the importance of the relative negative charge (RNCG): substituents with a high RNCG value have more binding affinity than the unsubstituted piperidine and phenyl (R1 position) congeners. The relative negative charge surface area (RNCS) is detrimental (e.g. R2 = 3,4-Cl2) for the activity. An increase in the length of the molecule in the Z dimension (Lz) is conducive (e.g. R3 = sulfonylmorpholino), while an increase in the area of the molecular shadow in the XZ plane (Sxz) is detrimental (e.g. R1 = N-c-hexylmethyl-5-oxopyrrolidin-3-yl) for the binding affinity. The presence of a chiral center makes the molecule less active (e.g. R1 = N-methyl-5-oxopyrrolidin-3-yl). An increase in the van der Waals area, the molecular volume, and the difference between the volume of the individual molecule and the shape reference compound are conducive (e.g. R3 = (CH3)2NSO2-) for the binding affinity. Substituents with higher JursFPSA_2 values (fractional charged partial surface area) like the N-methylsulfonylpiperidin-4-yl (R1 position) group have better binding affinity than the substituents such as 4-chlorophenylamino (R1 position). Unsubstituted piperidines (R1 position) with less JursFNSA_1 values have lower binding affinity than the 4-chlorophenyl substituted compounds. The MFA derived equation shows interaction energies at different grid points, while the RSA model shows the importance of hydrophobicity and charge at different regions of the molecules. The models were validated through the leave-one-out, leave-15%-out, and leave-25%-out cross-validation techniques. The developed models were also subjected to a randomization test (99% confidence level). Although the MSA derived models had excellent statistical qualities both for the training as well as test sets, RSA and MFA results for the test sets are not comparable statistically with the MSA derived models.     

Impact of halogen substituents on interactions between 2-phenyl-2,3-dihydroqulinazolin-4(1H)-one derivatives and human serum albumin

A novel type of 2-(un)substituted phenyl-2,3-dihydroquinazolin-4(1H)-one (DQL) derivatives were designed and synthesized to study the impact of halogen substituents on interactions between DQL and human serum albumin (HSA) by comparison methodology. The interactions between DQL and HSA were studied by fluorescence spectroscopy. The intrinsic fluorescence of human serum albumin was quenched by DQL through a static quenching mechanism. Site marker competitive experiments showed that DQL bound to HSA in site II (subdomain IIIA). The binding constants, the numbers of binding sites and the thermodynamic parameters were measured too. The results indicated that the interactions were spontaneous, mainly through hydrophobic forces, and the substitution by halogen atoms in the benzene ring could increase the interactions between DQL and HSA. Furthermore, the binding affinity was enhanced gradually with the increasing of halogen atomic number.     

(Thio)ureido anion receptors based on a 1,3-alternate oxacalix[2]arene[2]pyrimidine scaffold

In pursuit of highly preorganized macrocyclic host molecules for the complexation of anions, a series of oxacalix[2]arene[2]pyrimidine-based bis(thio)ureido receptors were synthesized and fully characterized. The pincer-like 1,3-alternate conformation of the oxacalix[4]arene scaffold, essential for an efficient host-guest interaction, was visualized by single-crystal X-ray analysis and supported by variable-temperature NMR studies. The anion binding properties of the receptors were evaluated via (1)H NMR titration experiments, showing intermolecular interactions with H(2)PO(4)(-), AcO(-), BzO(-), and Cl(-) ions. The host molecule bearing 4-nitrophenyl substituents on the bisurea binding pocket showed association constants in the range of 200-400 M(-1) in the strongly competitive solvent mixture of DMSO/0.5% H(2)O.     

Ortho-silylated derivatives of tetrakis(2-hydroxyphenyl)ethene: a sterically isolated structural model for oxo-surface binding domains

The introduction of sterically isolating ortho-trialkylsilyl, -aryldialkylsilyl, and -diarylalkylsilyl substituents onto the structurally preorganized tetrakis(2-hydroxyphenyl)ethene ligand framework has been accomplished by a 4-fold retro-Brook rearrangement. Installation of the most sterically demanding silyl substituents required the development of an iterative procedure, involving successive double silylation/metalation/migration sequences without the isolation of intermediates. This system was designed to function as a soluble structural model for the planar binding domains of heterogeneous "oxo-surfaces" of silica and alumina supports.     

Structural factors affecting Aryl Hydrocarbon Hydroxylase induction by Dibenzo-p-dioxins and Dibenzofurans

Quantitative structure-activity relationships have been developed to rationalize the experimental data obtained with a series of dibenzo-p-dioxins and dibenzofurans in the assays for receptor binding and aryl hydrocarbon hydroxylase (AHH) induction. Lateral substituents (in positions 2, 3, 7, and 8 of the tricyclic system) do not affect receptor binding and AHH induction in the same manner. Various hypotheses are suggested to explain this finding. Of special interest is the possibility that the lateral substituents are directly involved in the mechanism which transforms the receptor to the active state. The implications of this possibility are considered with regard to the design of an antidote for poisoning caused by the chlorinated congeners which occur as contaminants in certain commercial products.     

Design of conjugated microporous polymer nanotubes for efficient benzene molecular adsorptions

Single‐walled conjugated microporous polymer (CMP) nanotubes containing alternative phenylene and ethynylene units were described computationally for the first time in this work. The electronic structures and adsorption properties were studied by the density‐functional tight‐binding method augmented with a van der Waals dispersion term. Our calculations show that the morphology of CMP influences the benzene‐adsorption performance significantly. The tubes show smaller binding energies to benzene molecule than the film counterparts, consistent with the observation of low adsorption capacities of tubular materials in our experiments. Enlarging the linker or adding substituents in the node can both reduce the tube's band gap. The introduction of  OH or  NH₂ substituents in the tube node increases the binding strength between the adsorbent and the adsorbate, which is energetically favorable to enhance the adsorption capacity. Our results are expected to provide theoretical insights into the rational design of novel CMP nanotubes with improved adsorption capacities for organics.