Cooperative binding of an anticancer drug in a guest–host–protein assembly

The supramolecular formation of an anticancer drug (6-mercaptopurine (6-MP)) in an acetate buffer solution was demonstrated through a host–guest interaction with the macrocyclic host cucurbit[7]uril (Q[7]) and bovine serum albumin (BSA). With the help of ultraviolet absorption and fluorescence spectroscopy, it was shown that a binary complex formed between 6-MP and Q[7] and/or BSA, and a specific binding interaction took place between 6-MP and Q[7] in the presence of BSA. The inclusion constants and thermodynamic parameters were determined at different temperatures. The data suggested that the formation of the binary 6-MP–Q[7] complex was driven by enthalpy in the presence of an unfavourable entropy, which was attributed to the van der Waals and hydrophobic interactions. The fluorescence quenching of BSA by 6-MP was a result of the formation of the 6-MP–BSA complex. This quenching occurred by a static quenching mechanism, and hydrophobic forces played predominant roles in the binding process. Moreover, the absorption data suggested that the interaction between 6-MP and Q[7] or BSA was a competitive process. In addition, the effect of 6-MP on BSA conformation was investigated by synchronous and 3D fluorescence spectra.     

Synthesis of a β-cyclodextrin derivative bearing an azobenzene group on the secondary face

An oxidative coupling Sonogashira-type reaction has been used to synthesize a β-cyclodextrin derivative bearing an azobenzene group on the secondary face for the first time starting from a β-cyclodextrin propargylated at one of its C-2 positions. The de-O-propargylation reaction and the formation of an oxidative homocoupling dimer were found to compete with the desired product under several Sonogashira-type reaction conditions. However, the use of a diluted reductive atmosphere of H₂ avoided the former and diminished the latter.     

Synthesis and properties of group 9 metal complexes bearing a β-ketophosphenato ligand

A novel β-ketophosphenato ligand bearing a bulky substituent, Tbt(2,4,6-tris[bis(trimethylsilyl)methyl]phenyl), on the phosphorus atom was newly designed and synthesized as a heavier congener of a β-ketoiminato ligand. Rhodium and iridium complexes bearing this new β-ketophosphenato ligand have been synthesized and fully characterized by spectroscopic and elemental analyses together with X-ray crystallographic analyses. The results of NMR spectroscopic studies and the X-ray structural analyses suggested that the β-ketophosphenato ligand has unique electronic features due to the low-coordinated phosphorus atom. Comparison of properties between rhodium β-ketophosphenates 2a,b and rhodium β-ketoiminate 7 revealed the character of the β-ketophosphenato ligand, where the trans influence of the phosphorus atom should be stronger than the nitrogen atom of the β-ketoiminato ligand.     

Synthesis and fluorescence properties of novel pyrazine-boron complexes bearing a β-iminoketone ligand

A novel fluorescence dye based on pyrazine-boron complexes bearing a β-iminoketone ligand has been synthesized by using a simple two-step reaction. Synthesized complexes exhibited fluorescence in solution (F(max): 472-604 nm) and in the solid state (F(max): 496-624 nm). These complexes showed a larger Stokes shift (3690-4900 cm(-1)) than well-known boron dipyrromethene dyes (400-600 cm(-1), in most cases).     

Synthesis of novel β-lactams bearing an anthraquinone moiety,and evaluation of their antimalarial activities

A novel series of β-lactams bearing an anthraquinone moiety have been synthesized from imines derived from anthraquinone-2-carbaldehyde and ketenes by a [2+2] cycloaddition reaction. The cycloadducts were fully characterized and evaluated for their antimalarial activities against Plasmodium falciparum K14 resistant strain and showed moderate to excellent EC₅₀ values varying from 9 to 50 μM.     

Molecular and quantum mechanical studies on the monomer recognition of a highly-regular β-helical antifreeze protein

The possible interaction models for an antifreeze protein from Tenebrio molitar (TmAFP) have been systematically studied using the methods of molecular mechanics, molecular dynamics and quantum chemistry. It is hoped that these approaches would provide insights into the nature of interaction between protein monomers through sampling a number of interaction possibilities and evaluating their interaction energies between two monomers in the course of recognition. The results derived from the molecular mechanics indicate that monomer's β-sheets would be involved in interaction area and the side chains on two β-faces can match each other at the two-dimensional level. The results from molecular mechanics and ONIOM methods show that the strongest interaction energy could be gained through the formation of H-bonds when the two β-sheets are involved in the interaction model. Furthermore, the calculation of DFT and analysis of van der Waals bond charge density confirm further that recognition between the two     

Molecular and quantum mechanical studies on the monomer recognition of a highly-regular β-helical antifreeze protein

The possible interaction models for an antifreeze protein from Tenebrio molitar (TmAFP) have been systematically studied using the methods of molecular mechanics, molecular dynamics and quantum chemistry. It is hoped that these approaches would provide insights into the nature of interaction between protein monomers through sampling a number of interaction possibilities and evaluating their interaction energies between two monomers in the course of recognition. The results derived from the molecular mechanics indicate that monomerś β-sheets would be involved in interaction area and the side chains on two p-faces can match each other at the two-dimensional level. The results from molecular mechanics and ONIOM methods show that the strongest interaction energy could be gained through the formation of H-bonds when the twoβ-sheets are involved in the interaction model. Furthermore, the calculation of DFT and analysis of van der Waals bond charge density confirm further that recognition between the two TCTs mainly depends on inter-molecular hydroxyls. Therefore, our results demonstrate that during the course of interaction the most favorable association of TmAFPs is via their β-sheets.     

Fibrils and nanotubes assembled from a modified amyloid-β peptide fragment differ in the packing of the same β-sheet building blocks

The peptide AAKLVFF assembles into fibrils in water and nanotubes in methanol. Solid-state NMR data are consistent with fibrils constructed from β-sheet bilayers and nanotubes bounded by a wall of offset β-sheet monolayers. Remarkably distinct morphologies are thus traced to subtle differences in the arrangement of the same fundamental building blocks.     

Pyrrole β-amides: Synthesis and characterization of a dipyrrinone carboxylic acid and an N-Confused fluorescent dipyrrinone

Pyrrole β-amides are useful building blocks for the preparation of novel molecular architectures that can be used in supramolecular chemistry and sensor development. Under basic conditions, pyrrole β-amides with an α-aldehyde produce different condensation products when reacted with pyrrolinones depending on the amide substitution. Secondary amides form the expected dipyrrinones, but unexpectedly undergo a subsequent trans-amidation with the pyrrolinone nitrogen to produce an unsymmetrical imide (an N-confused fluorescent dipyrrinone). Under the same conditions, tertiary amides produce the expected dipyrrinone carboxylic acids, which have been shown to have strong self-association properties as determined by vapor pressure osmometry measurements, NMR studies, and X-ray crystal structure determination. Furthermore, an N-confused fluorescent dipyrrinone was produced from the same trans-amidation reaction during attempts to decarboxylate a dipyrrinone amide with a 9-carboxylic moiety.     

Synthesis and reactivity of an isolable cobalt(I) complex containing a β-diketiminate-based acyclic tetradentate ligand

A model for cobalamin was synthesized using a new monoanionic tetradentate nitrogen donor ligand; 2-(4-tolyl)-1,3-bis(2-isopropylpyridyl)propenediimine (Tol-BDI((2-pp)2)H) (1), which utilizes isopropylpyridines as pendant arms on a β-diketiminate (BDI) backbone. During the synthesis of 1, the rearrangement product, Tol-BDI((2-pp)(4-pp))H (2) was observed. Metalation of 1 with zinc iodide and cobalt chloride yielded the corresponding Tol-BDI((2-pp)2)ZnI (3) and Tol-BDI((2-pp)2)CoCl (4) complexes. The redox properties of 4 in comparison to cobalamin were examined through electrochemical studies. Electrochemical and bulk reduction of complex 4 gave a diamagnetic cobalt(I) complex, Tol-BDI((2-pp)2)Co (5). Reactivity of 5 toward C-X bonds was investigated using methyl iodide and 1-iodo-2-(trimethylsilyl)acetylene, yielding Tol-BDI((2-pp)2)Co(CH(3))I and Tol-BDI((2-pp)2)Co(C(2)Si(CH(3))(3))I respectively. Synthesis and characterization details for these complexes, including the crystal structure of 3, are reported.     

Identification of a lacosamide binding protein using an affinity bait and chemical reporter strategy: 14-3-3 ζ

We have advanced a useful strategy to elucidate binding partners of ligands (drugs) with modest binding affinity. Key to this strategy is attaching to the ligand an affinity bait (AB) and a chemical reporter (CR) group, where the AB irreversibly attaches the ligand to the receptor upon binding and the CR group is employed for receptor detection and isolation. We have tested this AB&CR strategy using lacosamide ((R)-1), a low-molecular-weight antiepileptic drug. We demonstrate that using a (R)-lacosamide AB&CR agent ((R)-2) 14-3-3 ζ in rodent brain soluble lysates is preferentially adducted, adduction is stereospecific with respect to the AB&CR agent, and adduction depends upon the presence of endogenous levels of the small molecule metabolite xanthine. Substitution of lacosamide AB agent ((R)-5) for (R)-2 led to the identification of the 14-3-3 ζ adduction site (K120) by mass spectrometry. Competition experiments using increasing amounts of (R)-1 in the presence of (R)-2 demonstrated that (R)-1 binds at or near the (R)-2 modification site on 14-3-3 ζ. Structure-activity studies of xanthine derivatives provided information concerning the likely binding interaction between this metabolite and recombinant 14-3-3 ζ. Documentation of the 14-3-3 ζ-xanthine interaction was obtained with isothermal calorimetry using xanthine and the xanthine analogue 1,7-dimethylxanthine.     

One-Pot Synthesis of Dialkyl Succinates Containing an α -Amino Group and a β-Ylide Moiety Using Electron-Deficient Acetylenic Esters

The new succinic esters containing an α -amino group and a β -ylide moiety have been prepared in excellent yields by the three-components approach starting with the commercially available activated acetylenic esters and 2-aminothiazole or 4,5-dihydrothiazole-2-thiol in the presence of trivalent phosphine.     

Synthesis,structure and spectroscopic studies on DNA binding,BSA interaction of a nickel(II) complex containing l–methionine Schiff base and 1,10-phenanthroline

A new nickel(II) complex, [Ni(o-van-L-met)(phen)(CH₃OH)] (o-van-L-met = Schiff base derived from o-vanillin and l-methionine, phen = 1,10–phenanthroline), has been synthesized and characterized by elemental analyses, IR spectra, and single-crystal X-ray diffraction. The crystal structure shows nickel is six-coordinate in a distorted octahedral geometry. In this crystal, molecules form a 2-D plane structure via hydrogen bonds and π–π interactions. The interaction of the complex with calf thymus DNA (CT-DNA) was investigated by absorption, fluorescence, circular dichroism (CD), spectroscopies, and viscosity measurement. The complex binds to CT-DNA in an intercalative mode with a binding constant of (4.7 ± 0.5) × 10⁴ M^?1. The interaction of the complex with bovine serum albumin (BSA) was also studied by the multispectroscopic methods. Results illustrated that the nickel(II) complex can effectively quench the intrinsic fluorescence of BSA via a static quenching mechanism and cause conformational changes. The binding constant K_b was (6.3 ± 1.6) × 10⁴ M^?1 and the binding site number n was 0.96 ± 0.04; its bind site was located within subunit IIA of BSA.     

Nuclear inelastic scattering and Mössbauer spectroscopy as local probes for ligand binding modes and electronic properties in proteins: vibrational behavior of a ferriheme center inside a β-barrel protein

In this work, we present a study of the influence of the protein matrix on its ability to tune the binding of small ligands such as NO, cyanide (CN(-)), and histamine to the ferric heme iron center in the NO-storage and -transport protein Nitrophorin 2 (NP2) from the salivary glands of the blood-sucking insect Rhodnius prolixus. Conventional M?ssbauer spectroscopy shows a diamagnetic ground state of the NP2-NO complex and Type I and II electronic ground states of the NP2-CN(-) and NP2-histamine complex, respectively. The change in the vibrational signature of the protein upon ligand binding has been monitored by Nuclear Inelastic Scattering (NIS), also called Nuclear Resonant Vibrational Spectroscopy (NRVS). The NIS data thus obtained have also been calculated by quantum mechanical (QM) density functional theory (DFT) coupled with molecular mechanics (MM) methods. The calculations presented here show that the heme ruffling in NP2 is a consequence of the interaction with the protein matrix. Structure optimizations of the heme and its ligands with DFT retain the characteristic saddling and ruffling only if the protein matrix is taken into account. Furthermore, simulations of the NIS data by QM/MM calculations suggest that the pH dependence of the binding of NO, but not of CN(-) and histamine, might be a consequence of the protonation state of the heme carboxyls.     

Synthesis and complexation of a new 1,1′-disubstituted ferrocene with two pendant chelating sites of an α,β-unsaturated β-keto amine subunit

Condensation of 1,1′-bis(aminomethyl) ferrocene with acetylacetone gave 1,1′ -bis(3 - methyl - 5 - oxo - 2 - aza - 3 - hexenyl)ferrocene in a 56% yield. In chloro-bridge splitting reactions of dinuclear cyclopalladated complexes of benzo[h] quinoline and NN-dimethylbenzylamine, the condensed compound served as a binucleating ligand of an α,β-unsaturated β-keto aminate subunit. These new compounds formed were characterized by means of ¹H and ¹³C NMR and IR spectroscopy. Their electrochemical properties were discussed also.     

Synthesis of a novel β-cyclodextrin derivative with high solubility and the electrochemical properties of ferrocene-carbonyl-β-cyclodextrin inclusion complex as an electron transfer mediator

A facile strategy for preparing water-soluble β-cyclodextrin derivative, carbonyl-β-cyclodextrin, was developed by partial oxidation of β-cyclodextrin. The solubility of carbonyl-β-cyclodextrin was greatly enhanced due to the breaking of intramolecular hydrogen bond network of β-cyclodextrin. Ferrocene was included into the cavity of carbonyl-β-cyclodextrin to form Fc-carbonyl-β-cyclodextrin inclusion complex. The electrochemical properties of Fc-carbonyl-β-cyclodextrin were studied. The Fc-carbonyl-β-cyclodextrin complex exhibited high solubility and was shown to be good electrochemical probe and efficient mediator for bioelectrocatalysis of glucose oxidase. The bioelectrocatalytic efficacy of Fc-carbonyl-β-cyclodextrin complex opened up homogeneous applications of ferrocene in amperometric biosensor systems.     

2-(p -toluidino)-6-naphthalene sulfonate as a fluorescent probe for flocculation studies of cationic potato amylopectin and nanosized silica particles. 2. Flocculation by binding of nanosized silica particles

2-(p-toluidino)-6-naphthalene sulfonate (TNS) is a probe that fluoresces strongly when bound to certain proteins and polymers, but weakly in aqueous solutions. The reversible association of TNS is used to monitor the binding of anionic nanosized silica particles (NSP) to cationic potato amylopectin starch (CApS) through the decreasing fluorescence emission as TNS is competitively released by the particle binding. Steady-state fluorescence measurements at different mixing ratios of CApS and NSP provide data on the equilibrium binding. The isotherm derived is used to establish the fact that the most efficient flocculation between CApS and NSP occurs when the polymer coils are nearly saturated by NSP, but still have positively charged parts left. This supports a patch-flocculation mechanism. Stopped-flow experiments show that NSP binding to CApS occurs within a few milli seconds. This observation allows turbidity changes which occur on longer timescales to be ascribed to particle-decorated polymers undergoing changes in the conformation or aggregation. Received: 14 August 1998 Accepted in revised form: 4 December 1998     

Synthesis, Crystal Structure and Spectroscopic Properties of an Octanuclear V-S-Cu Cluster {V_2S_6Cu_6}(PPh_3)_6(O)_2·2CH_2Cl_2·CH_3OH with a Metal-sulfur Dodecahedral Cage

1 INTRODUCTION The reactivities of the thiometalates [MOnS4-n]z－ (n=0~2) and their applications in synthetic chemistry are very attractive because they have been shown to act as multi-ligands to a wide variety of metal ions[1]. The chemistry of Mo(W)S clusters derived from thiometalates has been most highly developed[2] for some MoS clusters are closely relevant to biological activities[3,4]. As for thiovanadates, only [VS4]3－ species has been used as ligands to coordinate metal at…     

Synthesis, analytical characterization and initial capillary electrophoretic use in an acidic background electrolyte of a new, single-isomer chiral resolving agent: heptakis(2-O-sulfo-3-O-methyl-6-O-acetyl)-β-cyclodextrin

The sodium salt of heptakis(2-O-sulfo-3-O-methyl-6-O-acetyl)cyclomaltoheptaose (HAMS), the first single-isomer sulfated β-CD that carries the sulfo group exclusively at the C2 position, has been synthesized. The purity of each synthetic intermediate and of the final product was determined by hydrophilic interaction (HILIC) and reversed-phase HPLC. The structural identity of each intermediate and of the final product was verified by 1-D and 2-D NMR spectroscopy and MALDI-TOF MS. HAMS was used for the capillary electrophoretic separation of the enantiomers of a set of non-ionic and weak base analytes in pH 2.5 background electrolytes. Rapid separations with satisfactory peak resolution values were obtained for most enantiomers using low concentrations of HAMS. The effective mobilities and separation selectivities were dependent on the concentration of HAMS according to the predictions of the charged resolving agent migration model. The separation selectivities observed with HAMS, heptakis(2-O-methyl-3-O-acetyl-6-O-sulfo)cyclomaltoheptaose and heptakis(2-O-methyl-3,6-di-O-sulfo)cyclomaltoheptaose were different for some of the analytes studied in detail.