Binding Affinity of Novel Cyclodextrin Dimers to Ethyl Orange

The interaction between ethyl orange (Eto, guest) and β-cyclodextrin dimers (1a～d, host) bridged with 2-t-butoxycarbonyl(Boc)-amino diacid was investigated. A remarkable synergic complexation of two cavities in host molecule was observed.     

基于长波长光激发的光敏剂和载体在肿瘤光动力治疗中的应用

光动力疗法是近年来兴起的一种新型的微创性治疗肿瘤的方法,目前已经成功地应用于临床上多种恶性肿瘤治疗中,并取得了良好的效果。然而,由于生物组织对可见光的吸收和散射,使得光线无法穿透组织到达身体内的目标区域,所以该疗法更适用于浅表肿瘤的治疗。长波长光尤其是近红外光具有良好的组织穿透深度,其在治疗组织深处的肿瘤方面具有显著的优势。基于长波长光激发的光敏剂及载体在实体肿瘤的治疗领域已经取得了丰硕的研究成果。本文将从光敏剂的研发、双光子激光的使用、上转换纳米粒子的引入等方面简要概述近十年来用于光动力治疗中的组装体系,以及长波长激发光在光动力治疗方面的发展趋势。     

Unraveling the Photodynamic Activity of Cationic Benzoporphyrin-Based Photosensitizers against Bladder Cancer Cells

In this study, we report the preparation of new mono-charged benzoporphyrin complexes by reaction of the appropriate neutral benzoporphyrin with (2,2′-bipyridine)dichloroplatinum(II) and of the analogs’ derivatives synthesized through alkylation of the neutral scaffold with iodomethane. All derivatives were incorporated into polyvinylpyrrolidone (PVP) micelles. The ability of the resultant formulations to generate reactive oxygen species was evaluated, mainly the singlet oxygen formation. Then, the capability of the PVP formulations to act as photosensitizers against bladder cancer cells was assessed. Some of the studied formulations were the most active photosensitizers causing a decrease in HT-1376 cells’ viability. This creates an avenue to further studies related to bladder cancer cells.     

Development of Biotechnological Photosensitizers for Photodynamic Therapy: Cancer Research and Treatment—From Benchtop to Clinical Practice

Photodynamic therapy (PDT) is a noninvasive therapeutic approach that has been applied in studies for the treatment of various diseases. In this context, PDT has been suggested as a new therapy or adjuvant therapy to traditional cancer therapy. The mode of action of PDT consists of the generation of singlet oxygen (¹O₂) and reactive oxygen species (ROS) through the administration of a compound called photosensitizer (PS), a light source, and molecular oxygen (³O₂). This combination generates controlled photochemical reactions (photodynamic mechanisms) that produce ROS, such as singlet oxygen (¹O₂), which can induce apoptosis and/or cell death induced by necrosis, degeneration of the tumor vasculature, stimulation of the antitumor immune response, and induction of inflammatory reactions in the illuminated region. However, the traditional compounds used in PDT limit its application. In this context, compounds of biotechnological origin with photosensitizing activity in association with nanotechnology are being used in PDT, aiming at its application in several types of cancer but with less toxicity toward neighboring tissues and better absorption of light for more aggressive types of cancer. In this review, we present studies involving innovatively developed PS that aimed to improve the efficiency of PDT in cancer treatment. Specifically, we focused on the clinical translation and application of PS of natural origin on cancer.     

Binding neutral guests to concave surfaces of molecular hosts. Directional association of water and methylene chloride with hosts containing only cyclic urea binding sites

This paper is concerned with studies of weak intermolecular interactions in molecular inclusion type systems involving uncharged host and guest entities. Three new complexes of synthetic organic ligands with water and methylene chloride have been characterized by single-crystal X-ray diffraction. The hosts are composed of three cyclic urea units whose carbonyl groups are held in convergent positions by bonding their attached nitrogens to one another through two (noncyclic ligand) or three (macrocyclic ligand) rigid spacer units. Conformational organization is further enforced by an aliphatic bridge between two of the phenylene spacers in the macrocyclic hosts and an additional dimerization of the open-chain ligand. The host species were found to be particularly suitable to interact with proton donating H₂O and CH₂Cl₂ guest moieties, as their molecular surface contains appropriately sized polar cavities lined with the carbonyl functions. Association between the interacting components in these complexes is stabilized by O–HO and C–HO hydrogen bonds. In the corresponding crystal structures additional molecules of the solvent are located between units of the complex. The significance of preorganization of the host structure to an efficient guest binding is emphasized by an observation that no stable complexes of a similar but unbridged macrocyclic ligand could be crystallized from the same solvent. The structural features of the inclusion compounds are described in detail, and the host-guest interaction scheme is compared to that observed in complexes of 18-crown-6 with neutral guests. Supplementary Data relating to this article are deposited with the British Library as Supplementary Publication No. SUP 82039 (98 pages)     

Study of the complexation of 5,17-bis-(N-tolyliminomethyl)-25,27-dipropoxycalix[4]arene with pyridine carboxylic acids by RP HPLC and molecular modelling

Host–guest complexation process of 5,17-bis-(N-tolyliminomethyl)-25,27-dipropoxycalix[4]arene with pyridine carboxylic acids by RP HPLC method (mobile phase – MeCN/H₂O, 86/14 by volume, LiChrosorb RP 18, UV detector, λ = 254 nm) had been studied. The binding constants and Gibbs free energies of the complexes 5,17-bis(N-tolyliminomethyl)-25,27-dipropoxycalix[4]arene with the pyridine carboxylic acids are within 584 to 1914 M^? 1 and ? 15.76 to ? 18.69 kJ/mol, respectively. It was shown by the molecular modelling that the complexes are stabilised by hydrogen bonds between carboxylic groups of the acids and nitrogen atoms of imino groups at the upper rim or oxygen atoms of the hydroxyl groups at the lower rim of the macrocycle. Linear dependence of the binding constants from the acid lipophilicity log P indicates the role of solvophobic interactions during the complexation process.     

High Resolution NMR Spectroscopic Study of Complexation of Hydroxyzine Hydrochloride with β‐Cyclodextrin in Aqueous Solution

Hydroxyzine hydrochloride forms two 1:1 inclusion complexes with β‐cyclodextrin in aqueous solution as confirmed by the ¹H NMR titration and ROESY studies. One complex is formed by the deep penetration of the chlorophenyl ring from the wider rim side, while the mode of entry of the phenyl ring into the β‐CD cavity is not clear. The stoichiometry and overall association constant of the complexes have been determined by the treatment of ¹H NMR shift data. Some chiral discrimination by the host between the two enantiomers of hydroxyzine hydrochloride is also indicated.     

Water Structure Recovery in Chaotropic Anion Recognition: High‐Affinity Binding of Dodecaborate Clusters to γ‐Cyclodextrin

Dodecaborate anions of the type B₁₂X₁₂^2? and B₁₂X₁₁Y^2? (X=H, Cl, Br, I and Y=OH, SH, NH₃⁺, NR₃⁺) form strong (K_a up to 10⁶ L mol^?1, for B₁₂Br₁₂^2?) inclusion complexes with γ‐cyclodextrin (γ‐CD). The micromolar affinities reached are the highest known for this native CD. The complexation exhibits highly negative enthalpies (up to ?25 kcal mol^?1) and entropies (TΔS up to ?18.4 kcal mol^?1, both for B₁₂I₁₂^2?), which position these guests at the bottom end of the well‐known enthalpy‐entropy correlation for CDs. The high driving force can be traced back to a chaotropic effect, according to which chaotropic anions have an intrinsic affinity to hydrophobic cavities in aqueous solution. In line with this argument, salting‐in effects revealed dodecaborates as superchaotropic dianions.     

Host–Guest Interactions of Risperidone with Natural and Modified Cyclodextrins: Phase Solubility, Thermodynamics and Molecular Modeling Studies

The solubility of risperidone (Risp) in aqueous buffered cyclodextrin (CD) solution was investigated for α-, β-, γ- and HP-β-CD. The effects of pH, ionic strength and temperature on complex stability were also explored. Neutral Risp tends to form higher order complexes (1:2) with both β- and HP-β-CD, but only 1:1 type complexes with α-, and γ-CD. The tendency of Risp to complex with cyclodextrins is in the order β-CD > HP-β-CD > γ-CD > α-CD. The 1:1 complex formation constant of Risp/HP-β-CD increases with increasing ionic strength in an opposite trend to the inherent solubility (S ₀) of Risp, thus indicating significant hydrophobic effect. The hydrophobic effect contributes to the extent of 72% towards neutral Risp/HP-β-CD complex stability, while specific interactions contribute only 4.7 kJ/mol. Thermodynamic studies showed that 1:1 Risp/HP-β-CD complex formation is driven by a favorable enthalpy change (ΔH ⁰=−31.2 kJ/mol, ΔS ⁰=−7 J/mol.K) while the 1:2 complex is largely driven by entropy changes (ΔH ⁰=−5.0 kJ/mol, ΔS ⁰=42 J/mol.K). Complex stability was found to vary with pH, with a higher formation constant for neutral Risp. Molecular mechanical computations using MM (atomic charges and bond dipole algorithms) and Amber force fields, which were carried out to explore possible sites of interactions between Risp and CDs and to rationalize complex stoichiometry, produced similar results concerning optimal inclusion complex geometries and stoichiometries.     

High DNA‐Binding Affinity and Gene‐Transfection Efficacy of Bioreducible Cationic Nanomicelles with a Fluorinated Core

During the last two decades, cationic polymers have become one of the most promising synthetic vectors for gene transfection. However, the weak interactions formed between DNA and cationic polymers result in low transfection efficacy. Furthermore, the polyplexes formed between cationic polymers and DNA generally exhibit poor stability and toxicity because of the large excess of cationic polymer typically required for complete DNA condensation. Herein, we report the preparation of a novel class of bioreducible cationic nanomicelles by the use of disulfide bonds to connect the cationic shell to the fluorocarbon core. These bioreducible nanomicelles form strong interactions with DNA and completely condense DNA at an N/P ratio of 1. The resulting nanomicelle/DNA polyplexes exhibited high biocompatibility and performed very effectively as a gene‐delivery system.     

Determination of Binding Constants for Cyclodextrin Complexes with Alkanols by the 1H NMR Measurements of Longitudinal Relaxation Time Using Tetramethylammonium Chloride as an Internal Reference

The longitudinal relaxation times (T₁)of ¹H NMR signals for a variety of alkanols in D₂Omarkedly decreased with increasing concentrations (c)of - and -cyclodextrins (CD). Tetramethylammoniumchloride (TMA) used as an internal reference wasavailable for evaluating an effect of solutionviscosity on relaxation rates R(=1/T₁), since TMAshowed no appreciable interaction with CD. Changes inthe ratio of R for alkanol protons to R for TMAprotons with c were analyzed by the curve-fittingmethod to give K_a. These K_a values agreedwell with those obtained by the analysis of changesin , indicating that T₁ measurement is available forthe determination of K_a for CD complexes. 2D ROESYspectra provided definite information on the molecularstructures of CD complexes with alkanols.     

Use of a Dual-Marker Form of Analysis to Estimate Binding Constants Between Receptors and Ligands by Affinity Capillary Electrophoresis

This work describes the use of a dual-standard analysis approach termed the time-average ratio (TAR) in affinity capillary electrophoresis (ACE) to estimate binding constants of receptors to ligands. In this form of analysis the TAR is the migration time of the receptor divided by the average of the sum of the migration times of two non-interacting standards. This change in TAR as a function of the concentration of ligand yields a value for the binding constant. This concept is demonstrated using three model systems: carbonic anhydrase B (CAB, EC 4.2.1.1) and arylsulfonamides, vancomycin (Van) and ristocetin (Rist) from Streptomyces orientalis and Nocardia lurida, respectively, and d-Ala- d-Ala terminus peptides. Three ACE techniques are used to examine the three systems: standard ACE, flow-through partial-filling ACE (FTPFACE), and on-column derivatization coupled to ACE. The findings described here demonstrate that ACE data analyzed using the TAR form of analysis yield binding constants between receptors and ligands comparable to those estimated using other ACE forms of analysis. A comparison to three other forms of analysis is described.     

Determination of Binding Constants for Basic Drugs with Serum Albumin by Affinity Capillary Electrophoresis with the Partial Filling Technique

A simple, rapid, and accurate method is presented for determination of the binding constants of eight basic drugs with serum albumin by affinity capillary electrophoresis with the partial filling technique. Molecular modeling and multivariate regression analysis were used to investigate the relationship between the binding constants and the physicochemical properties of the drugs. The results show that hydrophobic attraction is responsible for interaction of most of the drugs with HAS, although interaction between sulfamethoxazole and HSA is because of electrostatic attraction.     

Synthesis of conjugates of 5,15-disubstituted aminoporphyrins and terpyridine derivatives with potential chelating properties

meso-Arylporphyrin containing two external chelating 2,2':6',2'-terpyridine fragments and its zinc complex were synthesized. The key step comprised the amide bond formation between the porphyrin diamine derivative and 4'-(4-carboxyphenyl)-2,2':6',2'-terpyridine. The compounds obtained seem to be potent for photodynamic therapy and diagnosis.     

Interaction of cationic chlorin photosensitizers with non-ionic surfactant Tween 80

1. Download : Download high-res image (131KB)
2. Download : Download full-size image

     

Cyanoarylporphyrazines with High Viscosity Sensitivity: A Step towards Dosimetry-Assisted Photodynamic Cancer Treatment

Despite the significant relevance of photodynamic therapy (PDT) as an efficient strategy for primary and adjuvant anticancer treatment, several challenges compromise its efficiency. In order to develop an “ideal photosensitizer” and the requirements applied to photosensitizers for PDT, there is still a need for new photodynamic agents with improved photophysical and photobiological properties. In this study, we performed a detailed characterization of two tetracyanotetra(aryl)porphyrazine dyes with 4-biphenyl (pz II) and 4-diethylaminophenyl (pz IV) groups in the periphery of the porphyrazine macrocycle. Photophysical properties, namely, fluorescence quantum yield and lifetime of both photosensitizers, demonstrate extremely high dependence on the viscosity of the environment, which enables them to be used as viscosity sensors. Pz II and pz IV easily enter cancer cells and efficiently induce cell death under light irradiation. Using fluorescence lifetime imaging microscopy, we demonstrated the possibility of assessing local intracellular viscosity and visualizing viscosity changes driven by PDT treatment with the compounds. Thus, pz II and pz IV combine the features of potent photodynamic agents and viscosity sensors. These data suggest that the unique properties of the compounds provide a tool for PDT dosimetry and tailoring the PDT treatment regimen to the individual characteristics of each patient.     

采用毛细管电泳技术筛选特异识别蓖麻毒素适配子的研究

采用指数富集配基的系统进化(SELEX)技术从随机寡核苷酸文库中筛选获得特异识别蓖麻毒素靶分子的适配子. 将毛细管电泳技术作为分离手段引入到SELEX筛选中, 利用毛细管电泳高效的分离能力使得筛选周期大大缩短. 酶联免疫和斑点杂交实验结果表明, 仅经4轮筛选即可获得特异识别蓖麻毒素蛋白的寡核苷酸适配子.