Acid Substituents Research Articles

Small molecules with tetrahydroquinoline-containing Povarov scaffolds as inhibitors disrupting the Protein–RNA interaction of LIN28–let-7

Inhibition of the RNA-binding protein LIN28 and disruption of the protein–RNA interaction of LIN28–let-7 with small molecules holds great potential to develop new anticancer therapeutics. Herein, we report the LIN28 inhibitory activities of a series of 30 small molecules with a tricyclic tetrahydroquinoline (THQ)-containing scaffold obtained from a Povarov reaction. The THQ molecules were structurally optimized by varying the 2-benzoic acid substituent, the fused ring at 3- and 4-positions, and the substituents at the phenyl moiety of the tetrahydroquinoline core. Among the tested compounds, GG-43 showed dose-dependent inhibition in an EMSA validation assay and low micromolar inhibitory activity in a fluorescence polarization-based assay measuring disruption of LIN28–let-7 interaction. Binding mode between GG-43 and the cold shock domain of LIN28 was proposed via a molecular docking analysis. The study provides one of the first systematic analyses on structural features that are required for LIN28 inhibition, and indicates the necessity to develop small molecules with new scaffolds as LIN28-targeting probes and therapeutic candidates. In parallel, this study demonstrates the polypharmacological nature of tricyclic THQ-containing scaffolds accessible through Povarov reactions.

2-Substituted perimidines: Zwitterionic tauterism in solid state, substituent effect on their crystal packing and biological activity

Structural and electronic properties of five 2-substituted 1H-perimidines: 3-(1H-perimidin-2-yl)propanoic acid (SPm), (Z)-3-(1H-perimidin-2-yl)acrylic acid) (MPm), (Z)-3-(1H-perimidin-2-yl)but-2-enoic acid (CPm-1), (Z)-2-methyl-3-(1H-perimidin-2-yl)acrylic acid (CPm-2) and 2-((1H-perimidin-2-yl)methyl)acrylic acid (IPm) have been studied. All perimidines bear aliphatic acidic substituents at 2-position andare distinguished by a carbon-carbon double bond in the substituents. The crystallographic X-ray diffraction analysis revealed that they exist in the solid state as zwitterions. Primary screening of 2-substituted 1H-perimidines against different cancer cell lines were also realized. The results obtained are discussed in terms of the structure-property relationships and compared with density functional theory calculations. Additionally, the effect of inclusion of water molecules in the crystal lattice on the molecular packing is analyzed.

Pharmacokinetics and tissue distribution characteristics of the novel photosensitizer 32-(4-methoxyphenyl)-152-aspartyl-chlorin e6

二氢卟吩类衍生物32-(4-甲氧基苯基)-152-天冬氨酸-二氢卟吩e6(DYSP-C34)是从程海湖螺旋藻中提取并合成的新型光敏剂。研究DYSP-C34在生物体内的药代动力学及组织分布过程对光动力疗法(PDT)的有效性和安全性至关重要。该文运用高效液相色谱-紫外(HPLC-UV)检测技术,建立了大鼠血浆中DYSP-C34的检测方法。采用沉淀蛋白-液液萃取法处理血浆和组织样品,采用Unitary C18色谱柱(250 mm×4.6 mm, 5 μm)分离,流动相为甲醇-5 mmol/L四丁基磷酸氢铵缓冲盐溶液(70:30, v/v),流速为1.0 mL/min,进样量为20 μL,检测波长为400 nm,柱温为40 ℃。实验结果表明,大鼠血浆药物质量浓度在1~200 μg/mL范围内线性良好,判定系数(r2)为0.9941。在低、中、高(8、40、120 μg/mL)3个添加水平下的提取回收率分别为74.39%、69.71%和65.89%,日内和日间相对标准偏差(RSD)均在5%以内。运用此方法测定静脉注射DYSP-C34(16 mg/kg)后大鼠血浆中以及荷瘤小鼠组织中的药物浓度,采用DAS 2.0计算出药物半衰期t1/2z为6.98 h,药-时曲线下面积AUC(0-∞)为1025.01 h·mg/L,平均驻留时间MRT(0-∞)为9.19 h。DYSP-C34在荷瘤小鼠体内的分布结果显示,DYSP-C34可以在肿瘤组织中蓄积,并具有一定的滞留作用。综上,该文建立了大鼠血浆中DYSP-C34的HPLC-UV测定方法,并进行了方法学验证,此方法简便、快速,结果准确。阐明了DYSP-C34在静脉给药方式下大鼠体内药代动力学和荷瘤小鼠组织中的分布特征,对临床合理用药和药效学研究具有重要意义。

Functionalized carbon black modified sulfonated polyether ether ketone membrane for highly stable vanadium redox flow battery

Sulfonated polyether ether ketone (SPEEK) membranes have attracted much attention as ion exchange membranes for vanadium redox flow batteries (VRFBs) owing to their affordability and low vanadium permeability. It's noted that they suffer from poor proton conductivity at low degree of sulfonation (DS) while poor mechanical stability at high DS. Therefore, it is a challenge to balance their performance and DS. In this work, functionalized carbon black (FCB) particles with sulfonic acid substituents were prepared and used as fillers to obtain advanced SPEEK composite membranes. This kind of SPEEK/FCB composite membranes show outstanding ion selectivity, low vanadium permeability, high proton conductivity and excellent stability. The VRFB cell with the optimized SPEEK/FCB composite membrane shows high energy efficiency (94.26%, at 50 mA cm−2), low-capacity fade rate (0.052% per cycle, at 120 mA cm−2) and long cycle life.

Partial acid-hydrolysis of TEMPO-oxidized arabinoxylans generates arabinoxylan-structure resembling oligosaccharides

Arabinoxylans (AXs) display biological activities that depend on their chemical structures. To structurally characterize and distinguish AXs using a non-enzymatic approach, various TEMPO-oxidized AXs were partially acid-hydrolysed to obtain diagnostic oligosaccharides (OS). Arabinurono-xylo-oligomer alditols (AUXOS-A) with degree of polymerization 2–5, comprising one and two arabinuronic acid (AraA) substituents were identified in the UHPLC-PGC–MS profiles of three TEMPO-oxidized AXs, namely wheat (ox-WAX), partially-debranched WAX (ox-pD-WAX), and rye (ox-RAX). Characterization of these AUXOS-A highlighted that single-substitution of the Xyl unit preferably occurs at position O-3 for these samples, and that ox-WAX has both more single substituted and more double-substituted xylose residues in its backbone than the other AXs. Characteristic UHPLC-PGC–MS OS profiles, differing in OS abundance and composition, were obtained for each AX. Thus, partial acid-hydrolysis of TEMPO-oxidized AXs with analysis of the released OS by UHPLC-PGC-MS is a promising novel non-enzymatic approach to distinguish AXs and obtain insights into their structures.

"Anti-electrostatic" Halogen Bonding between Ions of Like Charge.

Halogen bonding occurs between molecules featuring Lewis acidic halogen substituents and Lewis bases. It is often rationalized as a predominantly electrostatic interaction and thus interactions between ions of like charge (e. g., of anionic halogen bond donors with halides) seem counter‐intuitive. Herein, we provide an overview on such complexes. First, theoretical studies are described and their findings are compared. Next, experimental evidences are presented in the form of crystal structure database analyses, recent examples of strong “anti‐electrostatic” halogen bonding in crystals, and the observation of such interactions also in solution. We then compare these complexes to select examples of “counter‐intuitive” adducts formed by other interactions, like hydrogen bonding. Finally, we comment on key differences between charge‐transfer and electrostatic polarization.

Universal Access to Protease Chemiluminescent Probes through Solid-Phase Synthesis.

Protease chemiluminescent probes exhibit extremely high detection sensitivity for monitoring activity of various proteolytic enzymes. However, their synthesis, performed in solution, involves multiple synthetic and purification steps, thereby generating a major limitation for rapid preparation of such probes with diverse substrate scope. To overcome this limitation, we developed a general solid-phase-synthetic approach to prepare chemiluminescent protease probes, by peptide elongation, performed on an immobilized chemiluminescent enol-ether precursor. The enol-ether precursor is immobilized on a 2-chlorotrityl-chloride resin through an acrylic acid substituent by an acid-labile ester linkage. Next, a stepwise elongation of the peptide is performed using standard Fmoc solid-phase peptide synthesis. After cleavage of the peptide-enol-ether precursor from the resin, by hexafluoro-iso-propanol, a simple oxidation of the enol-ether yields the final chemiluminescent dioxetane protease probe. To validate the applicability of the methodology, two chemiluminescent probes were efficiently prepared by solid-phase synthesis with dipeptidyl substrates designed for activation by aminopeptidase and cathepsin-B proteases. A more complex example was demonstrated by the synthesis of a chemiluminescent probe for detection of PSA, which includes a peptidyl substrate of six amino acids. We anticipate that the described methodology would be useful for rapid preparation of chemiluminescent protease probes with vast and diverse peptidyl substrates.

Investigation of H-bonding of p-(3-carboxymethyl-1-adamantyl)calix[6]arene by IR spectroscopy

The IR spectra of calix[6]arenes with adamantylacetic acid (1) and adamantyl (2) substituents along the upper rim of the molecule were studied. It was shown that the formation of an intramolecular H-bond between carboxyl groups on the upper rim of the calix[6]arene molecules with adamantylacetic acid fragments does not weaken the cyclic cooperative H-bond at the lower rim of the macrocycle, which is confirmed by DFT calculations. The calculation has shown that molecules 1 and 2 take on the conformation of a compressed cone.The reactivity of adamantylcalix[6]arenes changes due to the association of carboxyl groups. The formation of dimeric complexes due to H-bonds of carboxyl groups along the upper rim of molecule 1 does not lead to a noticeable redistribution of the charges of hydroxyl groups on the lower rim.Heating a sample of 1 to a temperature of 180 °C destroys a small part of the H-bonds between neighboring carboxyl groups, as evidenced by the appearance of a weak band at 3535 cm–1. However, after cooling to room temperature, the H-bonds between the carboxyl groups are restored.Heating up to 355° С-leads to irreversible changes in the H-bonding system, but even at this temperature, structure destruction has not been observed.

Phosphonate functionalized N-heterocyclic carbene Pd(II) complexes as efficient catalysts for Suzuki-Miyaura cross coupling reaction

A N-heterocyclic carbene (NHC) ligand, L1 bearing a pendant phosphonate ester group is used to prepare two new NHC-Pd(II) complexes, [Pd(L1)2I2] (1) and [Pd(L1)(py)I2] (2) (py = pyridine). Hydrolysis of phosphonate ester group in 2 results another Pd(II)-NHC complex, [Pd(L2)(py)I2] (3) where a phosphonic acid group is attached to the NHC ligand L2. All the three complexes are characterized by analytical and spectroscopic studies while the molecular structures of 1-2 are also determined by single crystal X-ray diffraction measurement. The catalytic efficacies of 1-3 in Suzuki-Miyaura cross coupling reactions of aryl halides and aryl boronic acid are investigated. DFT calculations were performed to decipher the role phosphonate ester or phosphonic acid substituents on the catalytic efficacy.

Computational and NMR Conformational Analysis of Galactofuranoside Cycles Presented in Bacterial and Fungal Polysaccharide Antigens.

Unlike pyranoside cycles which are generally characterized by strictly defined conformational preferences, furanosides are flexible and may adopt a wide range of available conformations. During our previous studies, conformational changes of galactofuranoside cycles upon total sulfation were described computationally, using a simple Hartree–Fock (HF) method, and principal conformers of the 5-membered galactose ring were revealed. However, in the case of more complex disaccharide structures, it was found that this method and the widely applied DFT-B3LYP produced results that deviated from experimental evidence. In this study, other DFT functionals (PBE0 and double hybrid B2PLYP) along with RI-MP2 are employed to study the conformational behavior of the galactofuranoside ring. Reinvestigation of galactofuranosides with a lactic acid substituent at O-3 revealed that changes in the orientation of lactic acid residue at O-3 might induce conformational changes of the furanoside cycle. Such findings are important for further modeling of carbohydrate–protein interaction.

Preferential Solvation of 4-Carboxyl-2, 6-Dinitrophenylazohydroxynaphthalenes in Mixed Hydroxylic Solvents

Background: The applications of a group of 4-carboxyl-2,6-dintrophenylazohydroxynaphathalenes, AZ-01 to 04, as colourants, chemosensors or synthetic intermediates have been limited by their solubility.Aim: To investigate the effect of solvent mixture composition on the solubility, solution thermodynamics and position of equilibrium processes of the dyes.Method: The UV-visible spectral patterns of the dyes in binary mixtures including Methanol:Water, Ethanol:Water, Methanol:Ethanol, Methanol:Propan-1-ol, Methanol:Propan-2-ol, Propan-1-ol:Water and Propan-2-ol:Water were acquired. The type and quantitative estimation of solute-solvent interactions at play were determined by fitting spectral patterns to solvent parameters using multilinear regression.Results: Preferential solvation was detected by the non-ideality of the plots of E12 as against the mole fractions of co-solvent in all binary mixtures. In pure solvents, the spectral shifts of AZ-01, 03 and 04, which exist predominantly in the hydrazone form, were affected by polarity of solvent milieu while solvent basicity and acidity, in that order, were the significant parameters for AZ-02. In aqueous alcoholic mixtures, solvent polarity was contributory, although to different degrees, to the observed spectral data of the four dyes. However, solvent acidity and basicity were the primary determinants of spectral shifts observed with AZ-04 and AZ-03 respectively. Spectra-structure relationships identified the formation of the charged hydrazone tautomer which requires stabilisation by polar solvent milieu as responsible for the observed trend. In addition, interactions between new aggregated solvent-solvent species and the propionic acid substituent present in AZ-03 contributed to its spectral shifts.Conclusion: The solvatochromic properties of the phenylazonaphthalene series in binary mixtures have been successfully studied.

Photochemical and photophysical properties of tetracarboxylic acid phthalocyanines from glycolic and lactic acids in homogeneous and micro heterogeneous media

Glycolic acid and lactic acid substituted zinc phthalocyanines were studied concerning their photophysical and photochemical properties in eight organic solvents (homogeneous medium) and in aqueous media with the presence of CTAB and PVP 360 surfactants. Solvent effects were investigated according to several physical solvent parameters, including studies that used more than one parameter at a time, such as the ET(30) scale and the Lippet-Mataga equation. Computational studies were realized and was found in good agreement with experimental data indicating J-type dimers' formation through hydrogen bonds, which may not affect the spectroscopic properties. Fluorescence lifetimes were recorded using a time-correlated single-photon counting setup (TCSPC) technique. The direct method (analyzing the phosphorescence decay curves of singlet oxygen at 1270 nm) was employed to study singlet oxygen quantum yields. Phthalocyanine macrocycle with lactic acid substituent showed better solvation arrangement than the glycolic derivative, which can be explained based on the presence of the methyl group bonded to the chain. The water solvation of Pc’s in the presence of cationic surfactant (CTAB) and biocompatible polymer PVP 360 increses the importance of this study for appliance in photodynamic therapy (PDT).

Synthesis, characterization, molecular structure, and computational studies on 4(1H)-pyran-4-one and its derivatives

4(1H)-Pyridone-based compounds have shown promise as potent bioactive inhibitors against a broad range of diseases, particularly malaria. Our interest in 4(1H)-pyridones initiated the design and synthesis of a series of 4(1H)-pyridone derivatives, with the hope of finding new antimalarial leads. The synthesis of 4(1H)-pyran-4-one analogues (4(1H)-pyridone intermediates was successfully achieved using palladium catalyzed Suzuki-Miyaura coupling reactions. The synthesized 4(1H)-pyran-4-ones were unambiguously confirmed by TGA, 13C, 1H NMR, and IR spectroscopic analysis. Further comprehensive insights to rationalize the outcome of several reactions were deduced by means of single crystal X-ray diffraction, which was used to determine the single crystal structures of compounds 4 and 5. Compounds 5, 9 and 9a-e were successfully synthesized in moderate to excellent yields, apart from compound 9e which gave a very low yield. NMR and XRD analysis of the by-product of compound 9e showed that the boronic acid substituents reacted with each other in a side-reaction reminiscent to aryl boronic acid homo coupling or Ullmann coupling reactions. Complimentary DFT analysis of the pyranone and pyridone compounds provided insight into the substituent effect of the pyranone compounds with regards to the stability and lack of reactivity to form the corresponding pyridone compounds.

Easing oxygen into arenes

Organic Chemistry Although oxygen is all around us, it is often surprisingly difficult to use it for selective chemical oxidations, necessitating more expensive, wasteful alternatives. Li et al. report that careful ligand optimization produces palladium catalysts that can efficiently activate oxygen to hydroxylate a variety of aryl and heteroaromatic rings adjacent to a carboxylic acid substituent. The ligand binds to palladium through pyridine and pyridone components, and the authors posit that tautomerization between dative and anionic coordination modes plays a role in its effectiveness. Science , abg2362, this issue p. [1452][1] [1]: /lookup/doi/10.1126/science.abg2362

A tautomeric ligand enables directed C‒H hydroxylation with molecular oxygen.

Hydroxylation of aryl carbon-hydrogen bonds with transition metal catalysts has proven challenging when oxygen is used as the oxidant. Here, we report a palladium complex bearing a bidentate pyridine/pyridone ligand that efficiently catalyzes this reaction at ring positions adjacent to carboxylic acids. Infrared, x-ray, and computational analysis support a possible role of ligand tautomerization from mono-anionic (L,X) to neutral (L,L) coordination in the catalytic cycle of aerobic carbon-hydrogen hydroxylation reaction. The conventional site selectivity dictated by heterocycles is overturned by this catalyst, thus allowing late-stage modification of compounds of pharmaceutical interest at previously inaccessible sites.

Rhodium(III)‐Catalyzed Formal Cycloaddition between Thienopyridine/Thienopyrazine Carboxylic Acids and Alkynes, Triggered by C−H Activation

AbstractIn the last decade, a number of metal‐catalyzed technologies for the functionalization of C−H bonds in carbonaceous aromatic substrates have been developed. However, similar reactions with aza‐heteroaromatic precursors are more challenging and have been much less developed. Herein, we report for the first time catalytic formal cycloadditions of N,S‐heterocycles featuring carboxylic acid substituents, with unsaturated partners (alkynes). The reaction, which works with different symmetrical and unsymmetrical alkynes, produces appealing tricyclic ɑ‐pyrones in a straightforward manner. The optimized conditions established for a model reaction employing thieno[2,3‐b]pyridine‐2‐carboxylic acid as substrate, involved the use of Ag2CO3/AgSbF6 as additives, and proved to be general for different alkynes. Moreover, analogous cycloadditions using thieno[3,2‐b]pyridine‐2‐carboxylic acid and thieno[2,3‐b]pyrazine‐6‐carboxylic acid were successfully developed. Overall, this catalytic technology allows to build, in a single step, an interesting variety of pharmaceutically relevant tricyclic ɑ‐pyrones exhibiting nitrogen and sulfur heteroatoms.

A Versatile Method for Preparing Polysaccharide Conjugates via Thiol-Michael Addition.

Polysaccharide conjugates are important renewable materials. If properly designed, they may for example be able to carry drugs, be proactive (e.g., with amino acid substituents) and can carry a charge. These aspects can be particularly useful for biomedical applications. Herein, we report a simple approach to preparing polysaccharide conjugates. Thiol-Michael additions can be mild, modular, and efficient, making them useful tools for post-modification and the tailoring of polysaccharide architecture. In this study, hydroxypropyl cellulose (HPC) and dextran (Dex) were modified by methacrylation. The resulting polysaccharide, bearing α,β-unsaturated esters with tunable DS (methacrylate), was reacted with various thiols, including 2-thioethylamine, cysteine, and thiol functional quaternary ammonium salt through thiol-Michael addition, affording functionalized conjugates. This click-like synthetic approach provided several advantages including a fast reaction rate, high conversion, and the use of water as a solvent. Among these polysaccharide conjugates, the ones bearing quaternary ammonium salts exhibited competitive antimicrobial performance, as supported by a minimum inhibitory concentration (MIC) study and tracked by SEM characterization. Overall, this methodology provides a versatile route to polysaccharide conjugates with diverse functionalities, enabling applications such as antimicrobial activity, gene or drug delivery, and biomimicry.

Uncoordinated‐substituents‐induced zinc(II) coordination polymers exhibiting multifunctional fluorescent sensing activity for cations, anions and organochlorine pesticides

AbstractIn order to explore the influence of carboxylic acid substituents on the structures and properties of coordination polymers, three new coordination polymers (CPs) of [Zn2(L)2(IP)2] (1), [Zn(L)(HIP)] ⋅ 3H2O (2) and [Zn(L)(NIP)] ⋅ H2O (3) [H2IP=isophthalic acid, H2HIP=5‐hydroxyisophthalic acid, H2NIP=5‐nitroisophthalic acid] were designed and synthesized under hydrothermal conditions with a multi‐torsion‐centered N‐donor ligand of N,N′‐bis(4‐methylenepyridin‐4‐yl)‐1,4‐naphthalene dicarboxamide (L). All three CPs have similar 4,4‐connected two‐dimensional structures exhibiting different structural details, which is induced by uncoordinated‐substituents and discussed systematically. The title CPs 1 and 2 show multi‐functional fluorescent responses towards metal ion (Fe3+), anions (MnO4−, CrO42− and Cr2O72−) and pesticide (2,6‐dichloro‐4‐nitroaniline). The corresponding detection limits are 6.1×10−5 M−1, 3.7×10−4 M−1, 5.5×10−4 M−1, 3.0×10−4 M−1 and 6.7×10−5 M−1 for CP 1, 2.8×10−5 M−1, 4.1×10−4 M−1, 3.0×10−4 M−1, 4.1×10−4 and 2.8×10−5 M−1 for CP 2.

Regulating effects of anthraquinone substituents and additives in photo-catalytic oxygenation of p-xylene by molecular oxygen under visible light irradiation

This paper reports that the optical properties of anthraquinone (AQ) and its photo-catalytic performance in the visible light-driven p-xylene (PX) oxidation can be fine-tuned and improved through varying its skeleton substituents at the molecular level, and the electron-withdrawing substituent exhibits a better improvement effect than the electron-donating one. The best catalyst 2-carboxyanthraquinone (AQ-COOH) can achieve 70.9% PX conversion and 88.2% p-toluic acid selectivity under visible light illumination and 1 atm O2 pressure. The addition of benzenesulfonic acid in the above photocatalytic system can further increase PX conversion to 86.7%, along with a significant improvement in the selectivity of p-carboxybenzaldehyde and terephthalic acid, which likely originates from the unique recombination behavior of the photo-generated charge carriers of the catalyst and the additive driven by the strong interactions between their aromatic skeletons and acidic substituents. Furthermore, AQ-COOH can achieve almost quantitative yield of acetylacetone in ethylbenzene photooxidation and the regulating effect of toluene's para-position substituents on its reactivity is also reported in the AQ-COOH photocatalysis system. Based on quenching tests and EPR spectral characterizations, the oxygen vacancies (h+), superoxide free radicals (O2•-) and singlet oxygen (1O2) as the photo-generated active species are involved in the proposed photo-catalysis mechanism.

Mechanism of the Antioxidant Activity and Structure\u2013Activity Relationship of N-Monosubstituted Amino Acid Derivatives of Fullerene \u042160

The kinetic characteristics, mechanisms of activity, and relationship between the antioxidant activity and the molecular and supramolecular structure of fullerene C60 and some of its N-monosubstituted amino acid derivatives have been studied. The introduction of an amino acid substituent in the C60 fullerene molecule led to an increase in its antiradical activity in the free radical oxidation of a water-soluble target (fluorescein). The mechanism of the antioxidant activity of amino acid derivatives of fullerene is not associated with the hydrogen atom transfer, electron donation, or catalysis of peroxide decomposition. It was demonstrated that the structure of the amino acid substituent does not affect the antiradical properties, which are thus determined only by the effective total surface area of ​​the nanoparticles of the fullerene C60 derivatives and increase when their size decreases. This surface can be characterized as nanowalls on which the radical death occurs. A change in the concentration of the compounds in solution does not lead to a change in the relative antiradical activity and hence in the nanoparticle size. The results of this study are important for understanding the biological activity of this group of compounds.