Amino Acid Substituents Research Articles

Antimicrobial Peptides Incorporating Halogenated Marine-Derived Amino Acid Substituents.

Small synthetic mimics of cationic antimicrobial peptides represent a promising class of compounds with leads in clinical development for the treatment of persistent microbial infections. The activity and selectivity of these compounds rely on a balance between hydrophobic and cationic components, and here, we explore the activity of 19 linear cationic tripeptides against five different pathogenic bacteria and fungi, including clinical isolates. The compounds incorporated modified hydrophobic amino acids inspired by motifs often found in bioactive marine secondary metabolites in combination with different cationic residues to probe the possibility of generating active compounds with improved safety profiles. Several of the compounds displayed high activity (low μM concentrations), comparable with the positive controls AMC-109, amoxicillin, and amphotericin B. A higher activity was observed against the fungal strains, and a low in vitro off-target toxicity was observed against erythrocytes and HeLa cells, thereby illustrating effective means for tuning the activity and selectivity of short antimicrobial peptides.

Convenient Preparation of <i>tert</i>-Butyl Amino Acid Esters from <i>tert</i>-Butanol

A preparation of tert-butyl esters of amino acid is described that proceeds from protected amino acids and tert-butanol using anhydrous magnesium sulfate and an excess of boron trifluoride diethyl etherate as additional reagents. The method affords tert-butyl esters in good yields and a variety of amino acid side chains and substituents tolerate the reaction conditions.

A novel and versatile precursor for the synthesis of highly preorganized tetradentate ligands based on phenanthroline and their binding properties towards lanthanides(III) ions

Rare earth elements (REEs) are vitally important for both high-tech industry and homeland security. Current industrial production and purification of REEs rely mostly on solvent extraction, for which, the overall extraction efficiency is largely determined by the organic ligands used as extractants. Ligands based on 1,10-phenantroline-2,9-diamides (PhenDA) are promising candidates and have been intensively investigated for both lanthanides (Lns) and/or lanthanides/actinides (Lns/Ans) separations. The synthetic drawback for current PhenDA derivatives lies in the equivalent usage of acyl chloride for the key precursors, thus limiting functional group tolerance and large-scale production of the extractants. Herein, we have demonstrated a new synthetic approach for mild reaction condition, high-yield synthesis of various types of PhenDA derivatives ranging from alkyl, aromatic to amino acid substituents. The synthetic procedures are relatively green for the absence of corrosive, volatile reagents and easy of product purification. The in-group Lns discrimination of one ligand is investigated in detail to demonstrate the separation potential. Considering the broad functional group tolerance of the current method and ease of large-scale production, we believe the methodology will broaden the ligands scope based on PhenDA and inspire new functionalities of Lns complexes.

Stability Enhancement of a π-Stacked Helical Structure Using Substituents of an Amino Acid Side Chain: Helix Formation via a Nucleation-Elongation Mechanism.

Molecular design involving the incorporation of an α-amino acid residue into the side chain or main chain of a polymer is often used to stabilize artificial molecular architectures through intramolecular hydrogen bonding. However, this molecular design strategy rarely considers the importance of interactions between substituents at the α-position of amino acid moieties, as found in nature. Herein, we report the synthesis of a novel series of π-stacked helical poly(quinolylene-2,3-methylene) with amino acid derivatives bearing different substituents at the α-position. We found that the thermal stability of π-stacked helical poly(quinolylene-2,3-methylene) is significantly improved by packing the substituents in the empty spaces between the side chains. In particular, when a bulky cyclohexyl alanine derivative was used as the side chain, the π-stacked helical structure maintained its stability even in dimethylsulfoxide, a hydrogen bond competitor. The stabilization of the π-stacked structure by the amino acid substituents resulted in a unique polymerization behavior involving nucleation-elongation steps. In the case of derivatives with leucine and cyclohexyl alanine, which form stable π-stacked helical structures, metastable structures with entangled main chains were formed in the initial polymerization stage. These structures subsequently underwent an irreversible structural change to achieve a thermodynamically stable helical π-stacked conformation as a nucleus for subsequent polymerization. Thereafter, the polymerization reaction proceeded with the elongation of the π-stacked helical structure. Differences in the stability of these systems indicated that the amino acid substituents on the side chains determine the most thermodynamically stable π-stacked helical structure.

DFT-Based investigation of Amic–Acid extractants and their application to the recovery of Ni and Co from spent automotive Lithium–Ion batteries

• Various amino acids were used to synthesize amic-acid extractants. • Amic-acid extractants were investigated by density functional theory calculation. • Amino acid substituents were critical for nickel and cobalt separation. • Nickel and cobalt recovery from the lithium-ion batteries was demonstrated. To establish more efficient and environmentally friendly lithium-ion battery (LiB) recycling processes, novel extractants derived from amino acids that enable better separation of Ni and Co were explored using density functional theory (DFT) calculations. DFT calculations and experimental validation indicated that of the three coordination sites—namely amine, amide, and carboxyl groups in the amic-acid ligands—the bond strength of the central amine group to the metal determines the Ni and Co separation performance. Based on the findings, the glycine-derived amic-acid extractant N -[ N , N -di(2-ethylhexyl)aminocarbonylmethyl]glycine (D2EHAG) was applied for the recovery of Ni and Co from a spent automotive LiB leachate. Preferential and mutual recovery of Ni and Co from manganese by the D2EHAG-based recycling process was demonstrated. This study provides insights into the design of extractants that enable the mutual separation of Ni, Co, and Mn, and indicates the suitability of amic-acid extractants for LiB recycling processes.

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。

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.

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.

New Plant Growth Stimulants Based on Water-Soluble Nanoparticles of N-Substituted Monoamino-Acid Derivatives of Fullerene C60 and the Study of their Mechanisms of Action

Growth-stimulating effects of water-soluble nanoparticles of N-substituted monoamino-acid derivatives of fullerene C60 (L- and D-alanine, L- and D-valine, L- and D-aspartic acid, β-alanine, and γ-aminobutyric and e-aminocaproic acids in potassium salt form) were investigated. It was found that the nanoparticle size and relative antiradical activity of fullerene derivatives were factors that influence such physiological parameters of field peas as seed germination rate, germination energy, and root growth capacity. It was shown that the relative antiradical activity of nanoparticles in the selected group of compounds was determined by the total surface area of the nanoparticles regardless of the structure of the amino-acid substituent. The possibility of using amino-acid derivatives of fullerene as effective growth stimulating substances has been demonstrated. A dose-dependent effect of N-(monohydrofullerenyl)-D-alanine potassium salt in a concentration range of 10–9–10–11 M on the seed-germination rate and germination energy of field peas has been demonstrated.

The Immobilization of Oxindole Derivatives Using New Designed Functionalized C60 Nanomolecules

Indirubin and its analogs such as oxindole derivatives are well known as competitive inhibitors of cyclin-dependent kinase 2 (CDK2) and play an important role in the creation of therapies in many cancer diseases. Recent research, in order to increase efficiency, is aimed at creating targeted therapy, which is often based on the immobilization of drugs on the surface of nanocarriers. In this work, two oxindole derivatives were used to test the binding capabilities of newly in silico designed C60 fullerene derivatives. Seventy functionalized nanostructures were created by the addition of amino acid substituents to the single phenyl ring attached to the fullerene surface. Realized calculations, based on flexible docking methods, allowed for obtaining energetic characteristics and structural aspects of complexes created by nanomolecules with considered ligands. Analysis of obtained complexes shows that symmetric substitution to position R3 and R5 allows obtaining fullerene derivatives exhibiting the highest binding capabilities, while the lowest ones are the effect of asymmetric substitution (R2; R4). Obtained values clearly allowed to select a group of substituents and substitution sites that provide the most stable complexes which can be used to create new nanocarriers for the group of drugs under consideration.

Synthesis of 4-substituted-3-Hydroxyquinolin-2(1H)-ones with anticancer activity

Abstract Herein we show that the 3-hydroxyquinolin-2(1H)-one (3HQ) core is a suitable platform to develop new compounds with anticancer activity against MCF-7 (IC50 up to 4.82 μM) and NCI–H460 (IC50 up to 1.8 μM) cancer cell lines. The ring-expansion reaction of isatins with diazo esters catalysed by di-rhodium (II) complexes proved to be a simple and effective strategy to synthesize 4-carboxylate-3HQs (yields up to 92%). 4-Carboxamide-3HQs were more efficiently prepared using NHS-diazoacetate in yields up to 88%. This innovative methodology enabled the construction of “peptidic-like” 3HQs, with several amino acid substituents. Among this series, the L-leucine derivative induced the cell death of MCF-7 (IC50 of 15.1 μM) and NCI–H460 (IC50 of 2.7 μM) cancer cell lines without causing any appreciable cytotoxicity against the non-cancer cell model (CHOK1).

Revealing the Sequence-Structure-Electronic Property Relation of Self-Assembling π-Conjugated Oligopeptides by Molecular and Quantum Mechanical Modeling.

Self-assembled nanoaggregates of π-conjugated synthetic peptides present a biocompatible and highly tunable alternative to silicon-based optical and electronic materials. Understanding the relationship between structural morphology and electronic properties of these assemblies is critical for understanding and controlling their mechanical, optical, and electronic responses. In this work, we combine all-atom classical molecular simulations with quantum mechanical electronic structure calculations to ascertain the sequence-structure-electronic property relationship within a family of Asp-X-X-quaterthiophene-X-X-Asp (DXX-OT4-XXD) oligopeptides in which X is one of the five amino acids {Ala, Phe, Gly, Ile, Val} ({A, F, G, I, V}). Molecular dynamics simulations reveal that smaller amino acid substituents (A, G) favor linear stacking within a peptide dimer, whereas larger groups (F, I, V) induce larger twist angles between the peptides. Density functional theory calculations on the dimer show the absorption spectrum to be dominated by transitions between carbon and sulfur p orbitals. Although the absorption spectrum is largely insensitive to the relative twist angle, the highest occupied molecular orbital strongly localizes onto one molecule within the dimer at large twist angles, impeding the efficiency of transport between molecules. Our results provide a fundamental understanding of the relation between peptide orientation and electronic structure and offer design precepts for rational engineering of these systems.

Synthetic Transformations of Higher Terpenoids. 37. Synthesis and Cytotoxicity of 4-(Oxazol-2-Yl)-18-Norisopimaranes

The synthesis and properties of tricyclic diterpenoids containing a C-4 functionalized oxazole ring are reported. The reaction of 4-[5-(bromomethyl)oxazol-2-yl]-18-norisopimarane with sodium azide in the presence of hydrated copper sulfate and sodium ascorbate in DMF gave the corresponding azide, from which new diterpenoid derivatives containing a 1H-substituted 1,2,3-triazol-4-yl substituent were synthesized. Reduction of the azide produced the terpenoid 5-aminomethyloxazole. Reaction of 4-[5-(bromomethyl)oxazol-2-yl]-18-norisopimarane with methyl esters of amino acids in DMF in the presence of potash synthesized compounds with oxazole C-5 amino-acid substituents. Cytotoxicity of the new isopimaric acid derivatives gainst CEM-13, MT-4, U-937, MCF-7, and MDA-MB-231 human tumor cells was studied.

Biological impact of octyl d-glucopyranoside based surfactants

Development of many branches of industry has stimulated the search for new, effective surfactants with interesting properties. Potential use of alkyl glucose derivatives on a large scale, raises questions about the possible risks associated with their entry into the natural environment. To be able to evaluate this risk, the aim of the study was to determine the physicochemical properties of octyl d-glucopyranoside and its three derivatives: N-(octyl d-glucopyranosiduronyl)aspartic acid, N-(octyl d-glucopyranosiduronyl)glicyne and octyl d-glucopyranosiduronic acid. Moreover, their biodegradability by pure bacterial strains and biocenosis present in river water was examined. While descriptions of sugar-based surfactants on microbial cells are limited, the essential element of the study was to determine the effect of surfactants on cell surface properties of microorganisms isolated from activated sludge and compare it to the effects of the petroleum based surfactants and the surfactants produced from renewable materials. The results obtained indicate that physicochemical properties of surface active agents differ depending on the presence of functional groups in the surfactants molecules. What is more, the presence of amino acid substituent in the derivatives of octyl d-glucopyranoside resulted in a slight decrease in the surfactants biodegradation efficiency, in comparison to the compounds that did not contain such a substituent, prolonging this process from 5 to 10 days. Interestingly, even relatively slightly different derivatives modified the cell surface properties in a different way. Importantly, the surfactants based on octyl d-glucopyranoside have less negative impact on environmental microorganism and better biodegradability than the surfactant synthesized from petroleum products.

Phase behaviour, structural properties and intermolecular interactions of systems based on substituted thiacalix[4]arene and nonionic surfactants

ABSTRACTSupramolecular organised materials were prepared from nonionic surfactants and the following macrocyclic ionic liquids: n-tert-butylthiacalix[4]arenes containing quaternary ammonium fragments with amino acid substituents. Tetraethylene glycol monododecyl ether and decadiethylene glycol monododecyl ether were used as nonionic surfactants. They form lamellar and hexagonal mesophases in aqueous media, respectively. Liquid crystal and structural properties of these systems were studied. Intermolecular interactions of system components leading to formation of lyomesophases were estimated. Molecular structure of thiacalixarene contributes to the formation of a hydrogen bonding with surfactants. This process, in turn, initiates formation of a denser packed hexagonal structure.

Novel amino acid-substituted diphenylpyrimidine derivatives as potent BTK inhibitors against B cell lymphoma cell lines

A new family of diphenylpyrimidine derivatives bearing an amino acid substituent were identified as potent BTK inhibitors. Among them, compound 7b, which features an l-proline substituent, was identified as the strongest BTK inhibitor, with an IC50 of 8.7 nM. Compound 7b also displayed similar activity against B-cell lymphoma cell lines as ibrutinib. Moreover, 7b exhibited low cytotoxic activity against normal PBMC cells. In addition, the acridine orange/ethidium bromide (AO/EB) staining assay, Western blot analysis and flow cytometry analysis also showed its effectiveness in interfering with B-cell lymphoma cell growth. The molecular simulation performance showed that 7b forms additional strong hydrogen bonds with the BTK protein. All these findings provided new clues about the pyrimidine scaffold as an effective BTK inhibitor for the treatment of B-cell lymphoma.

Simultaneous formation of 3-deoxy-d-threo-hexo-2-ulose and 3-deoxy-d-erythro-hexo-2-ulose during the degradation of d-glucose derived Amadori rearrangement products: Mechanistic considerations

Analyzing classical model reaction systems of Amadori rearrangement products (ARP) it became apparent that the formation of 3-deoxy-d-threo-hexo-2-ulose (3-deoxygalactosone, 3-DGal) during the degradation of ARPs is highly dependent on pH and the amino acid residue of the respective ARP. Based on a detailed analysis of the NMR chemical shifts of the sugar moieties of different ARPs, it could be derived that the formation of 3-DGal is sensitive to the stability of a co-operative hydrogen bond network which involves HO-C3, the deprotonated carboxyl functionality and the protonated amino nitrogen of the amino acid substituent. Participating in this bond network, HO-C3 is partially protonated which facilitates the elimination of water at C3. Based on that, a new mechanism of 3-deoxyglycosone formation is proposed.

Molecular baskets nab nerve agent simulants

Sequestering chemical warfare agents, pesticides, and other toxic compounds could be a slam dunk, thanks to molecular baskets designed by chemists at Ohio State University. Jovica D. Badjic and coworkers created a series of basket-shaped molecules that feature a flat aromatic base fused to three bicyclic rings to form a curved unit. Three phthalimides extend this curvature into a cavitand with threefold symmetry. The phthalimides carry amino acid substituents, placing three carboxylates at the rim of each basket (shown in dotted red rings). In water, these baskets form supramolecular complexes with organophosphonates that are similar in size and shape to certain nerve agents. When exposed to light with a wavelength of 300 nm, the baskets shed the carboxylates, trapping the nerve agent simulants inside (shown, bottom). Without the carboxylates, the complexes are no longer soluble in water; they precipitate for easy removal (J. Am. Chem. Soc. 2017, DOI: 10.1021/jacs.7b11960). “In

Synthesis of pyridines with an amino acid residue by [2+2] cycloadditions of electron-poor acetylenes on enaminone systems derived from N-Boc protected amino acids

In this paper we present a pyridine synthesis, starting from N-protected amino acids. Amino acids are firstly converted to an ynone system, which is later converted to an enaminone system. Following a formal [2 + 2] cycloaddition of electron poor acetylenes and subsequent ring closure the final products are pyridines bearing an amino-acid substituent.

Synthesis and Antibacterial Evaluation of Novel 3-Substituted Ocotillol-Type Derivatives as Leads.

Due to the rapidly growing bacterial antibiotic-resistance and the scarcity of novel agents in development, bacterial infection is still a global problem. Therefore, new types of antibacterial agents, which are effective both alone and in combination with traditional antibiotics, are urgently needed. In this paper, a series of antibacterial ocotillol-type C-24 epimers modified from natural 20(S)-protopanaxadiol were synthesized and evaluated for their antibacterial activity. According to the screening results of Gram-positive bacteria (B. subtilis 168 and MRSA USA300) and Gram-negative bacteria (P. aer PAO1 and A. baum ATCC19606) in vitro, the derivatives exhibited good antibacterial activity, particularly against Gram-positive bacteria with an minimum inhibitory concentrations (MIC) value of 2–16 µg/mL. The subsequent synergistic antibacterial assay showed that derivatives 5c and 6c enhanced the susceptibility of B. subtilis 168 and MRSA USA300 to chloramphenicol (CHL) and kanamycin (KAN) (FICI < 0.5). Our data showed that ocotillol-type derivatives with long-chain amino acid substituents at C-3 were good leads against antibiotic-resistant pathogens MRSA USA300, which could improve the ability of KAN and CHL to exhibit antibacterial activity at much lower concentrations with reduced toxicity.