Probable Conformations Research Articles

Structural Space of the Duffy Antigen/Receptor for Chemokines' Intrinsically Disordered Ectodomain 1 Explored by Temperature Replica-Exchange Molecular Dynamics Simulations.

Plasmodium vivax malaria affects 14 million people each year. Its invasion requires interactions between the parasitic Duffy-binding protein (PvDBP) and the N-terminal extracellular domain (ECD1) of the host's Duffy antigen/receptor for chemokines (DARC). ECD1 is highly flexible and intrinsically disordered, therefore it can adopt different conformations. We computationally modeled the challenging ECD1 local structure. With T-REMD simulations, we sampled its dynamic behavior and collected its most representative conformations. Our results suggest that most of the DARC ECD1 domain remains in a disordered state during the simulated time. Globular local conformations are found in the analyzed local free-energy minima. These globular conformations share an α-helix spanning residues Ser18 to Ser29 and in many cases they comprise an antiparallel β-sheet, whose β-strands are formed around residues Leu10 and Ala49. The formation of a parallel β-sheet is almost negligible. So far, progress in understanding the mechanisms forming the basis of the P. vivax malaria infection of reticulocytes has been hampered by experimental difficulties, along with a lack of DARC structural information. Our collection of the most probable ECD1 structural conformations will help to advance modeling of the DARC structure and to explore DARC-ECD1 interactions with a range of physiological and pathological ligands.

Investigation of Iminosugars as Antiviral Agents against SARS-CoV-2 Main Protease: Inhibitor Design and Optimization, Molecular Docking, and Molecular Dynamics Studies to Explore Potential Inhibitory Effect of 1-Deoxynojirmycin Series.

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) poses an enormous challenge to human health and economy at a global level. According to WHO's latest data, till now, there have been a total of 641,435,884 confirmed cases of COVID-19, and the associated deaths are 6,621,060. Though few vaccinations have been approved for emergency usage, antiviral medications for long-term therapeutics are still being sought. The current research seeks to identify the inhibitory effect of iminosugars, particularly 1-deoxynojirmycin (IDNJ) series, against SARS-CoV-2 main protease (SARS-CoV2-Mpro) using an inhibitor optimization approach for 1DNJ series. The aim of this study was to investigate the inhibitory effect of iminosugars, specifically 1-deoxynojirmycin (1-DNJ) derivatives, on SARS-CoV-2 main protease (Mpro) as it plays a vital role in viral propagation and transcription and is shaped like a heart. The main objective of this study was to find the possibility of 1-DNJ derivatives being potent inhibitors against SARS CoV2 Mpro. This study was focused on finding the most probable conformation in which DNJ derivatives could bind to Mpro. Another objective was to obtain molecular-level details by getting insights into stable interactions formed between the ligand and receptor. In silico molecular mechanics (MM) based techniques were employed to identify the best-docked inhibitors using molecular docking, and complexes that showed stable interactions were further subjected to 200 ns of molecular dynamics (MD) simulations to check the stability of ligand into the binding pocket of SARS-CoV2-Mpro. The inhibitors that formed stable complexes were further tested for their ADME properties in order to check the pharmacokinetic parameters as well as their therapeutic importance. Docking was performed on 29 compounds from two different series against SARS-CoV-2 main protease, Mpro (PDB ID: 6LZE). Twelve compounds were found to have high docking scores and better interactions with the active site of Mpro, as compared to the co-crystallized ligand. Furthermore, the three highest-scoring docked compounds (17a, 7, and 8) depicted strong and stable complex formation, throughout the 200 ns molecular dynamics simulation, by analyzing the binding energy (MM/GBSA). The molecules were discovered to form stable interactions with conserved active-site residues, which play an important role in demonstrating activity in structure-based drug design. The ADMET analysis was performed using Qikprop, and the proposed stable derivatives passed all of the needed drug discovery standards, potentially inhibiting the Mpro of SARS-CoV-2. The present findings confer opportunities for compounds 17a, 7, and 8 that could be developed as new therapeutic agents against COVID-19. These compounds are suggested on the basis of pharmacokinetic parameters as well as therapeutic importance and hence could be tested in-vitro.

New Insights into the Intrinsic Electron-Based Dissociation Behavior of Cytochrome c Oligomers.

Between 2003 and 2017, four reports were published that demonstrated the intrinsic ability of the native iron-containing proteins cytochrome c and ferritin to undergo radical-based backbone fragmentation in the gas phase without the introduction of exogenous electrons. For cytochrome c in particular, this effect has so far only been reported to occur in the ion source, preventing the in-depth study of reactions occurring after gas-phase isolation of specific precursors. Here, we report the first observation of this intrinsic native electron capture dissociation behavior after quadrupole isolation of specific charge states of the cytochrome c dimer and trimer, providing direct experimental support for key aspects of the mechanism proposed 20 years ago. Furthermore, we provide evidence that, in contrast to some earlier proposals, these oligomeric states are formed in bulk solution rather than during the electrospray ionization process and that the observed fragmentation site preferences can be rationalized through the structure and interactions within these native oligomers rather than the monomer. We also show that the observed fragmentation pattern─and indeed, whether or not fragmentation occurs─is highly sensitive to the provenance and history of the protein samples, to the extent that samples can show distinct fragmentation behavior despite behaving identically in ion mobility experiments. This rather underexplored method therefore represents an exquisitely sensitive conformational probe and will hopefully receive more attention from the biomolecular mass spectrometry community in the future.

Discovery of Selective P2Y6R Antagonists with High Affinity and In Vivo Efficacy for Inflammatory Disease Therapy.

As a member of purinoceptors, the P2Y6 receptor (P2Y6R) plays a crucial role in modulating immune signals and has been considered as a potential therapeutic target for inflammatory diseases. On the basis of the speculated probable conformation and binding determinants of P2Y6R, a hierarchical strategy that combines virtual screening, bioassays, and chemical optimization was presented. A potent P2Y6R antagonist (compound 50) was identified to possess excellent antagonistic activity (IC50 = 5.914 nM) and high selectivity. In addition, binding assays and chemical pull-down experiments confirmed that compound 50 was nicely bound to P2Y6R. Notably, compound 50 could effectively ameliorate DSS-induced ulcerative colitis in mice through inhibiting the activation of NLRP3 inflammasome in colon tissues. Moreover, treatment with compound 50 reduced LPS-induced pulmonary edema and infiltration of inflammatory cells in mice. These findings suggest that compound 50 could serve as a specific P2Y6R antagonist for treating inflammatory diseases and deserve further optimization studies.

Nucleic Acid Probes for Single-Molecule Localization Imaging of Cellular Biomolecules.

Endogenous biomolecules in cells are the basis of all life activities. Directly visualizing the structural characteristics and dynamic behaviors of cellular biomolecules is significant for understanding the molecular mechanisms in various biological processes. Single-molecule localization microscopy (SMLM) can circumvent the optical diffraction limit, achieving analysis of the fine structures and biological processes in living cells with nanoscale resolution. However, the large size of traditional imaging probes prevents SMLM from accurately locating fine structures and densely distributed biomolecules within cells. In recent years, nucleic acid probes have emerged as potential tools to replace conventional SMLM probes by virtue of their small size and high specificity. In addition, due to their programmability, nucleic acid probes with different conformations can be constructed via sequence design, further extending the application of SMLM in bioanalysis. Here, we discuss the design concepts of different conformational nucleic acid probes for SMLM and summarize the application of SMLM based on nucleic acid probes in the field of biomolecules. Furthermore, we provide a summary and future perspectives of the nucleic acid probe-based SMLM technology, aiming to provide guidance for the acquisition of nanoscale information about cellular biological processes.

Abstract 3834: Antiproliferative activity of substituted chromone-2-carboxamides on MDA-MB-231 cells and their 3D pharmacophore models

Abstract After lung cancer, breast cancer is the second leading cause of cancer death in women in the United States, accounting for 12.5 % of all new cancer cases globally. Triple-negative breast cancer (TNBC) remains the hardest breast cancer and is difficult to treat. The current treatment option for TNBC is the surgical removal of the tumor, followed by chemotherapy. However, patients with advanced diseases respond poorly to current treatments. Therefore, discovering more effective and less toxic small drug molecules with a unique mechanism of action is one of the top priorities in drug discovery programs. Chromones have a benzo-pyrone skeleton and display interesting pharmacological activities, such as anti-cancer, anti-HIV, antiviral and anti-inflammatory, with low toxicity. In continuation of our current research work, we report the design and synthesis of substituted chromone-2-carboxamides by attaching substituted phenyl, tetrahydropyridine, and tetrahydroisoquinoline groups as anti-breast cancer agents. The starting material, substituted chromone-2-carbonyl chloride, was obtained by the acylation reaction of corresponding carboxylic acids using phosphorous pentachloride in dry cyclohexane. An equimolar amount of acyl chloride was slowly added to a stirred solution of corresponding substituted N-amino salt in dry THF in the presence of triethyl amine and refluxed at 70 °C that led to the formation of the ylides. The ylides were reduced using sodium borohydride to yield the desired substituted chromone-2-carboxamides in moderate to good yields. The synthesized compounds were characterized by NMR and elemental analysis. These compounds were evaluated for their cytotoxic effects on MBA-MB-231 ER-ve breast cancer cell lines using a Synergy HTX multi-mode reader (Bio-Tek, Winooski, VT, USA) with excitation/emission wavelength settings at 550/580. Compound MG-KKR-5-140A showed the most potent cytotoxicity with an IC50 value of 0.82 µg/mL on the MDA-MB-231 cell line. In-silico pharmacophore hypotheses were generated using GALAHAD and PHASE, and the best models with probable bioactive conformation(s) for these compounds were proposed. These confirmations and the alignments of the molecular structures give us an insight into designing compounds with better biological activity. This research was supported by the National Institute on Minority Health and Health Disparities of the National Institutes of Health under Award Number U54 MD007582. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Citation Format: Kinfe Ken Redda, Madhavi Gangapuram, Suresh Eyunni, Elizabeth Mazzio, Karam F. A. Soliman. Antiproliferative activity of substituted chromone-2-carboxamides on MDA-MB-231 cells and their 3D pharmacophore models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3834.

Hairpin DNA-enabled ratiometric electrochemical aptasensor for detection of malathion

A hairpin DNA-enabled ratiometric electrochemical aptasensor is reported for sensitive and reliable detection of malathion (MAL). The approach employs hairpin DNA (ferrocene-labeled, Fc-hDNA) as a carrier to hybridize MAL aptamers (methylene blue-labeled, MB-Apt) to form double-stranded DNA structures on an electrode. The presence of MAL induces the removal of aptamers, and hDNA re-forms hairpin structures, causing a decrease in the oxidation current of MB (IMB) and an increase in the oxidation current of Fc (IFc). The ratiometric signal of IFc/IMB responds quantitatively to MAL concentrations. To compare analytical performances, a linear single-stranded DNA (ssDNA) is also used to construct the ssDNA-based aptasensor. We demonstrate that hairpin DNA possessing a rigid two-dimensional structure can improve the assembly efficiency of aptamers and the stability of redox probes. The approach combines the advantages of the ratiometric electrochemical method with hairpin DNA-based conformational switching probes, enabling hDNA-based aptasensor with enhanced sensitivity and reliability, offering a linear range of 0.001 to 1.0 ng mL-1. The platform was applied to detect MAL in lettuce, and the statistical analysis indicated that no significant differences were found between the developed platform and HPLC-MS.

Carboxyl substituted Bambus[6]uril as a novel macrocyclic receptor for cyanide anion: A DFT study

Using density functional theory calculations, the most probable conformation of CN– based carboxyl substituted bambus[6]uril complex was investigated. The molecular complex shows the C3 symmetry in which the cyanide anion resides in the cavity of the macrocyclic complex. The parent macrocycle reduces the diameter of its inner cavity to adjust the anionic specie. Furthermore, we report the AIM and NCI analysis to interpret various non-covalent interactions between the CN– and carboxyl-substituted BU[6] macrocycle. The results of NCI analysis show certain types of noncovalent interactions between the receptor and anion, which are responsible for the stability of the complex. Four N….…H-type interactions between the anion and hydrogen atoms of the methine group in the macrocycle exhibit H-bonds, which are analyzed by QTAIM. The interaction energy of the optimized complex was –81.25 kcal/mol.

A convergent multicomponent synthesis, spectral analysis, molecular modelling and docking studies of novel 2H-pyrido[1,2-a]pyrimidine-2,4(3H)-dione derivatives as potential anti-cervical cancer agents

A series of Novel hybrid 3,3-dimethyl-13-(substituted-phenyl)-3,4,5,13-tetrahydro-1H-pyrido[1′,2′:1,2]pyrimido[4,5-b]quinoline-1,12(2H)-dione derivatives were designed and chemically synthesized in useful yields. The newly synthesized compounds were characterized on the basis of spectral (FT-IR, 1H, 13C NMR, Mass spectral) analyses, and biologically screened in-vitro for their anti-cervical cancer activity against HeLa cancer cell line. The results of cytotoxic evaluation indicated that compounds 7a, 7b, 7c and 7e were appeared to have broad-spectrum cytotoxic activity with IC50 values of 270 µM, 320, 330, and 400 µM, against HeLa cell line. Compound 7a exhibited the most promising inhibitory activity against HeLa cell line as compared to 7b, 7c and 7e. Structural-Activity Relationship (SAR) results show that the presence of electron withdrawing substituents play an important role in the anti-cervical cancer activity of these tested compounds. Moreover, molecular docking studies were conducted to investigate the probable binding conformations of these anti-cancer agents and in-silico ADME (Absorption, Distribution, Metabolism, and Excretion) properties were calculated to predict physicochemical, lipophilicity, pharmacokinetics and medicinal properties of the target compounds.

Antibacterial activity and DNA interaction of triazine iron and ruthenium complexes: spectroscopic, voltammetric and theoretical studies.

The 2,4,6-tris(2-pyridyl)-1,3,5-triazine (tptz), [Ru(μ-tptz)2]Cl2 and [Fe(μ-tptz)2]Cl2, complexes containing Ru (1) and Fe (2) are created. Using electronic absorption spectroscopy, fluorescence spectroscopy, circular dichroism spectroscopy, viscosity measurement and electrochemistry, as well as two complexes with Fish Salmon DNA (FS-DNA), the binding interactions of these complexes were investigated. According to binding assays, complexes bind to DNA through a mild intercalation mechanism, most likely via the DNA helix's base pairs being intercalated by the tptz ligand. Additionally, complex (2) is more capable of binding than complex (1). The electrochemical method offers a quick and easy way to determine the binding constant (Kb). The antibacterial performance of these complexes versus Gram-positive and Gram-negative bacteria was examined using the zone of inhibition test, MIC, and MBC method, and the results revealed that complex (2) exhibits strong antibacterial activity against these bacteria. The outcomes of this investigation will help in understanding DNA interaction mechanisms as well as the creation of a prospective one. Additionally, the density functional theory (DFT) computation included probes of DNA structure and conformation as well as potential pharmacological regulators for particular disorders to fully explain the experimental results.

Theoretical Study on Spectrum and Luminescence Mechanism of Indocyanine Green Dye Based on Density Functional Theory (DFT)

Indocyanine green is a great near-infrared fluorescence with good luminescent properties and important medical applications. In this paper, the theoretical spectrum and orbital model of its molecular level are established. The two most probable conformations were studied, and their energies, vibrational spectra, UV-Vis absorption spectra, frontier molecular orbitals (HOMO and LUMO), and energy gaps were obtained by density functional theory (DFT) calculations, respectively. This provides a theoretical and design basis for the development of novel dyes similar to indocyanine green dyes and a reference case for improved application methods and synthetic predesign of novel fluorescent dyes.

A Spectroscopic Approach to Unravel the Local Conformations of a G-Quadruplex Using CD-Active Fluorescent Base Analogues.

The formation of a stable G-quadruplex (GQ) can inhibit the increased telomerase activity that is common in most cancers. The global structure and the thermal stability of the GQs are usually evaluated by spectroscopic methods and thermal denaturation properties. However, most biochemical processes involving GQs might require local conformational changes at the guanine tetrad (G4) level. These local conformational changes of individual G4 layers during protein and drug interactions have not yet been explored in detail. In this study, we monitored the local conformations of individual G4 layers in GQs using 6-methylisoxanthopterine (6MI) chromophores, which are circular dichroism (CD)-active fluorescent base analogues of guanine, as local conformational probes. A synthetic, tetramolecular, parallel GQ with site-specifically positioned 6MI monomers or dimers was used as the experimental construct. Analytical ultracentrifugation studies and gel electrophoretic studies showed that properly positioned 6MI monomers and dimers could form stable GQs with CD-active fluorescent G4 layers. The local conformation of individual fluorescent G4 layers in the GQ structure was then tracked by monitoring the absorbance, fluorescence intensity, thermal melting, fluorescence quenching, and CD changes of the incorporated probes. Overall, these studies showed that site-specifically incorporated fluorescent base analogues could be used as probes to monitor the local conformational changes of individual G4 layers of a GQ structure. This method can be applied to explore the details of small molecule-GQ interaction at the level of the individual G4 layers, which may prove to be useful in designing drugs to treat GQ-related genetic disorders, cancer, and aging.

Design, Synthesis and Antitumor Activities of Novel Quinazolinone Derivatives as Potential EGFR Inhibitors.

Human epidermal growth factor (EGFR) is an important target for antitumor drug research. A series of novel quinazolinone derivatives were synthesized and developed as potent inhibitors of EGFR. The results showed that most of the aimed compounds had potential anti-tumor cell proliferation activities. Some compounds were tested for their EGFR inhibitory activity. Especially, compound 6d showed the most potent antitumor activity with IC50 values of 1.58 µM against human breast cancer (MCF-7) cell lines and exhibited the most potent EGFR inhibitory activity with IC50 of 0.77 µM. Docking simulation was performed to position compound 6d into the EGFR active site to determine the probable binding conformation.

Narrowing down the conformational space with solid-state NMR in crystal structure prediction of linezolid cocrystals

Many solids crystallize as microcrystalline powders, thus precluding the application of single crystal X-Ray diffraction in structural elucidation. In such cases, a joint use of high-resolution solid-state NMR and crystal structure prediction (CSP) calculations can be successful. However, for molecules showing significant conformational freedom, the CSP-NMR protocol can meet serious obstacles, including ambiguities in NMR signal assignment and too wide conformational search space to be covered by computational methods in reasonable time. Here, we demonstrate a possible way of avoiding these obstacles and making as much use of the two methods as possible in difficult circumstances. In a simple case, our experiments led to crystal structure elucidation of a cocrystal of linezolid (LIN), a wide-range antibiotic, with 2,3-dihydroxybenzoic acid, while a significantly more challenging case of a cocrystal of LIN with 2,4-dihydroxybenzoic acid led to the identification of the most probable conformations of LIN inside the crystal. Having four rotatable bonds, some of which can assume many discreet values, LIN molecule poses a challenge in establishing its conformation in a solid phase. In our work, a set of 27 conformations were used in CSP calculations to yield model crystal structures to be examined against experimental solid-state NMR data, leading to a reliable identification of the most probable molecular arrangements.

Design, Synthesis and Antibacterial Activities of Novel Amide Derivatives Bearing Dioxygenated Rings as Potential β-Ketoacyl-acyl Carrier Protein Synthase III (FabH) Inhibitors.

Fatty acid biosynthesis is essential for bacterial survival. Of these promising targets, β-ketoacyl-acyl carrier protein (ACP) synthase III (FabH) is the most attractive target. FabH would trigger the initiation of fatty acid biosynthesis and it is highly conserved among Gram-positive and -negative bacteria. A series of novel amide derivatives bearing dioxygenated rings were synthesized and developed as potent inhibitors of FabH. These compounds were determined by 1H-NMR, 13C-NMR, MS and further confirmed by crystallographic diffraction study for compound 19. Furthermore, these compounds were evaluated strong broad-spectrum antibacterial activity. Some compounds with potent antibacterial activities were tested for their Escherichia coli (E. coli) FabH inhibitory activity. Especially, compound 19 showed the most potent antibacterial activity with minimum inhibitory concentration (MIC) values of 1.56-3.13 mg/mL against the tested bacterial strains and exhibited the most potent E. coli FabH inhibitory activity with IC50 of 2.4 µM. Docking simulation was performed to position compound 19 into the E. coli FabH active site to determine the probable binding conformation.

AlphaFold2 fails to predict protein fold switching.

AlphaFold2 has revolutionized protein structure prediction by leveraging sequence information to rapidly model protein folds with atomic-level accuracy. Nevertheless, previous work has shown that these predictions tend to be inaccurate for structurally heterogeneous proteins. To systematically assess factors that contribute to this inaccuracy, we tested AlphaFold2's performance on 98-fold-switching proteins, which assume at least two distinct-yet-stable secondary and tertiary structures. Topological similarities were quantified between five predicted and two experimentally determined structures of each fold-switching protein. Overall, 94% of AlphaFold2 predictions captured one experimentally determined conformation but not the other. Despite these biased results, AlphaFold2's estimated confidences were moderate-to-high for 74% of fold-switching residues, a result that contrasts with overall low confidences for intrinsically disordered proteins, which are also structurally heterogeneous. To investigate factors contributing to this disparity, we quantified sequence variation within the multiple sequence alignments used to generate AlphaFold2's predictions of fold-switching and intrinsically disordered proteins. Unlike intrinsically disordered regions, whose sequence alignments show low conservation, fold-switching regions had conservation rates statistically similar to canonical single-fold proteins. Furthermore, intrinsically disordered regions had systematically lower prediction confidences than either fold-switching or single-fold proteins, regardless of sequence conservation. AlphaFold2's high prediction confidences for fold switchers indicate that it uses sophisticated pattern recognition to search for one most probable conformer rather than protein biophysics to model a protein's structural ensemble. Thus, it is not surprising that its predictions often fail for proteins whose properties are not fully apparent from solved protein structures. Our results emphasize the need to look at protein structure as an ensemble and suggest that systematic examination of fold-switching sequences may reveal propensities for multiple stable secondary and tertiary structures.

A Single-Molecule Strategy to Capture Non-native Intramolecular and Intermolecular Protein Disulfide Bridges.

Non-native disulfide bonds are dynamic covalent bridges that form post-translationally between two cysteines within the same protein (intramolecular) or with a neighboring protein (intermolecular), frequently due to changes in the cellular redox potential. The reversible formation of non-native disulfides is intimately linked to alterations in protein function; while they can provide a mechanism to protect against cysteine overoxidation, they are also involved in the early stages of protein multimerization, a hallmark of several protein aggregation diseases. Yet their identification using current protein chemistry technology remains challenging, mainly because of their fleeting reactivity. Here, we use single-molecule spectroscopy AFM and molecular dynamics simulations to capture both intra- and intermolecular disulfide bonds in γD-crystallin, a cysteine-rich, structural human lens protein involved in age-related eye cataracts. Our approach showcases the power of mechanical force as a conformational probe in dynamically evolving proteins and presents a platform to detect non-native disulfide bridges with single-molecule resolution.

CRISPR-Cas9 bends and twists DNA to read its sequence.

In bacterial defense and genome editing applications, the CRISPR-associated protein Cas9 searches millions of DNA base pairs to locate a 20-nucleotide, guide-RNA-complementary target sequence that abuts a protospacer-adjacent motif (PAM). Target capture requires Cas9 to unwind DNA at candidate sequences using an unknown ATP-independent mechanism. Here we show that Cas9 sharply bends and undertwists DNA upon PAM binding, thereby flipping DNA nucleotides out of the duplex and toward the guide RNA for sequence interrogation. Cryo-electron-microscopy (EM) structures of Cas9:RNA:DNA complexes trapped at different states of the interrogation pathway, together with solution conformational probing, reveal that global protein rearrangement accompanies formation of an unstacked DNA hinge. Bend-induced base flipping explains how Cas9 “reads” snippets of DNA to locate target sites within a vast excess of non-target DNA, a process crucial to both bacterial antiviral immunity and genome editing. This mechanism establishes a physical solution to the problem of complementarity-guided DNA search and shows how interrogation speed and local DNA geometry may influence genome editing efficiency.

SYNTHESIS, CHARACTERIZATION, IN SILICO OPTIMIZATION, AND CONFORMATIONAL STUDIES OF METHYL 4-O-PIVALOYL-α-L-RHAMNOPYRANOSIDES

Considering promising biological activities of natural and synthetic rhamnopyranoside esters, we have synthesized several methyl 4-O-pivaloyl-α-L-rhamnopyranosides via selective 2,3-O-acetonide protection of methyl α-L-rhamnopyranoside (4) followed by C-4 pivaloylation, and deprotection. The synthesized 4-O-pivaloate 7 and its 2,3-di-O-esters 8a-e are characterized by spectroscopy and are optimized by using density functional theory (DFT). The free energy and bond angles thus calculated are used to establish the probable conformation(s). The 2,3-O-acetonide protected rhamnopyranosides 5-6 are found to be slightly distorted from the regular 1C4 conformation, and exist between the chair and twist-boat (skew) conformation while other pivaloyl esters 7-8a-e exist in regular 1C4 chair conformation.

Antioxidant and cytotoxic activities of selected salicylidene imines: experimental and computational study.

Selected salicylidene imines were evaluated for their antioxidant and cytotoxic potentials. Several of them exerted potent scavenging capacity towards ABTS radical and hydrogen peroxide. The insight into the preferable antioxidative mechanism was reached employing density functional theory. In the absence of free radicals, the SPLET mechanism is dominant in polar surroundings, while HAT is prevailing in a non-polar environment. The results obtained for the reactions of the most active compounds with some medically relevant radicals pointed out competition between HAT and SPLET mechanisms. The assessment of their cytotoxic properties revealed inhibition of ER-a human breast adenocarcinoma cells or estrogen-independent prostate cancer cells. Molecular docking study with the cyclooxygenase (COX) 2 enzyme was performed to examine the most probable bioactive conformations and possible interactions between the tested derivatives and COX-2 binding pocket.