Molecules

11 pages, 2403 KiB

Open AccessFeature PaperArticle

Potent GH20 N-Acetyl-β-d-hexosaminidase Inhibitors: N-Substituted 3-acetamido-4-amino-5-hydroxymethyl-cyclopentanediols

by Patrick Weber, Seyed A. Nasseri, Bettina M. Pabst, Ana Torvisco, Philipp Müller, Eduard Paschke, Marion Tschernutter, Werner Windischhofer, Stephen G. Withers, Tanja M. Wrodnigg and Arnold E. Stütz

Molecules 2018, 23(3), 708; https://doi.org/10.3390/molecules23030708 - 20 Mar 2018

Cited by 8 | Viewed by 5219

Abstract

From 1,2;3,4-di-O-isopropylidene-d-galactopyranose, a preliminary series of highly functionalized amino(hydroxymethyl)cyclopentanes was easily available. These amine-containing basic carbasugars featuring the d-galacto configuration are potent inhibitors of the GH20 β-d-hexosaminidases probed and may bear potential as regulators of [...] Read more.

From 1,2;3,4-di-O-isopropylidene-d-galactopyranose, a preliminary series of highly functionalized amino(hydroxymethyl)cyclopentanes was easily available. These amine-containing basic carbasugars featuring the d-galacto configuration are potent inhibitors of the GH20 β-d-hexosaminidases probed and may bear potential as regulators of N-acetyl-d-hexosaminidase activities in vivo. Full article

(This article belongs to the Special Issue Glycomimetics: Design, Synthesis and Therapeutic Applications)

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11 pages, 3018 KiB

Open AccessArticle

Antioxidant Activity of Coconut (Cocos nucifera L.) Protein Fractions

by Yan Li, Yajun Zheng, Yufeng Zhang, Jianguo Xu and Gang Gao

Molecules 2018, 23(3), 707; https://doi.org/10.3390/molecules23030707 - 20 Mar 2018

Cited by 43 | Viewed by 7799

Abstract

Coconut cake is an abundant and good potential edible protein source. However, until now it has not been extensively used in the food industry. To promote its usage, the characterization, nutrition value and antioxidant activity of coconut cake protein fractions (albumin, globulin, prolamine, [...] Read more.

Coconut cake is an abundant and good potential edible protein source. However, until now it has not been extensively used in the food industry. To promote its usage, the characterization, nutrition value and antioxidant activity of coconut cake protein fractions (albumin, globulin, prolamine, glutelin-1 and glutelin-2) were studied. Results revealed that all the albumin, globulin, glutelin-1 and glutelin-2 fractions showed a high nutrition value. The prolamine, glutelin-1 and glutelin-2 all exhibited good radical scavenging activity and reducing power, and the globulin and prolamine showed high ion chelating ability (89.14–80.38%). Moreover, all the fractions except glutelin-2 could effectively protect DNA against oxidative damage. Several peptides containing five to eight amino acids with antioxidant activity were also identified by LC-MS/MS from the globulin and glutelin-2 fractions. The results demonstrated that the coconut cake protein fractions have potential usages in functional foods. Full article

(This article belongs to the Special Issue Plant Derived Natural Products and Age Related Diseases)

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17 pages, 6571 KiB

Open AccessArticle

Transcript Profiling and Gene Identification Involved in the Ethylene Signal Transduction Pathways of Creeping Bentgrass (Agrostis stolonifera) during ISR Response Induced by Butanediol

by Han-Yu Jiang, Jin-Lin Zhang, Jiang-Wei Yang and Hui-Ling Ma

Molecules 2018, 23(3), 706; https://doi.org/10.3390/molecules23030706 - 20 Mar 2018

Cited by 8 | Viewed by 4458

Abstract

Creeping bentgrass (Agrostis stolonifera) is the preferred green lawn grass, with excellent turf characteristics but poor disease resistance. At present, the mechanisms of disease resistance in creeping bentgrass are poorly understood, especially the ethylene signal transduction pathway under the induced systemic [...] Read more.

Creeping bentgrass (Agrostis stolonifera) is the preferred green lawn grass, with excellent turf characteristics but poor disease resistance. At present, the mechanisms of disease resistance in creeping bentgrass are poorly understood, especially the ethylene signal transduction pathway under the induced systemic resistance (ISR) response. In this study, butanediol (BDO), as a new type of disease-resistance compound, was applied to creeping bentgrass seedlings to induce the ISR response. Then, we measured ethylene production and related enzyme activities. Additionally, transcript profiling and gene identification were performed in association to ethylene signal transduction pathways. The changes of ethylene production and related enzyme 1-aminocyclopropane-1-carboxylic acid oxidase (ACO) and 1-aminocyclopropane-1-carboxylic acid synthases (ACS) activities showed significant difference at 24 h after Rhizoctonia solani inoculation among five treatments of various BDO concentrations. After 100 µmol L⁻¹ BDO treatment, ethylene production and related enzyme activities reached their peak levels. Additionally, 208,672 unigenes of creeping bentgrass were obtained by de novo assembly. In total, 15,903 annotated unigenes were grouped into 33 canonical pathways in the KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis. Among those, 1803 unigenes were classified as ‘signal transduction’. There were 6766 differentially expressed genes (DEGs) among B24 (inoculated-rhizobacteria in MS medium with 100 µmol L⁻¹ BDO for 24 h), NB24, B72 and NB24 (no rhizobacteria in MS medium with 100 µmol L⁻¹ BDO for 24 h) libraries, and 4,639 DEGs between B24 and B72 (inoculated-rhizobacteria in MS medium with 100 µmol L⁻¹ BDO for 72 h) libraries, with 4489 DEGs in all three libraries. As suggested by the RT-PCR assay, the expression levels of ethylene-responsive and defense-related genes were variable among treated samples during the BDO-induced ISR responses. The expression levels of EIN, ERF, NPR1, PR3 and PR4 genes increased and reached their peaks in the first 24 h after R. solani infection in the BDO-induced ISR reaction compared with NB24 treatments. This results is consistent with the changes of important ethylene biosynthetic enzymes and ethylene concentrations during the BDO-induced ISR responses. We further found the intermediate substances for the signaling pathway, and the relationships between the expression levels of BDO-induced ISR disease-resistance genes and those of the response genes for ethylene signal pathway. Our findings present a genetic basis for systemic resistance of creeping bentgrass through transcriptomic analysis and our study provides a theoretical and practical basis for the improvement of turfgrass disease resistance and quality. Full article

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16 pages, 3564 KiB

Open AccessArticle

Xylobiose Prevents High-Fat Diet Induced Mice Obesity by Suppressing Mesenteric Fat Deposition and Metabolic Dysregulation

by Soo-min Lim, Eunju Kim, Jae-Ho Shin, Pu Reum Seok, Sangwon Jung, Sang-Ho Yoo and Yuri Kim

Molecules 2018, 23(3), 705; https://doi.org/10.3390/molecules23030705 - 20 Mar 2018

Cited by 27 | Viewed by 7007

Abstract

Obesity is a public concern and is responsible for various metabolic diseases. Xylobiose (XB), an alternative sweetener, is a major component of xylo-oligosaccharide. The purpose of this study was to investigate the effects of XB on obesity and its associated metabolic changes in [...] Read more.

Obesity is a public concern and is responsible for various metabolic diseases. Xylobiose (XB), an alternative sweetener, is a major component of xylo-oligosaccharide. The purpose of this study was to investigate the effects of XB on obesity and its associated metabolic changes in related organs. For these studies, mice received a 60% high-fat diet supplemented with 15% d-xylose, 10% XB, or 15% XB as part of the total sucrose content of the diet for ten weeks. Body weight, fat and liver weights, fasting blood glucose, and blood lipids levels were significantly reduced with XB supplementation. Levels of leptin and adipokine were also improved and lipogenic and adipogenic genes in mesenteric fat and liver were down-regulated with XB supplementation. Furthermore, pro-inflammatory cytokines, fatty acid uptake, lipolysis, and β-oxidation-related gene expression levels in mesenteric fat were down-regulated with XB supplementation. Thus, XB exhibited therapeutic potential for treating obesity which involved suppression of fat deposition and obesity-related metabolic disorders. Full article

(This article belongs to the Special Issue Sugar Substitutes and Obesity, Diabetes and Metabolic Syndrome)

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1 pages, 135 KiB

Open AccessErratum

Erratum: Antonsen, S.; et al. Synthesis of Racemic β-Chamigrene, a Spiro[5.5]undecane Sequiterpene. Molecules 2014, 19, 20664–20670

by Molecules Editorial Office

Molecules 2018, 23(3), 704; https://doi.org/10.3390/molecules23030704 - 20 Mar 2018

Viewed by 2790

Abstract

The Molecules Editorial Office wishes to make the following erratum to this paper [1].[...] Full article

12 pages, 1244 KiB

Open AccessArticle

Association of Melatonin Production with Seasonal Changes, Low Temperature, and Immuno-Responses in Hamsters

by Xiaoying Xu, Xiaoyan Liu, Shuran Ma, Ya Xu, Ying Xu, Xiazhen Guo and Dekui Li

Molecules 2018, 23(3), 703; https://doi.org/10.3390/molecules23030703 - 20 Mar 2018

Cited by 13 | Viewed by 5345

Abstract

Seasonal changes impact the melatonin production and immuno-activities in vertebrates. This is believed due to the photoperiodic alterations of the different seasons which impact the functions of pineal gland. The short photoperiod promotes pineal melatonin production. As a result, during the winter, animals [...] Read more.

Seasonal changes impact the melatonin production and immuno-activities in vertebrates. This is believed due to the photoperiodic alterations of the different seasons which impact the functions of pineal gland. The short photoperiod promotes pineal melatonin production. As a result, during the winter, animals have significantly higher levels of melatonin than in summer. However, the seasonal changes also include temperature changes. This factor has never been systemically investigated in animals. In the current study, we observed that increased temperature had limited influence on melatonin production. In contrast, cold temperature is the major factor to induce melatonin production in hamsters. Cold temperature per se can upregulate the expressions of melatonin synthetic gene AANAT and ASMT, which are the important enzymes for melatonin biosynthesis. The elevated melatonin levels induced by the cold exposure in hamster in turn, improve the immuno-responses of the animals with increased levels of IL1, 6, and 10 as well CD3. In addition, melatonin as a potent antioxidant and thermogenic agent would improve the survival chance of animals during cold weather. Full article

(This article belongs to the Special Issue Melatonin as an Antioxidant and a Functionally Pleiotropic Molecule: Synthesis, Metabolism and Activities in Organisms)

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13 pages, 3722 KiB

Open AccessArticle

Bridging from Brain to Tumor Imaging: (S)-(−)- and (R)-(+)-[¹⁸F]Fluspidine for Investigation of Sigma-1 Receptors in Tumor-Bearing Mice

by Mathias Kranz, Ralf Bergmann, Torsten Kniess, Birgit Belter, Christin Neuber, Zhengxin Cai, Gang Deng, Steffen Fischer, Jiangbing Zhou, Yiyun Huang, Peter Brust, Winnie Deuther-Conrad and Jens Pietzsch

Molecules 2018, 23(3), 702; https://doi.org/10.3390/molecules23030702 - 20 Mar 2018

Cited by 9 | Viewed by 5545

Abstract

Sigma-1 receptors (Sig1R) are highly expressed in various human cancer cells and hence imaging of this target with positron emission tomography (PET) can contribute to a better understanding of tumor pathophysiology and support the development of antineoplastic drugs. Two Sig1R-specific radiolabeled enantiomers ( [...] Read more.

Sigma-1 receptors (Sig1R) are highly expressed in various human cancer cells and hence imaging of this target with positron emission tomography (PET) can contribute to a better understanding of tumor pathophysiology and support the development of antineoplastic drugs. Two Sig1R-specific radiolabeled enantiomers (S)-(−)- and (R)-(+)-[¹⁸F]fluspidine were investigated in several tumor cell lines including melanoma, squamous cell/epidermoid carcinoma, prostate carcinoma, and glioblastoma. Dynamic PET scans were performed in mice to investigate the suitability of both radiotracers for tumor imaging. The Sig1R expression in the respective tumors was confirmed by Western blot. Rather low radiotracer uptake was found in heterotopically (subcutaneously) implanted tumors. Therefore, a brain tumor model (U87-MG) with orthotopic implantation was chosen to investigate the suitability of the two Sig1R radiotracers for brain tumor imaging. High tumor uptake as well as a favorable tumor-to-background ratio was found. These results suggest that Sig1R PET imaging of brain tumors with [¹⁸F]fluspidine could be possible. Further studies with this tumor model will be performed to confirm specific binding and the integrity of the blood-brain barrier (BBB). Full article

(This article belongs to the Special Issue Current Aspects of Radiopharmaceutical Chemistry)

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9 pages, 2485 KiB

Open AccessArticle

Synthesis, Characterization, Crystal Structure, and DFT Study of a New Square Planar Cu(II) Complex Containing Bulky Adamantane Ligand

by Monther A. Khanfar, Areej M. Jaber, Murad A. AlDamen and Raed A. Al-Qawasmeh

Molecules 2018, 23(3), 701; https://doi.org/10.3390/molecules23030701 - 20 Mar 2018

Cited by 14 | Viewed by 5336

Abstract

A copper complex with square planar geometry, [(L)CuBr₂] (1), (L = N′-(furan-2-ylmethylene)adamantne-1-carbohydrazide) has been synthesized and characterized by Fourier transfer infrared (FTIR) spectroscopy, elemental analysis, mass spectrometry, and single crystal X-ray diffraction. The crystal of 1 is solved [...] Read more.

A copper complex with square planar geometry, [(L)CuBr₂] (1), (L = N′-(furan-2-ylmethylene)adamantne-1-carbohydrazide) has been synthesized and characterized by Fourier transfer infrared (FTIR) spectroscopy, elemental analysis, mass spectrometry, and single crystal X-ray diffraction. The crystal of 1 is solved as monoclinic, space group P2₁/m with unit cell parameters: a = 10.8030(8), b = 6.6115(8), c = 12.1264(12) Å, β = 101.124(8)°, V = 849.84(15) Å³, Z = 2, and R₁ = 0.0751 with wR₂ = 0.1581 (I > 2 σ). The structure of 1 shows intramolecular hydrogen bonding between the N–H and the furan oxygen which stabilizes the configuration of the complex. Furthermore, inside the lattice there are other weak interactions between bromo ligands and the ligand L. DFT calculations where performed to study the stability of this geometry. Full article

(This article belongs to the Special Issue Metal Complexes of Biological Ligands)

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12 pages, 3784 KiB

Open AccessArticle

Friedelin in Maytenus ilicifolia Is Produced by Friedelin Synthase Isoforms

by Thaís B. Alves, Tatiana M. Souza-Moreira, Sandro R. Valentini, Cleslei F. Zanelli and Maysa Furlan

Molecules 2018, 23(3), 700; https://doi.org/10.3390/molecules23030700 - 20 Mar 2018

Cited by 16 | Viewed by 6620

Abstract

Triterpenes are interesting compounds because they play an important role in cell homeostasis and a wide variety exhibiting defense functions is produced by plant secondary metabolism. Those same plant secondary metabolites also exhibit biological properties with promising therapeutic potential as anti-inflammatory and antitumor [...] Read more.

Triterpenes are interesting compounds because they play an important role in cell homeostasis and a wide variety exhibiting defense functions is produced by plant secondary metabolism. Those same plant secondary metabolites also exhibit biological properties with promising therapeutic potential as anti-inflammatory and antitumor agents. Friedelin is a triterpene ketone with anti-inflammatory and gastroprotective activities and it is a precursor of relevant antitumor quinonemethides. Although many triterpene synthases have been described, only two friedelin synthases were characterized and there is no information about their genomic features and alleles. In the present work, we aimed to identify the gene and new isoforms of friedelin synthase in Maytenus ilicifolia leaves to be functionally characterized in Saccharomyces cerevisiae. The gene sequence analysis elucidated the exon/intron structure and confirmed the presence of single nucleotide polymorphisms with four non-synonymous mutations outside the active site of the enzyme. Therefore, two new isoforms were observed and the heterologous production of the enzymes in yeast showed similar production of friedelin. This first description of different alleles of the gene of friedelin synthase in M. ilicifolia can guide their validation as markers for friedelin-producer specimens. Full article

(This article belongs to the Special Issue Diversity of Terpenoids)

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11 pages, 2705 KiB

Open AccessArticle

Chalcogen ‘like-like’ Interactions Involving Trisulphide and Triselenide Compounds: A Combined CSD and Ab Initio Study

by Antonio Bauzá and Antonio Frontera

Molecules 2018, 23(3), 699; https://doi.org/10.3390/molecules23030699 - 19 Mar 2018

Cited by 21 | Viewed by 4294

Abstract

In this manuscript, we combined a search in the Cambridge Structural Database (CSD) and ab initio calculations (RI-MP2/def2-TZVPD level of theory) to analyze the ability of trisulphide and triselenide moieties to establish chalcogen ‘like-like’ interactions. A preliminary CSD inspection revealed two predominant structural [...] Read more.

In this manuscript, we combined a search in the Cambridge Structural Database (CSD) and ab initio calculations (RI-MP2/def2-TZVPD level of theory) to analyze the ability of trisulphide and triselenide moieties to establish chalcogen ‘like-like’ interactions. A preliminary CSD inspection revealed two predominant structural patterns, depending on the anti or syn conformation adopted by the substituents of the S₃/Se₃ bridge, leading to bifurcated or double chalcogen bonding interactions, respectively. In order to analyze these two relevant structural motifs we have used a series of S and Se derivatives Ch₃X₂ (Ch = S and Se and X = H, F, CN, and CF₃) which act as both electron donor (using the lone pairs) and acceptor (using the σ-holes) entities. Besides, we have carried out “atoms in molecules” (AIM) and natural bonding orbital (NBO) analyses to further describe and characterize the chalcogen bonding interactions described herein. As far as we know, chalcogen···chalcogen interactions involving trichalconides (S₃/Se₃) have not been previously described in literature a may be of great importance in the preparation and characterization of new solids based on this subclass of σ-hole bonding. Full article

(This article belongs to the Special Issue Noncovalent Interactions: A Useful Tool for Crystal Design)

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19 pages, 7554 KiB

Open AccessArticle

Structure-Based Discovery of a Series of 5H-Pyrrolo[2,3-b]pyrazine FGFR Kinase Inhibitors

by Alan Jiang, Qiufeng Liu, Ruifeng Wang, Peng Wei, Yang Dai, Xin Wang, Yechun Xu, Yuchi Ma, Jing Ai, Jingkang Shen, Jian Ding and Bing Xiong

Molecules 2018, 23(3), 698; https://doi.org/10.3390/molecules23030698 - 19 Mar 2018

Cited by 11 | Viewed by 4986

Abstract

Fibroblast growth factor receptors (FGFRs), a subfamily of receptor tyrosine kinases, are aberrant in various cancer types, and considered to be promising targets for cancer therapy. We started with a weak-active compound that was identified from our internal hepatocyte growth factor receptor (also [...] Read more.

Fibroblast growth factor receptors (FGFRs), a subfamily of receptor tyrosine kinases, are aberrant in various cancer types, and considered to be promising targets for cancer therapy. We started with a weak-active compound that was identified from our internal hepatocyte growth factor receptor (also called c-Met) inhibitor project, and optimized it with the guidance of a co-crystal structure of compound 8 with FGFR1. Through rational design, synthesis, and the biological evaluation of a series of 5H-pyrrolo[2,3-b]pyrazine derivatives, we discovered several potent FGFR kinase inhibitors. Among them, compound 13 displayed high selectivity and favorable metabolic properties, demonstrating a promising lead for further development. Full article

(This article belongs to the Section Medicinal Chemistry)

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17 pages, 2590 KiB

Open AccessArticle

Feature-Based and String-Based Models for Predicting RNA-Protein Interaction

by Donald Adjeroh, Maen Allaga, Jun Tan, Jie Lin, Yue Jiang, Ahmed Abbasi and Xiaobo Zhou

Molecules 2018, 23(3), 697; https://doi.org/10.3390/molecules23030697 - 19 Mar 2018

Cited by 16 | Viewed by 5016

Abstract

In this work, we study two approaches for the problem of RNA-Protein Interaction (RPI). In the first approach, we use a feature-based technique by combining extracted features from both sequences and secondary structures. The feature-based approach enhanced the prediction accuracy as it included [...] Read more.

In this work, we study two approaches for the problem of RNA-Protein Interaction (RPI). In the first approach, we use a feature-based technique by combining extracted features from both sequences and secondary structures. The feature-based approach enhanced the prediction accuracy as it included much more available information about the RNA-protein pairs. In the second approach, we apply search algorithms and data structures to extract effective string patterns for prediction of RPI, using both sequence information (protein and RNA sequences), and structure information (protein and RNA secondary structures). This led to different string-based models for predicting interacting RNA-protein pairs. We show results that demonstrate the effectiveness of the proposed approaches, including comparative results against leading state-of-the-art methods. Full article

(This article belongs to the Special Issue Selected Papers from the 10th Computational Structural Bioinformatics Workshop (CSBW-2017))

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15 pages, 4037 KiB

Open AccessArticle

Molecular Modeling and Structural Stability of Wild-Type and Mutant CYP51 from Leishmania major: In Vitro and In Silico Analysis of a Laboratory Strain

by Masoud Keighobadi, Saeed Emami, Milad Lagzian, Mahdi Fakhar, Alireza Rafiei and Reza Valadan

Molecules 2018, 23(3), 696; https://doi.org/10.3390/molecules23030696 - 19 Mar 2018

Cited by 12 | Viewed by 5307

Abstract

Cutaneous leishmaniasis is a neglected tropical disease and a major public health in the most countries. Leishmania major is the most common cause of cutaneous leishmaniasis. In the Leishmania parasites, sterol 14α-demethylase (CYP51), which is involved in the biosynthesis of sterols, has been [...] Read more.

Cutaneous leishmaniasis is a neglected tropical disease and a major public health in the most countries. Leishmania major is the most common cause of cutaneous leishmaniasis. In the Leishmania parasites, sterol 14α-demethylase (CYP51), which is involved in the biosynthesis of sterols, has been identified as an attractive target for development of new therapeutic agents. In this study, the sequence and structure of CYP51 in a laboratory strain (MRHO/IR/75/ER) of L. major were determined and compared to the wild-type strain. The results showed 19 mutations including seven non-synonymous and 12 synonymous ones in the CYP51 sequence of strain MRHO/IR/75/ER. Importantly, an arginine to lysine substitution at position of 474 resulted in destabilization of CYP51 (ΔΔG = 1.17 kcal/mol) in the laboratory strain; however, when the overall effects of all substitutions were evaluated by 100 ns molecular dynamics simulation, the final structure did not show any significant changes (p-value < 0.05) in stability parameter of the strain MRHO/IR/75/ER compared to the wild-type protein. The energy level for the CYP51 of wild-type and MRHO/IR/75/ER strain were −40,027.1 and −39,706.48 Kcal/mol respectively. The overall Root-mean-square deviation (RMSD) deviation between two proteins was less than 1 Å throughout the simulation and Root-mean-square fluctuation (RMSF) plot also showed no substantial differences between amino acids fluctuation of the both protein. The results also showed that, these mutations were located on the protein periphery that neither interferes with protein folding nor with substrate/inhibitor binding. Therefore, L. major strain MRHO/IR/75/ER is suggested as a suitable laboratory model for studying biological role of CYP51 and inhibitory effects of sterol 14α-demethylase inhibitors. Full article

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15 pages, 1971 KiB

Open AccessArticle

Gallic Acid Content and an Antioxidant Mechanism Are Responsible for the Antiproliferative Activity of ‘Ataulfo’ Mango Peel on LS180 Cells

by Gustavo. R. Velderrain-Rodríguez, Heriberto Torres-Moreno, Mónica A. Villegas-Ochoa, J. Fernando Ayala-Zavala, Ramón E. Robles-Zepeda, Abraham Wall-Medrano and Gustavo A. González-Aguilar

Molecules 2018, 23(3), 695; https://doi.org/10.3390/molecules23030695 - 19 Mar 2018

Cited by 100 | Viewed by 9038

Abstract

Mango “Ataulfo” peel is a rich source of polyphenols (PP), with antioxidant and anti-cancer properties; however, it is unknown whether such antiproliferative activity is related to PP’s antioxidant activity. The content (HPLC-DAD), antioxidant (DPPH, FRAP, ORAC), and antiproliferative activities (MTT) of free (FP) [...] Read more.

Mango “Ataulfo” peel is a rich source of polyphenols (PP), with antioxidant and anti-cancer properties; however, it is unknown whether such antiproliferative activity is related to PP’s antioxidant activity. The content (HPLC-DAD), antioxidant (DPPH, FRAP, ORAC), and antiproliferative activities (MTT) of free (FP) and chemically-released PP from mango ‘Ataulfo’ peel after alkaline (AKP) and acid (AP) hydrolysis, were evaluated. AKP fraction was higher (µg/g DW) in gallic acid (GA; 23,816 ± 284) than AP (5610 ± 8) of FR (not detected) fractions. AKP fraction and GA showed the highest antioxidant activity (DPPH/FRAP/ORAC) and GA’s antioxidant activity follows a single electron transfer (SET) mechanism. AKP and GA also showed the best antiproliferative activity against human colon adenocarcinoma cells (LS180; IC₅₀ (µg/mL) 138.2 ± 2.5 and 45.7 ± 5.2) and mouse connective cells (L929; 93.5 ± 7.7 and 65.3 ± 1.2); Cheminformatics confirmed the hydrophilic nature (LogP, 0.6) and a good absorption capacity (75%) for GA. Data suggests that GA’s antiproliferative activity appears to be related to its antioxidant mechanism, although other mechanisms after its absorption could also be involved. Full article

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10 pages, 2898 KiB

Open AccessCommunication

π-π Conjugation Enhances Oligostilbene’s Antioxidant Capacity: Evidence from α-Viniferin and Caraphenol A

by Xican Li, Yulu Xie, Hong Xie, Jian Yang and Dongfeng Chen

Molecules 2018, 23(3), 694; https://doi.org/10.3390/molecules23030694 - 19 Mar 2018

Cited by 25 | Viewed by 4813

Abstract

α-Viniferin and caraphenol A, the two oligostilbenes, have the sole difference of the presence or absence of an exocyclic double bond at the π-π conjugative site. In this study, the antioxidant capacity and relevant mechanisms for α-viniferin and caraphenol A were comparatively explored [...] Read more.

α-Viniferin and caraphenol A, the two oligostilbenes, have the sole difference of the presence or absence of an exocyclic double bond at the π-π conjugative site. In this study, the antioxidant capacity and relevant mechanisms for α-viniferin and caraphenol A were comparatively explored using spectrophotometry, UV-visible spectral analysis, and electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UPLC–ESI–Q–TOF–MS/MS) analysis. The spectrophotometric results suggested that caraphenol A always gave lower IC₅₀ values than α-viniferin in cupric ion-reducing antioxidant capacity assay, ferric-reducing antioxidant power assay, 1,1-diphenyl-2-picryl-hydrazl radical (DPPH•)-scavenging, and 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide radical-scavenging assays. In UV-visible spectra analysis, caraphenol A was observed to show enhanced peaks at 250–350 nm when mixed with Fe²⁺, but α-viniferin exhibited no similar effects. UPLC–ESI–Q–TOF–MS/MS analysis revealed that α-viniferin mixed with DPPH• produced radical adduct formation (RAF) peak (m/z = 1070–1072). We conclude that the antioxidant action of α-viniferin and caraphenol A may involve both redox-mediated mechanisms (especially electron transfer and H⁺-transfer) and non-redox-mediated mechanisms (including Fe²⁺-chelating or RAF). The π-π conjugation of the exocyclic double bond in caraphenol A can greatly enhance the redox-mediated antioxidant mechanisms and partially promote the Fe²⁺-chelating mechanism. This makes caraphenol A far superior to α-viniferin in total antioxidant levels. Full article

(This article belongs to the Special Issue The Antioxidant Capacities of Natural Products)

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24 pages, 4066 KiB

Open AccessArticle

Synthesis of Some Novel Fused Pyrimido[4″,5″:5′,6′]-[1,2,4]triazino[3′,4′:3,4] [1,2,4]triazino[5,6-b]indoles with Expected Anticancer Activity

by Rania S. Ali and Hosam A. Saad

Molecules 2018, 23(3), 693; https://doi.org/10.3390/molecules23030693 - 19 Mar 2018

Cited by 12 | Viewed by 5049

Abstract

Our current goal is the synthesis of polyheterocyclic compounds starting from 3-amino-[1,2,4]triazino[5,6-b]indole 1 and studying their anticancer activity to determine whether increasing of the size of the molecules increases the anticancer activity or not. 1-Amino[1,2,4]triazino[3′,4′:3,4]-[1,2,4]triazino[5,6-b]indole-2-carbonitrile (4) was [...] Read more.

Our current goal is the synthesis of polyheterocyclic compounds starting from 3-amino-[1,2,4]triazino[5,6-b]indole 1 and studying their anticancer activity to determine whether increasing of the size of the molecules increases the anticancer activity or not. 1-Amino[1,2,4]triazino[3′,4′:3,4]-[1,2,4]triazino[5,6-b]indole-2-carbonitrile (4) was prepared by the diazotization of 3-amino[1,2,4]-triazino[5,6-b]indole 1 followed by coupling with malononitrile in basic medium then cyclization under reflux to get 4. Also, new fused pyrimido[4″,5″:5′,6′][1,2,4]triazino-[3′,4′:3,4][1,2,4]triazino[5,6-b]indole derivative 6 was prepared and used to obtain polycyclic heterocyclic systems. Confirmation of the synthesized compounds’ structures was carried out using elemental analyses and spectral data (IR, ¹H-NMR and ¹³C-NMR and mass spectra). The anticancer activity of some of the synthesized compounds was tested against HepG2, HCT-116 and MCF-7 cell lines. The anticancer screening results showed that some derivatives display good activity which was more potent than that of the reference drug used. Molecular docking was used to predict the binding between some of the synthesized compounds and the prostate cancer 2q7k hormone and breast ‎cancer 3hb5 receptors. Full article

(This article belongs to the Collection Heterocyclic Compounds)

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21 pages, 601 KiB

Open AccessReview

Anticancer Activity of Toxins from Bee and Snake Venom—An Overview on Ovarian Cancer

by Marius Alexandru Moga, Oana Gabriela Dimienescu, Cristian Andrei Arvătescu, Petru Ifteni and Liana Pleş

Molecules 2018, 23(3), 692; https://doi.org/10.3390/molecules23030692 - 19 Mar 2018

Cited by 43 | Viewed by 10040

Abstract

Cancer represents the disease of the millennium, a major problem in public health. The proliferation of tumor cells, angiogenesis, and the relationship between the cancer cells and the components of the extracellular matrix are important in the events of carcinogenesis, and these pathways [...] Read more.

Cancer represents the disease of the millennium, a major problem in public health. The proliferation of tumor cells, angiogenesis, and the relationship between the cancer cells and the components of the extracellular matrix are important in the events of carcinogenesis, and these pathways are being used as targets for new anticancer treatments. Various venoms and their toxins have shown possible anticancer effects on human cancer cell lines, providing new perspectives in drug development. In this review, we observed the effects of natural toxins from bee and snake venom and the mechanisms through which they can inhibit the growth and proliferation of cancer cells. We also researched how several types of natural molecules from venom can sensitize ovarian cancer cells to conventional chemotherapy, with many toxins being helpful for developing new anticancer drugs. This approach could improve the efficiency of standard therapies and could allow the administration of decreased doses of chemotherapy. Natural toxins from bee and snake venom could become potential candidates for the future treatment of different types of cancer. It is important to continue these studies concerning therapeutic drugs from natural resource and, more importantly, to investigate their mechanism of action on cancer cells. Full article

(This article belongs to the Special Issue Natural Toxins/Molecules (and Derivatives) from Animal Venoms: From Basic Research to Therapeutic Applications)

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15 pages, 4016 KiB

Open AccessArticle

Efficient (3S)-Acetoin and (2S,3S)-2,3-Butanediol Production from meso-2,3-Butanediol Using Whole-Cell Biocatalysis

by Yuanzhi He, Feixue Chen, Meijing Sun, Huifang Gao, Zewang Guo, Hui Lin, Jiebo Chen, Wensong Jin, Yunlong Yang, Liaoyuan Zhang and Jun Yuan

Molecules 2018, 23(3), 691; https://doi.org/10.3390/molecules23030691 - 19 Mar 2018

Cited by 32 | Viewed by 5705

Abstract

(3S)-Acetoin and (2S,3S)-2,3-butanediol are important platform chemicals widely applied in the asymmetric synthesis of valuable chiral chemicals. However, their production by fermentative methods is difficult to perform. This study aimed to develop a whole-cell biocatalysis strategy for [...] Read more.

(3S)-Acetoin and (2S,3S)-2,3-butanediol are important platform chemicals widely applied in the asymmetric synthesis of valuable chiral chemicals. However, their production by fermentative methods is difficult to perform. This study aimed to develop a whole-cell biocatalysis strategy for the production of (3S)-acetoin and (2S,3S)-2,3-butanediol from meso-2,3-butanediol. First, E. coli co-expressing (2R,3R)-2,3-butanediol dehydrogenase, NADH oxidase and Vitreoscilla hemoglobin was developed for (3S)-acetoin production from meso-2,3-butanediol. Maximum (3S)-acetoin concentration of 72.38 g/L with the stereoisomeric purity of 94.65% was achieved at 24 h under optimal conditions. Subsequently, we developed another biocatalyst co-expressing (2S,3S)-2,3-butanediol dehydrogenase and formate dehydrogenase for (2S,3S)-2,3-butanediol production from (3S)-acetoin. Synchronous catalysis together with two biocatalysts afforded 38.41 g/L of (2S,3S)-butanediol with stereoisomeric purity of 98.03% from 40 g/L meso-2,3-butanediol. These results exhibited the potential for (3S)-acetoin and (2S,3S)-butanediol production from meso-2,3-butanediol as a substrate via whole-cell biocatalysis. Full article

(This article belongs to the Special Issue Frontier in Biocatalysis for Organic Synthesis)

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19 pages, 352 KiB

Open AccessArticle

Representation Learning for Class C G Protein-Coupled Receptors Classification

by Raúl Cruz-Barbosa, Erik-German Ramos-Pérez and Jesús Giraldo

Molecules 2018, 23(3), 690; https://doi.org/10.3390/molecules23030690 - 19 Mar 2018

Cited by 3 | Viewed by 4035

Abstract

G protein-coupled receptors (GPCRs) are integral cell membrane proteins of relevance for pharmacology. The complete tertiary structure including both extracellular and transmembrane domains has not been determined for any member of class C GPCRs. An alternative way to work on GPCR structural models [...] Read more.

G protein-coupled receptors (GPCRs) are integral cell membrane proteins of relevance for pharmacology. The complete tertiary structure including both extracellular and transmembrane domains has not been determined for any member of class C GPCRs. An alternative way to work on GPCR structural models is the investigation of their functionality through the analysis of their primary structure. For this, sequence representation is a key factor for the GPCRs’ classification context, where usually, feature engineering is carried out. In this paper, we propose the use of representation learning to acquire the features that best represent the class C GPCR sequences and at the same time to obtain a model for classification automatically. Deep learning methods in conjunction with amino acid physicochemical property indices are then used for this purpose. Experimental results assessed by the classification accuracy, Matthews’ correlation coefficient and the balanced error rate show that using a hydrophobicity index and a restricted Boltzmann machine (RBM) can achieve performance results (accuracy of 92.9%) similar to those reported in the literature. As a second proposal, we combine two or more physicochemical property indices instead of only one as the input for a deep architecture in order to add information from the sequences. Experimental results show that using three hydrophobicity-related index combinations helps to improve the classification performance (accuracy of 94.1%) of an RBM better than those reported in the literature for class C GPCRs without using feature selection methods. Full article

(This article belongs to the Special Issue Computational Analysis for Protein Structure and Interaction)

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19 pages, 4150 KiB

Open AccessArticle

Screening of Genes Related to Early and Late Flowering in Tree Peony Based on Bulked Segregant RNA Sequencing and Verification by Quantitative Real-Time PCR

by Xiaogai Hou, Qi Guo, Weiqiang Wei, Lili Guo, Dalong Guo and Lin Zhang

Molecules 2018, 23(3), 689; https://doi.org/10.3390/molecules23030689 - 19 Mar 2018

Cited by 32 | Viewed by 5473

Abstract

Tree peony (Paeonia suffruticosa Andrews) is a perennial woody shrub bearing large and colorful flowers. However, the flowering period is short and relatively uniform, which to an important extent hinders the cultivation and exploitation of ornamental peonies. In this study, the segregation [...] Read more.

Tree peony (Paeonia suffruticosa Andrews) is a perennial woody shrub bearing large and colorful flowers. However, the flowering period is short and relatively uniform, which to an important extent hinders the cultivation and exploitation of ornamental peonies. In this study, the segregation of an F₁ population derived from P. ostti ‘Feng Dan’ (an early-flowering cultivar) × P. suffruticosa ‘Xin Riyuejin’ (a late-flowering cultivar) was used to screen and analyze candidate genes associated with flowering period of the two parents. Extreme early- and late-flowering genotypes of the F₁ population at full-bloom stage were sampled to establish an early-flowering mixed pool (T03), a late-flowering mixed pool (T04), a late-flowering male pool (T01), and an early-flowering female pool (T02), using the Sequencing By Synthesis (SBS) technology on the Illumina HiSeq TM2500 platform. A total of 56.51 Gb of clean reads data, comprising at least 87.62% of Quality30 (Q30), was generated, which was then combined into 173,960 transcripts (N50 = 1781) and 78,645 (N50 = 1282) unigenes, with a mean length of 1106.76 and 732.27 base pairs (bp), respectively. Altogether, 58,084 genes were annotated by comparison with public databases, based on an E-value parameter of less than 10⁻⁵ and 10⁻¹⁰ for BLAST and HMMER, respectively. In total, 291 unigene sequences were finally screened out by BSR-seq (bulked segregant RNA-seq) association analysis. To validate these unigenes, we finally confirmed seven unigenes that were related to early and late flowering, which were then verified by quantitative real-time PCR (qRT-PCR). This is the first reported study to screen genes associated with early and late flowering of tree peony by the BSA (bulked sample analysis) method of transcriptome sequencing, and to construct a high-quality transcriptome database. A set of candidate functional genes related to flowering time was successfully obtained, providing an important genetic resource for further studies of flowering in peony and the mechanism of regulation of flowering time in tree peony. Full article

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15 pages, 2458 KiB

Open AccessArticle

Atypical Kinetics and Albumin Effect of Glucuronidation of 5-n-Butyl-4-{4-[2-(1H-tetrazole-5- yl)-1H-pyrrol-1-yl]phenylmethyl}-2,4-dihydro-2-(2,6- dichlorophenyl)-3H-1,2,4-triazol-3-one, a Novel Nonpeptide Angiotensin Type 1 Receptor Antagonist, in Liver Microsomes and UDP-Glucuronosyl-transferase

by Ying Peng, Xueyuan Zhang, Yinci Zhu, Hui Wu, Shiyin Gu, Qingqing Chang, Yi Zhou, Guangji Wang and Jianguo Sun

Molecules 2018, 23(3), 688; https://doi.org/10.3390/molecules23030688 - 19 Mar 2018

Cited by 3 | Viewed by 3988

Abstract

Ib is a new nonpeptide AT1 receptor antagonist, which plays an active role in cardiovascular protection. Ib monoglucuronide has been identified as its main metabolite. A detailed study of Ib glucuronidation is important for predicting potential DDI. Besides, the elucidation of the “BSA [...] Read more.

Ib is a new nonpeptide AT1 receptor antagonist, which plays an active role in cardiovascular protection. Ib monoglucuronide has been identified as its main metabolite. A detailed study of Ib glucuronidation is important for predicting potential DDI. Besides, the elucidation of the “BSA effect” in Ib glucuronidation would make obtained kinetic parameters more predictive in IVIVE. “BSA effect” means that there is a significant change in in vitro kinetic parameters when generated from incubations performed in the presence of bovine serum albumin (BSA). Five UGTs (UGT1A3, UGT2B4, UGT2B7, UGT1A9 and UGT1A8) were identified that produced abundant Ib monoglucuronide, especially UGT1A3. We investigated Ib glucuronidation in liver microsomes from different species (rat, dog, human) and in five identified major human UGTs. Ib glucuronidation in liver microsomes and recombinant human UGTs all showed substrate inhibition kinetics. DLM showed the strongest affinity and activity, HLM showed the lowest affinity, and RLM showed the weakest activity. The addition of BSA did not alter the enzyme kinetics, but significantly altered enzyme kinetic parameters resulting in a reduction in K_m value and an increase in CL_int value. However, high concentrations of BSA could significantly attenuate this positive effect on enzyme affinity and activity, and the effect of BSA on the V_max of Ib glucuronidation was opposite in different enzyme sources. In conclusion, this study demonstrated the substrate inhibition kinetics of Ib glucuronidation in the liver metabolism and the effect of BSA on its kinetic parameters, in order to provide more accurate in vitro data for in vivo prediction. Full article

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14 pages, 5097 KiB

Open AccessArticle

Miro1 Enhances Mitochondria Transfer from Multipotent Mesenchymal Stem Cells (MMSC) to Neural Cells and Improves the Efficacy of Cell Recovery

by Valentina A. Babenko, Denis N. Silachev, Vasily A. Popkov, Ljubava D. Zorova, Irina B. Pevzner, Egor Y. Plotnikov, Gennady T. Sukhikh and Dmitry B. Zorov

Molecules 2018, 23(3), 687; https://doi.org/10.3390/molecules23030687 - 19 Mar 2018

Cited by 146 | Viewed by 11081

Abstract

A recently discovered key role of reactive oxygen species (ROS) in mitochondrial traffic has opened a wide alley for studying the interactions between cells, including stem cells. Since its discovery in 2006, intercellular mitochondria transport has been intensively studied in different cellular models [...] Read more.

A recently discovered key role of reactive oxygen species (ROS) in mitochondrial traffic has opened a wide alley for studying the interactions between cells, including stem cells. Since its discovery in 2006, intercellular mitochondria transport has been intensively studied in different cellular models as a basis for cell therapy, since the potential of replacing malfunctioning organelles appears to be very promising. In this study, we explored the transfer of mitochondria from multipotent mesenchymal stem cells (MMSC) to neural cells and analyzed its efficacy under normal conditions and upon induction of mitochondrial damage. We found that mitochondria were transferred from the MMSC to astrocytes in a more efficient manner when the astrocytes were exposed to ischemic damage associated with elevated ROS levels. Such transport of mitochondria restored the bioenergetics of the recipient cells and stimulated their proliferation. The introduction of MMSC with overexpressed Miro1 in animals that had undergone an experimental stroke led to significantly improved recovery of neurological functions. Our data suggest that mitochondrial impairment in differentiated cells can be compensated by receiving healthy mitochondria from MMSC. We demonstrate a key role of Miro1, which promotes the mitochondrial transfer from MMSC and suggest that the genetic modification of stem cells can improve the therapies for the injured brain. Full article

(This article belongs to the Special Issue Biology of Reactive Oxygen and Nitrogen Species: Redox Signaling, Metabolic Effects, Cellular Functions and Oxidative Damage)

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20 pages, 10809 KiB

Open AccessArticle

Diabetes Drug Discovery: hIAPP_1–37 Polymorphic Amyloid Structures as Novel Therapeutic Targets

by Isaac Fernández-Gómez, Marquiza Sablón-Carrazana, Alberto Bencomo-Martínez, Guadalupe Domínguez, Reyna Lara-Martínez, Nelly F. Altamirano-Bustamante, Luis Felipe Jiménez-García, Karina Pasten-Hidalgo, Rosa Angélica Castillo-Rodríguez, Perla Altamirano, Suchitil Rivera Marrero, Cristina Revilla-Monsalve, Peter Valdés-Sosa, Fabio Salamanca-Gómez, Eulalia Garrido-Magaña, Chryslaine Rodríguez-Tanty and Myriam M. Altamirano-Bustamante

Molecules 2018, 23(3), 686; https://doi.org/10.3390/molecules23030686 - 19 Mar 2018

Cited by 19 | Viewed by 5742

Abstract

Human islet amyloid peptide (hIAPP_1–37) aggregation is an early step in Diabetes Mellitus. We aimed to evaluate a family of pharmaco-chaperones to act as modulators that provide dynamic interventions and the multi-target capacity (native state, cytotoxic oligomers, protofilaments and fibrils of [...] Read more.

Human islet amyloid peptide (hIAPP_1–37) aggregation is an early step in Diabetes Mellitus. We aimed to evaluate a family of pharmaco-chaperones to act as modulators that provide dynamic interventions and the multi-target capacity (native state, cytotoxic oligomers, protofilaments and fibrils of hIAPP_1–37) required to meet the treatment challenges of diabetes. We used a cross-functional approach that combines in silico and in vitro biochemical and biophysical methods to study the hIAPP_1–37 aggregation-oligomerization process as to reveal novel potential anti-diabetic drugs. The family of pharmaco-chaperones are modulators of the oligomerization and fibre formation of hIAPP_1–37. When they interact with the amino acid in the amyloid-like steric zipper zone, they inhibit and/or delay the aggregation-oligomerization pathway by binding and stabilizing several amyloid structures of hIAPP_1–37. Moreover, they can protect cerebellar granule cells (CGC) from the cytotoxicity produced by the hIAPP_1–37 oligomers. The modulation of proteostasis by the family of pharmaco-chaperones A–F is a promising potential approach to limit the onset and progression of diabetes and its comorbidities. Full article

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21 pages, 4810 KiB

Open AccessReview

Thiazoles and Thiazolidinones as COX/LOX Inhibitors

by Konstantinos Liaras, Maria Fesatidou and Athina Geronikaki

Molecules 2018, 23(3), 685; https://doi.org/10.3390/molecules23030685 - 18 Mar 2018

Cited by 119 | Viewed by 10171

Abstract

Inflammation is a natural process that is connected to various conditions and disorders such as arthritis, psoriasis, cancer, infections, asthma, etc. Based on the fact that cyclooxygenase isoenzymes (COX-1, COX-2) are responsible for the production of prostaglandins that play an important role in [...] Read more.

Inflammation is a natural process that is connected to various conditions and disorders such as arthritis, psoriasis, cancer, infections, asthma, etc. Based on the fact that cyclooxygenase isoenzymes (COX-1, COX-2) are responsible for the production of prostaglandins that play an important role in inflammation, traditional treatment approaches include administration of non-steroidal anti-inflammatory drugs (NSAIDs), which act as selective or non-selective COX inhibitors. Almost all of them present a number of unwanted, often serious, side effects as a consequence of interference with the arachidonic acid cascade. In search for new drugs to avoid side effects, while maintaining high potency over inflammation, scientists turned their interest to the synthesis of dual COX/LOX inhibitors, which could provide numerous therapeutic advantages in terms of anti-inflammatory activity, improved gastric protection and safer cardiovascular profile compared to conventional NSAIDs. Τhiazole and thiazolidinone moieties can be found in numerous biologically active compounds of natural origin, as well as synthetic molecules that possess a wide range of pharmacological activities. This review focuses on the biological activity of several thiazole and thiazolidinone derivatives as COX-1/COX-2 and LOX inhibitors. Full article

(This article belongs to the Special Issue Recent Trends on Enzymes Inhibitors and Activators in Drug Research)

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15 pages, 5163 KiB

Open AccessArticle

A Greener and Efficient Method for Nucleophilic Aromatic Substitution of Nitrogen-Containing Fused Heterocycles

by Joana F. Campos, Mohammed Loubidi, Marie-Christine Scherrmann and Sabine Berteina-Raboin

Molecules 2018, 23(3), 684; https://doi.org/10.3390/molecules23030684 - 18 Mar 2018

Cited by 15 | Viewed by 6631

Abstract

A simple and efficient methodology for the nucleophilic aromatic substitution of nitrogen-containing fused heterocycles with interesting biological activities has been developed in an environmentally sound manner using polyethylene glycol (PEG-400) as the solvent, leading to the expected compounds in excellent yields in only [...] Read more.

A simple and efficient methodology for the nucleophilic aromatic substitution of nitrogen-containing fused heterocycles with interesting biological activities has been developed in an environmentally sound manner using polyethylene glycol (PEG-400) as the solvent, leading to the expected compounds in excellent yields in only five minutes. Full article

(This article belongs to the Special Issue Focusing on Sulfur in Medicinal Chemistry)

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8 pages, 1228 KiB

Open AccessArticle

Hyperjaponol H, A New Bioactive Filicinic Acid-Based Meroterpenoid from Hypericum japonicum Thunb. ex Murray

by Rongrong Wu, Zijun Le, Zhenzhen Wang, Shuying Tian, Yongbo Xue, Yong Chen, Linzhen Hu and Yonghui Zhang

Molecules 2018, 23(3), 683; https://doi.org/10.3390/molecules23030683 - 18 Mar 2018

Cited by 14 | Viewed by 5264

Abstract

Hyperjaponol H (1), a new filicinic acid-based meroterpenoid, with a 6/6/10 ring system trans-fused by hetero-Diels–Alder cycloaddition between a germacrane sesquiterpenoid and a filicinic acid moiety, was isolated from aerial parts of Hypericum japonicum. The elucidation of its structure [...] Read more.

Hyperjaponol H (1), a new filicinic acid-based meroterpenoid, with a 6/6/10 ring system trans-fused by hetero-Diels–Alder cycloaddition between a germacrane sesquiterpenoid and a filicinic acid moiety, was isolated from aerial parts of Hypericum japonicum. The elucidation of its structure and absolute configuration were accomplished by the analyses of extensive spectroscopic data and the comparison of Cotton effects of electron circular dichroism (ECD) with previously reported ones. The bioactivity assay showed that hyperjaponol H exhibited a moderate inhibitory efficacy on lytic Epstein-Barr virus (EBV) DNA replication in B95-8 cells. Full article

(This article belongs to the Collection Bioactive Compounds)

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18 pages, 4960 KiB

Open AccessArticle

Synthesis of Nanometer Sized Bis- and Tris-trityl Model Compounds with Different Extent of Spin–Spin Coupling

by J. Jacques Jassoy, Andreas Meyer, Sebastian Spicher, Christine Wuebben and Olav Schiemann

Molecules 2018, 23(3), 682; https://doi.org/10.3390/molecules23030682 - 17 Mar 2018

Cited by 19 | Viewed by 6362

Abstract

Tris(2,3,5,6-tetrathiaaryl)methyl radicals, so-called trityl radicals, are emerging as spin labels for distance measurements in biological systems based on Electron Paramagnetic Resonance (EPR). Here, the synthesis and characterization of rigid model systems carrying either two or three trityl moieties is reported. The monofunctionalized trityl [...] Read more.

Tris(2,3,5,6-tetrathiaaryl)methyl radicals, so-called trityl radicals, are emerging as spin labels for distance measurements in biological systems based on Electron Paramagnetic Resonance (EPR). Here, the synthesis and characterization of rigid model systems carrying either two or three trityl moieties is reported. The monofunctionalized trityl radicals are connected to the molecular bridging scaffold via an esterification reaction employing the Mukaiyama reagent 2-chloro-methylpyridinium iodide. The bis- and tris-trityl compounds exhibit different inter-spin distances, strength of electron–electron exchange and dipolar coupling and can give rise to multi-spin effects. They are to serve as benchmark systems in comparing EPR distance measurement methods. Full article

(This article belongs to the Special Issue Radical Chemistry)

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16 pages, 777 KiB

Open AccessReview

Transdermal and Topical Drug Administration in the Treatment of Pain

by Wojciech Leppert, Malgorzata Malec–Milewska, Renata Zajaczkowska and Jerzy Wordliczek

Molecules 2018, 23(3), 681; https://doi.org/10.3390/molecules23030681 - 17 Mar 2018

Cited by 117 | Viewed by 20184

Abstract

The comprehensive treatment of pain is multidimodal, with pharmacotherapy playing a key role. An effective therapy for pain depends on the intensity and type of pain, the patients’ age, comorbidities, and appropriate choice of analgesic, its dose and route of administration. This review [...] Read more.

The comprehensive treatment of pain is multidimodal, with pharmacotherapy playing a key role. An effective therapy for pain depends on the intensity and type of pain, the patients’ age, comorbidities, and appropriate choice of analgesic, its dose and route of administration. This review is aimed at presenting current knowledge on analgesics administered by transdermal and topical routes for physicians, nurses, pharmacists, and other health care professionals dealing with patients suffering from pain. Analgesics administered transdermally or topically act through different mechanisms. Opioids administered transdermally are absorbed into vessels located in subcutaneous tissue and, subsequently, are conveyed in the blood to opioid receptors localized in the central and peripheral nervous system. Non–steroidal anti–inflammatory drugs (NSAIDs) applied topically render analgesia mainly through a high concentration in the structures of the joint and a provision of local anti–inflammatory effects. Topically administered drugs such as lidocaine and capsaicin in patches, capsaicin in cream, EMLA cream, and creams containing antidepressants (i.e., doxepin, amitriptyline) act mainly locally in tissues through receptors and/or ion channels. Transdermal and topical routes offer some advantages over systemic analgesic administration. Analgesics administered topically have a much better profile for adverse effects as they relieve local pain with minimal systemic effects. The transdermal route apart from the above-mentioned advantages and provision of long period of analgesia may be more convenient, especially for patients who are unable to take drugs orally. Topically and transdermally administered opioids are characterised by a lower risk of addiction compared to oral and parenteral routes. Full article

(This article belongs to the Special Issue Medicinal Chemistry in Europe)

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6 pages, 1186 KiB

Open AccessArticle

Anticancer Phenolics from Dryopteris fragrans (L.) Schott

by Zhen-Dong Liu, Dan-Dan Zhao, Shuai Jiang, Bei Xue, Yan-Long Zhang and Xiu-Feng Yan

Molecules 2018, 23(3), 680; https://doi.org/10.3390/molecules23030680 - 17 Mar 2018

Cited by 12 | Viewed by 4813

Abstract

Cancer is one of the most major diseases that threatens human health and life. The aim of this work was to obtain novel anticancer molecules from D. fragrans, a kind of medicinal plant. The structure of the new compound was identified using [...] Read more.

Cancer is one of the most major diseases that threatens human health and life. The aim of this work was to obtain novel anticancer molecules from D. fragrans, a kind of medicinal plant. The structure of the new compound was identified using spectroscopic data (¹H-NMR, ¹³C-NMR and two dimensions NMR). Its anticancer properties were evaluated using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay against four human cells including lung cancer cells (A549), breast cancer cells (MCF-7), gastric cancer cells (SGC7901) and noncancerous human umbilical vein endothelial cells (HUVEC). A new phenylpropanoid—(E)-caffeic acid-9-O-β-d-xylpyranosyl-(1→2)-β-d-glucopyranosyl ester (1), with seven known compounds (2–8)—was isolated. The IC₅₀ value of compound 1 against MCF-7 cells was 2.65 ± 0.14 µM, and the IC₅₀ values of compound 8 against three cancer cells were below 20 µM. Full article

(This article belongs to the Collection Natural Products: Anticancer Potential and Beyond)

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19 pages, 1335 KiB

Open AccessFeature PaperArticle

Novel Semisynthetic Derivatives of Bile Acids as Effective Tyrosyl-DNA Phosphodiesterase 1 Inhibitors

by Oksana V. Salomatina, Irina I. Popadyuk, Alexandra L. Zakharenko, Olga D. Zakharova, Dmitriy S. Fadeev, Nina I. Komarova, Jóhannes Reynisson, H. John Arabshahi, Raina Chand, Konstantin P. Volcho, Nariman F. Salakhutdinov and Olga I. Lavrik

Molecules 2018, 23(3), 679; https://doi.org/10.3390/molecules23030679 - 17 Mar 2018

Cited by 24 | Viewed by 5408

Abstract

An Important task in the treatment of oncological and neurodegenerative diseases is the search for new inhibitors of DNA repair system enzymes. Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is one of the DNA repair system enzymes involved in the removal of DNA damages caused by [...] Read more.

An Important task in the treatment of oncological and neurodegenerative diseases is the search for new inhibitors of DNA repair system enzymes. Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is one of the DNA repair system enzymes involved in the removal of DNA damages caused by topoisomerase I inhibitors. Thus, reducing the activity of Tdp1 can increase the effectiveness of currently used anticancer drugs. We describe here a new class of semisynthetic small molecule Tdp1 inhibitors based on the bile acid scaffold that were originally identified by virtual screening. The influence of functional groups of bile acids (hydroxy and acetoxy groups in the steroid framework and amide fragment in the side chain) on inhibitory activity was investigated. In vitro studies demonstrate the ability of the semisynthetic derivatives to effectively inhibit Tdp1 with IC₅₀ up to 0.29 µM. Furthermore, an excellent fit is realized for the ligands when docked into the active site of the Tdp1 enzyme. Full article

(This article belongs to the Special Issue Hit Generation and Verification for Novel Lead Compounds)

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