Molecules

13 pages, 11875 KB

Open AccessArticle

Virtual Screening against Phosphoglycerate Kinase 1 in Quest of Novel Apoptosis Inhibitors

by Jie Xia¹

, Bo Feng¹, Qianhang Shao², Yuhe Yuan², Xiang Simon Wang³, Naihong Chen² and Song Wu^1,*

¹ State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of New Drug Research and Development, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China

² Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China

³ Molecular Modeling and Drug Discovery Core Laboratory for District of Columbia Center for AIDS Research (DC CFAR), Department of Pharmaceutical Sciences, College of Pharmacy, Howard University, Washington, DC 20059, USA

Molecules 2017, 22(6), 1029; https://doi.org/10.3390/molecules22061029 - 21 Jun 2017

Cited by 11 | Viewed by 6108

Abstract

Inhibition of apoptosis is a potential therapy to treat human diseases such as neurodegenerative disorders (e.g., Parkinson’s disease), stroke, and sepsis. Due to the lack of druggable targets, it remains a major challenge to discover apoptosis inhibitors. The recent repositioning of a marketed [...] Read more.

Inhibition of apoptosis is a potential therapy to treat human diseases such as neurodegenerative disorders (e.g., Parkinson’s disease), stroke, and sepsis. Due to the lack of druggable targets, it remains a major challenge to discover apoptosis inhibitors. The recent repositioning of a marketed drug (i.e., terazosin) as an anti-apoptotic agent uncovered a novel target (i.e., human phosphoglycerate kinase 1 (hPgk1)). In this study, we developed a virtual screening (VS) pipeline based on the X-ray structure of Pgk1/terazosin complex and applied it to a screening campaign for potential anti-apoptotic agents. The hierarchical filters in the pipeline (i.e., similarity search, a pharmacophore model, a shape-based model, and molecular docking) rendered 13 potential hits from Specs chemical library. By using PC12 cells (exposed to rotenone) as a cell model for bioassay, we first identified that AK-918/42829299, AN-465/41520984, and AT-051/43421517 were able to protect PC12 cells from rotenone-induced cell death. Molecular docking suggested these hit compounds were likely to bind to hPgk1 in a similar mode to terazosin. In summary, we not only present a versatile VS pipeline for potential apoptosis inhibitors discovery, but also provide three novel-scaffold hit compounds that are worthy of further development and biological study. Full article

(This article belongs to the Section Medicinal Chemistry)

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8 pages, 498 KB

Open AccessArticle

Synthesis and Bioactivity Characterization of Scutellarein Sulfonated Derivative

by Ting Gu^1,2, Yue Zhong^1,2, Yu-Ting Lu^1,2, Ying Sun^1,2, Ze-Xi Dong^1,2, Wen-Yu Wu^1,2, Zhi-Hao Shi³, Nian-Guang Li^1,2,*, Xin Xue^1,2, Fang Fang^1,2, He-Min Li^1,2 and Yu-Ping Tang^1,*

¹ National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China

² Department of Medicinal Chemistry, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China

³ Department of Organic Chemistry, China Pharmaceutical University, Nanjing, Jiangsu 211198, China

Molecules 2017, 22(6), 1028; https://doi.org/10.3390/molecules22061028 - 21 Jun 2017

Cited by 8 | Viewed by 5169

Abstract

Scutellarin (1) has been widely used to treat acute cerebral infarction in clinic, but poor aqueous solubility decreases its bioavailability. Interestingly, scutellarin (1) could be metabolized into scutellarein (2) in vivo. In this study, a sulfonic group [...] Read more.

Scutellarin (1) has been widely used to treat acute cerebral infarction in clinic, but poor aqueous solubility decreases its bioavailability. Interestingly, scutellarin (1) could be metabolized into scutellarein (2) in vivo. In this study, a sulfonic group was introduced at position C-8 of scutellarein (2) to enhance the aqueous solubility of the obtained derivative (3). DPPH (1,1-diphenyl-2-picrylhydrazyl)-radical scavenging ability and antithrombic activity were also conducted to determine its bioactivity. The result showed that scutellarein derivate (3) could be a better agent for ischemic cerebrovascular disease treatment. Full article

(This article belongs to the Special Issue Synthesis and Modification of Natural Product)

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23 pages, 9431 KB

Open AccessArticle

Molecular Quantum Similarity, Chemical Reactivity and Database Screening of 3D Pharmacophores of the Protein Kinases A, B and G from Mycobacterium tuberculosis

by Alejandro Morales-Bayuelo

Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT), Proyecto Postdoctoral No. 3150035, Talca, 3660300, Chile

Molecules 2017, 22(6), 1027; https://doi.org/10.3390/molecules22061027 - 21 Jun 2017

Cited by 14 | Viewed by 5129

Abstract

Mycobacterium tuberculosis remains one of the world’s most devastating pathogens. For this reason, we developed a study involving 3D pharmacophore searching, selectivity analysis and database screening for a series of anti-tuberculosis compounds, associated with the protein kinases A, B, and G. This theoretical [...] Read more.

Mycobacterium tuberculosis remains one of the world’s most devastating pathogens. For this reason, we developed a study involving 3D pharmacophore searching, selectivity analysis and database screening for a series of anti-tuberculosis compounds, associated with the protein kinases A, B, and G. This theoretical study is expected to shed some light onto some molecular aspects that could contribute to the knowledge of the molecular mechanics behind interactions of these compounds, with anti-tuberculosis activity. Using the Molecular Quantum Similarity field and reactivity descriptors supported in the Density Functional Theory, it was possible to measure the quantification of the steric and electrostatic effects through the Overlap and Coulomb quantitative convergence (alpha and beta) scales. In addition, an analysis of reactivity indices using global and local descriptors was developed, identifying the binding sites and selectivity on these anti-tuberculosis compounds in the active sites. Finally, the reported pharmacophores to PKn A, B and G, were used to carry out database screening, using a database with anti-tuberculosis drugs from the Kelly Chibale research group (http://www.kellychibaleresearch.uct.ac.za/), to find the compounds with affinity for the specific protein targets associated with PKn A, B and G. In this regard, this hybrid methodology (Molecular Mechanic/Quantum Chemistry) shows new insights into drug design that may be useful in the tuberculosis treatment today. Full article

(This article belongs to the Section Molecular Diversity)

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16 pages, 2448 KB

Open AccessArticle

Screening and Identification of the Metabolites in Rat Plasma and Urine after Oral Administration of Areca catechu L. Nut Extract by Ultra-High-Pressure Liquid Chromatography Coupled with Linear Ion Trap–Orbitrap Tandem Mass Spectrometry

by Lulu Li^1,†, Zhiqiang Luo^1,†, Yang Liu^1,*, Hao Wang¹, Aoxue Liu¹, Guohua Yu¹, Mengwei Li¹, Ruirui Yang¹, Xinjing Chen¹, Jialian Zhu¹ and Baosheng Zhao^2,*

¹ School of Chinese Materia Medica, Beijing University of Chinese Medicine, No. 6, Zhonghuan South Road, Wangjing, Chaoyang District, Beijing 100102, China

² Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, No. 11, North Third Ring Road, Chaoyang District, Beijing 100029, China

^† These authors contributed equally to this work.

Molecules 2017, 22(6), 1026; https://doi.org/10.3390/molecules22061026 - 21 Jun 2017

Cited by 14 | Viewed by 6147

Abstract

Areca catechu L. nut, a well-known toxic traditional herbal medicine, has been widely used to treat various diseases in China and many other Asian countries for centuries. However, to date the in vivo absorption and metabolism of its multiple bioactive or toxic components [...] Read more.

Areca catechu L. nut, a well-known toxic traditional herbal medicine, has been widely used to treat various diseases in China and many other Asian countries for centuries. However, to date the in vivo absorption and metabolism of its multiple bioactive or toxic components still remain unclear. In this study, liquid chromatography coupled with tandem mass spectrometry was used to analyze the major components and their metabolites in rat plasma and urine after oral administration of Areca catechu L. nut extract (ACNE). A total of 12 compounds, including 6 alkaloids, 3 tannins and 3 amino acids, were confirmed or tentatively identified from ACNE. In vivo, 40 constituents, including 8 prototypes and 32 metabolites were identified in rat plasma and urine samples. In summary, this study showed an insight into the metabolism of ACNE in vivo, which may provide helpful chemical information for better understanding of the toxicological and pharmacological profiles of ACNE. Full article

(This article belongs to the Section Metabolites)

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13 pages, 2383 KB

Open AccessReview

From Farm to Pharma: An Overview of Industrial Heparin Manufacturing Methods

by Jan-Ytzen Van der Meer^*, Edwin Kellenbach

and Leendert J. Van den Bos

Development and Technical Support Aspen Oss, Kloosterstraat 6, P.O. Box 98, 5340 AB Oss, The Netherlands

Molecules 2017, 22(6), 1025; https://doi.org/10.3390/molecules22061025 - 21 Jun 2017

Cited by 98 | Viewed by 14720

Abstract

The purification of heparin from offal is an old industrial process for which commercial recipes date back to 1922. Although chemical, chemoenzymatic, and biotechnological alternatives for this production method have been published in the academic literature, animal-tissue is still the sole source for [...] Read more.

The purification of heparin from offal is an old industrial process for which commercial recipes date back to 1922. Although chemical, chemoenzymatic, and biotechnological alternatives for this production method have been published in the academic literature, animal-tissue is still the sole source for commercial heparin production in industry. Heparin purification methods are closely guarded industrial secrets which are not available to the general (scientific) public. However by reviewing the academic and patent literature, we aim to provide a comprehensive overview of the general methods used in industry for the extraction of heparin from animal tissue. Full article

(This article belongs to the Special Issue Looking Forward to the Future of Heparin: New Sources, Developments and Applications)

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14 pages, 1832 KB

Open AccessReview

Deoxyelephantopin and Isodeoxyelephantopin as Potential Anticancer Agents with Effects on Multiple Signaling Pathways

by Tahir Mehmood¹, Amara Maryam¹, Hamed A. Ghramh^2,3, Muhammad Khan^1,*

and Tonghui Ma^1,*

¹ College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China

² Research Center for Advanced Materials Science, King Khalid University, Abha 61413, P.O. Box 9004, Saudi Arabia

³ Department of Biology, Faculty of Science, King Khalid University, Abha 61413, P.O. Box 9004, Saudi Arabia

Molecules 2017, 22(6), 1013; https://doi.org/10.3390/molecules22061013 - 21 Jun 2017

Cited by 36 | Viewed by 7903

Abstract

Cancer is the 2nd leading cause of death worldwide. The development of drugs to target only one specific signaling pathway has limited therapeutic success. Developing chemotherapeutics to target multiple signaling pathways has emerged as a new prototype for cancer treatment. Deoxyelephantopin (DET) and [...] Read more.

Cancer is the 2nd leading cause of death worldwide. The development of drugs to target only one specific signaling pathway has limited therapeutic success. Developing chemotherapeutics to target multiple signaling pathways has emerged as a new prototype for cancer treatment. Deoxyelephantopin (DET) and isodeoxyelephantopin (IDET) are sesquiterpene lactone components of “Elephantopus scaber and Elephantopus carolinianus”, traditional Chinese medicinal herbs that have long been used as folk medicines to treat liver diseases, diabetes, diuresis, bronchitis, fever, diarrhea, dysentery, cancer, and inflammation. Recently, the anticancer activity of DET and IDET has been widely investigated. Here, our aim is to review the current status of DET and IDET, and discuss their anticancer activity with specific emphasis on molecular targets and mechanisms used by these compounds to trigger apoptosis pathways which may help to further design and conduct research to develop them as lead therapeutic drugs for cancer treatments. The literature has shown that DET and IDET induce apoptosis through multiple signaling pathways which are deregulated in cancer cells and suggested that by targeting multiple pathways simultaneously, these compounds could selectively kill cancer cells. This review suggests that DET and IDET hold promising anticancer activity but additional studies and clinical trials are needed to validate and understand their therapeutic effect to develop them into potent therapeutics for the treatment of cancer. Full article

(This article belongs to the Collection Bioactive Compounds)

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23 pages, 6048 KB

Open AccessReview

Insights into Penicillium brasilianum Secondary Metabolism and Its Biotechnological Potential

by Jaqueline Moraes Bazioli¹, Luciana Da Silva Amaral²

, Taícia Pacheco Fill^1,* and Edson Rodrigues-Filho^2,*

¹ Instituto de Química, Universidade Estadual de Campinas, CP 6154, 13083-970 Campinas, Brazil

² Departamento de Química, Universidade Federal de São Carlos, CP 676, 13.565-905 São Carlos, SP, Brazil

Molecules 2017, 22(6), 858; https://doi.org/10.3390/molecules22060858 - 20 Jun 2017

Cited by 33 | Viewed by 10139

Abstract

Over the past few years Penicillium brasilianum has been isolated from many different environmental sources as soil isolates, plant endophytes and onion pathogen. All investigated strains share a great ability to produce bioactive secondary metabolites. Different authors have investigated this great capability and [...] Read more.

Over the past few years Penicillium brasilianum has been isolated from many different environmental sources as soil isolates, plant endophytes and onion pathogen. All investigated strains share a great ability to produce bioactive secondary metabolites. Different authors have investigated this great capability and here we summarize the metabolic potential and the biological activities related to P. brasilianum’s metabolites with diverse structures. They include secondary metabolites of an alkaloid nature, i.e., 2,5-diketopiperazines, cyclodepsipeptides, meroterpenoids and polyketides. Penicillium brasilianum is also described as a great source of enzymes with biotechnological application potential, which is also highlighted in this review. Additionally, this review will focus on several aspects of Penicillium brasilianum and interesting genomic insights. Full article

(This article belongs to the Special Issue Expanding the Potential of Metabolomics for Under Investigated Organisms and in Drug Discovery)

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18 pages, 3692 KB

Open AccessArticle

The Antiproliferative Effect of Cyclodipeptides from Pseudomonas aeruginosa PAO1 on HeLa Cells Involves Inhibition of Phosphorylation of Akt and S6k Kinases

by Laura Hernández-Padilla¹, Dolores Vázquez-Rivera¹, Luis A. Sánchez-Briones¹, Alma L. Díaz-Pérez¹, José Moreno-Rodríguez², Mario A. Moreno-Eutimio², Victor Meza-Carmen¹, Homero Reyes-De la Cruz³

and Jesús Campos-García^1,*

¹ Laboratorio de Biotecnología Microbiana, Instituto de Investigaciones Químico-Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, 58030 Morelia, Michoacán, Mexico

² División de Investigación, Hospital Juárez de México, 07760 Ciudad de México, Mexico

³ Laboratorio de Control Traduccional, Instituto de Investigaciones Químico-Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, 58030 Morelia, Michoacán, Mexico. delacruz@umich.mx

Molecules 2017, 22(6), 1024; https://doi.org/10.3390/molecules22061024 - 20 Jun 2017

Cited by 22 | Viewed by 6911

Abstract

Pseudomonas aeruginosa PAO1, a potential pathogen of plants and animals, produces the cyclodipeptides cyclo(l-Pro-l-Tyr), cyclo(l-Pro-l-Phe), and cyclo(l-Pro-l-Val) (PAO1-CDPs), whose effects have been implicated in inhibition of human tumor cell line proliferation. Our purpose was to investigate in depth in the mechanisms of HeLa [...] Read more.

Pseudomonas aeruginosa PAO1, a potential pathogen of plants and animals, produces the cyclodipeptides cyclo(l-Pro-l-Tyr), cyclo(l-Pro-l-Phe), and cyclo(l-Pro-l-Val) (PAO1-CDPs), whose effects have been implicated in inhibition of human tumor cell line proliferation. Our purpose was to investigate in depth in the mechanisms of HeLa cell proliferation inhibition by the PAO1-CDPs. The results indicate that PAO1-CDPs, both purified individually and in mixtures, inhibited HeLa cell proliferation by arresting the cell cycle at the G0–G1 transition. The crude PAO1-CDPs mixture promoted cell death in HeLa cells in a dose-dependent manner, showing efficacy similar to that of isolated PAO1-CDPs (LD₅₀ of 60–250 µM) and inducing apoptosis with EC₅₀ between 0.6 and 3.0 µM. Moreover, PAO1-CDPs showed a higher proapoptotic activity (~10³–10⁵ fold) than their synthetic analogs did. Subsequently, the PAO1-CDPs affected mitochondrial membrane potential and induced apoptosis by caspase-9-dependent pathway. The mechanism of inhibition of cells proliferation in HeLa cells involves inhibition of phosphorylation of both Akt-S473 and S6k-T389 protein kinases, showing a cyclic behavior of their expression and phosphorylation in a time and concentration-dependent fashion. Taken together our findings indicate that PI3K–Akt–mTOR–S6k signaling pathway blockage is involved in the antiproliferative effect of the PAO1-CDPs. Full article

(This article belongs to the Special Issue Peptide-Based Drugs and Drug Delivery Systems)

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8 pages, 596 KB

Open AccessArticle

Phenolic Glycosides from Capsella bursa-pastoris (L.) Medik and Their Anti-Inflammatory Activity

by Joon Min Cha¹, Won Se Suh¹, Tae Hyun Lee¹, Lalita Subedi^2,3, Sun Yeou Kim^2,3

and Kang Ro Lee^1,*

¹ Natural Products Laboratory, School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea

² Gachon Institute of Pharmaceutical Science, Gachon University, 191 Hambakmoero, Yeonsu-gu, Incheon 21936, Korea

³ College of Pharmacy, Gachon University, 191 Hambakmoero, Yeonsu-gu, Incheon 21936, Korea

Molecules 2017, 22(6), 1023; https://doi.org/10.3390/molecules22061023 - 20 Jun 2017

Cited by 31 | Viewed by 9954

Abstract

A new sesquilignan glycoside 1, together with seven known phenolic glycosides 2–8 were isolated from the aerial parts of Capsella bursa-pastoris. The chemical structure of the new compound 1 was elucidated by extensive nuclear magnetic resonance (NMR) data (¹ [...] Read more.

A new sesquilignan glycoside 1, together with seven known phenolic glycosides 2–8 were isolated from the aerial parts of Capsella bursa-pastoris. The chemical structure of the new compound 1 was elucidated by extensive nuclear magnetic resonance (NMR) data (¹H- and ¹³C-NMR, ¹H-¹H correlation spectroscopy (¹H-¹H COSY), heteronuclear single-quantum correlation (HSQC), heteronuclear multiple bond correlation (HMBC), and nuclear overhauser effect spectroscopy (NOESY)) and HR-FABMS analysis. The anti-inflammatory effects of 1–8 were evaluated in lipopolysaccharide (LPS)-stimulated murine microglia BV-2 cells. Compounds 4 and 7 exhibited moderate inhibitory effects on nitric oxide production in LPS-activated BV-2 cells, with IC₅₀ values of 17.80 and 27.91 µM, respectively. Full article

(This article belongs to the Collection Bioactive Compounds)

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10 pages, 6331 KB

Open AccessArticle

Complex Coacervation of Soy Proteins, Isoflavones and Chitosan

by Yu-Hsuan Hsiao¹, Sheng-Yang Hsia², Yin-Ching Chan^3,† and Jung-Feng Hsieh^1,2,*,†

¹ Ph.D. Program in Nutrition & Food Science, Fu Jen Catholic University, Taipei 24205, Taiwan

² Department of Food Science, Fu Jen Catholic University, Taipei 24205, Taiwan

³ Department of Food and Nutrition, Providence University, Shalu District, Taichung 43301, Taiwan

^† These authors contributed equally to this work.

Molecules 2017, 22(6), 1022; https://doi.org/10.3390/molecules22061022 - 20 Jun 2017

Cited by 10 | Viewed by 8297

Abstract

In this study, the chitosan-induced coacervation of soy protein-isoflavone complexes in soymilk was investigated. Most of the soymilk proteins, including β-conglycinin (7S), glycinin (11S), and isoflavones, were found to coacervate into the soymilk pellet fraction (SPF) following the addition of 0.5% chitosan. The [...] Read more.

In this study, the chitosan-induced coacervation of soy protein-isoflavone complexes in soymilk was investigated. Most of the soymilk proteins, including β-conglycinin (7S), glycinin (11S), and isoflavones, were found to coacervate into the soymilk pellet fraction (SPF) following the addition of 0.5% chitosan. The total protein in the soymilk supernatant fraction (SSF) decreased from 18.1 ± 0.3 mg/mL to 1.6 ± 0.1 mg/mL, and the pH values decreased slightly, from 6.6 ± 0.0 to 6.0 ± 0.0. The results of SDS-PAGE revealed that the 7S α’, 7S α, 7S β, 11S A3, and 11S acidic subunits, as well as the 11S basic proteins in the SSF, decreased to 0.7 ± 0.5%, 0.2 ± 0.1%, 0.1 ± 0.0%, 0.2 ± 0.2%, 0.2 ± 0.2% and 0.3 ± 0.2%, respectively. We also found that isoflavones in the SSF, including daidzein, glycitein, and genistein, decreased to 9.6 ± 2.3%, 5.7 ± 0.9% and 5.9 ± 1.5%, respectively. HPLC analysis indicated that isoflavones mixed with soy proteins formed soy protein-isoflavone complexes and were precipitated into the SPF by 0.5% chitosan. Full article

(This article belongs to the Special Issue Protein-Carbohydrate Interactions)

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10 pages, 4489 KB

Open AccessArticle

The Effects of Selected Sesquiterpenes from Myrica rubra Essential Oil on the Efficacy of Doxorubicin in Sensitive and Resistant Cancer Cell Lines

by Martin Ambrož¹, Petra Matoušková¹

, Adam Skarka², Martina Zajdlová¹, Kateřina Žáková¹ and Lenka Skálová^1,*

¹ Department of Biochemical Sciences, Faculty of Pharmacy, Charles University, Heyrovského 1203, 50005 Hradec Králové, Czech Republic

² Department of Chemistry, Faculty of Science, University of Hradec Králové, Hradecká 1285, 50003 Hradec Králové, Czech Republic

Molecules 2017, 22(6), 1021; https://doi.org/10.3390/molecules22061021 - 20 Jun 2017

Cited by 32 | Viewed by 6476

Abstract

β-caryophyllene oxide (CAO), α-humulene (HUM), trans-nerolidol (NER) and valencene (VAL) are constituents of the essential oil of Myrica rubra (MEO), which has significant antiproliferative effect in various cancer cell lines. In the present study, we compared the antiproliferative effect of these sesquiterpenes alone [...] Read more.

β-caryophyllene oxide (CAO), α-humulene (HUM), trans-nerolidol (NER) and valencene (VAL) are constituents of the essential oil of Myrica rubra (MEO), which has significant antiproliferative effect in various cancer cell lines. In the present study, we compared the antiproliferative effect of these sesquiterpenes alone and in combination with the cytostatic drug doxorubicin (DOX) in cancer cell lines with different sensitivity to DOX. Two ovarian cancer cell lines (sensitive A2780 and partly resistant SKOV3) and two lymphoblast cancer cell lines (sensitive CCRF/CEM and completely resistant CEM/ADR) were used. The observed effects varied among sesquiterpenes and also differed in individual cell lines, with only VAL being effective in all the cell lines. A strong synergism of DOX with NER was found in the A2780 cells, while DOX acted synergistically with HUM and CAO in the SKOV3 cells. In the CCRF/CEM cells, a synergism of DOX with CAO and NER was observed. In resistant CEM/ADR cells, sesquiterpenes did not increase DOX efficacy, although they significantly increased accumulation of DOX (up to 10-times) and rhodamine-123 (substrate of efflux transporter ABCB1) within cancer cells. In conclusion, the tested sesquiterpenes were able to improve DOX efficacy in the sensitive and partly resistant cancer cells, but not in cells completely resistant to DOX. Full article

(This article belongs to the Special Issue Essential Oils: Chemistry and Bioactivity)

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14 pages, 3608 KB

Open AccessArticle

Determination of Structural Requirements of N-Substituted Tetrahydro-β-Carboline Imidazolium Salt Derivatives Using in Silico Approaches for Designing MEK-1 Inhibitors

by Jingwei Liang^†, Mingyang Wang^†, Xinyang Li, Xin He, Chong Cao and Fanhao Meng^*

¹ School of Pharmacy, China Medical University, Liaoning 110122, China

^† These authors contributed equally to this work

Molecules 2017, 22(6), 1020; https://doi.org/10.3390/molecules22061020 - 19 Jun 2017

Cited by 7 | Viewed by 6181

Abstract

Novel N-substituted tetrahydro-β-carboline imidazolium salt derivatives proved to have potent antitumor activity in past research. The Topomer CoMFA and CoMSIA function in Sybyl-X 2.0 software was applied for the identification of important features of N-substituted tetrahydro-β-carboline-imidazolium salt derivative moieties. In the [...] Read more.

Novel N-substituted tetrahydro-β-carboline imidazolium salt derivatives proved to have potent antitumor activity in past research. The Topomer CoMFA and CoMSIA function in Sybyl-X 2.0 software was applied for the identification of important features of N-substituted tetrahydro-β-carboline-imidazolium salt derivative moieties. In the case of Topomer CoMFA, all the compounds were split into two fragments which were used to generate a 3D invariant representation, the statistical results of the Topomer CoMFA model: q² value of 0.700; r² value of 0.954; with 5 optimum components. The database alignment was utilized for building the CoMSIA model, and the CoMSIA model had q² and r² values of 0.615 and 0.897, with 4 optimum components. Target fishing of the PharmMapper platform was utilised for finding potential targets, the human mitogen-activated protein kinase 1 (MEK-1) was found to be the primary potential target for the three compounds with the fit scores of 6.288, 5.741, and 6.721. The molecular docking technique of MOE 2015 was carried out to identify the interactions of amino acids surrounding the ligand, and correlating QASR contour maps were used to identify structural requirements of N-substituted tetrahydro-β-carboline imidazolium salt moieties. Molecular dynamics and simulation studies proved that the target protein was stable for 0.8–5 ns. The pivotal moieties of N-substituted tetrahydro-β-carboline imidazolium salt derivatives and its potential targets were verified by the QASR study, PharmMapper, and the molecular docking study which would be helpful to design novel MEK-1 inhibitors for anticancer drugs. Full article

(This article belongs to the Collection Efficient Pharmaceutical and Chemical Approaches for Anticancer Therapy: Design, Preliminary Evaluations, and Further Developments)

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27 pages, 1849 KB

Open AccessReview

Leptadenia reticulata (Retz.) Wight & Arn. (Jivanti): Botanical, Agronomical, Phytochemical, Pharmacological, and Biotechnological Aspects

by Sudipta Kumar Mohanty^1,2, Mallappa Kumara Swamy^2,3,*

, Uma Rani Sinniah^3,* and Maniyam Anuradha²

¹ Instituto de Biología, Universidad Nacional Autónoma de México, Ciudad Universitaria, Coyoacan, Ciudad de México C.P. 04510, Mexico

² School of Life Sciences, Padmashree Institute of Management and Sciences, Kommagatta, Kengeri, Bengaluru 560060, India

³ Department of Crop Science, Faculty of Agriculture, Universiti Putra Malaysia, Serdang, Selangor, Darul Ehsan 43400, Malaysia

Molecules 2017, 22(6), 1019; https://doi.org/10.3390/molecules22061019 - 19 Jun 2017

Cited by 94 | Viewed by 13292

Abstract

Leptadenia reticulata (Retz.) Wight & Arn. (Apocynaceae), is a traditional medicinal plant species widely used to treat various ailments such as tuberculosis, hematopoiesis, emaciation, cough, dyspnea, fever, burning sensation, night blindness, cancer, and dysentery. In Ayurveda, it is known for its revitalizing, rejuvenating, [...] Read more.

Leptadenia reticulata (Retz.) Wight & Arn. (Apocynaceae), is a traditional medicinal plant species widely used to treat various ailments such as tuberculosis, hematopoiesis, emaciation, cough, dyspnea, fever, burning sensation, night blindness, cancer, and dysentery. In Ayurveda, it is known for its revitalizing, rejuvenating, and lactogenic properties. This plant is one of the major ingredients in many commercial herbal formulations, including Speman, Envirocare, Calshakti, Antisept, and Chyawanprash. The therapeutic potential of this herb is because of the presence of diverse bioactive compounds such as α-amyrin, β-amyrin, ferulic acid, luteolin, diosmetin, rutin, β-sitosterol, stigmasterol, hentricontanol, a triterpene alcohol simiarenol, apigenin, reticulin, deniculatin, and leptaculatin. However, most biological studies on L. reticulata are restricted to crude extracts, and many biologically active compounds are yet to be identified in order to base the traditional uses of L. reticulata on evidence-based data. At present, L. reticulata is a threatened endangered plant because of overexploitation, unscientific harvesting, and habitat loss. The increased demand from pharmaceutical, nutraceutical, and veterinary industries has prompted its large-scale propagation. However, its commercial cultivation is hampered because of the non-availability of genuine planting material and the lack of knowledge about its agronomical practices. In this regard, micropropagation techniques will be useful to obtain true-to-type L. reticulata planting materials from an elite germplasm to meet the current demand. Adopting other biotechnological approaches such as synthetic seed technology, cryopreservation, cell culture, and genetic transformation can help conservation as well as increased metabolite production from L. reticulata. The present review summarizes scientific information on the botanical, agronomical, phytochemical, pharmacological, and biotechnological aspects of L. reticulata. This comprehensive information will certainly allow better utilization of this industrially important herb towards the discovery of lead drug molecules. Full article

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17 pages, 2393 KB

Open AccessArticle

Systemic Induction of the Defensin and Phytoalexin Pisatin Pathways in Pea (Pisum sativum) against Aphanomyces euteiches by Acetylated and Nonacetylated Oligogalacturonides

by Sameh Selim^1,*

, Jean Sanssené², Stéphanie Rossard³ and Josiane Courtois⁴

¹ HydrISE, UniLaSalle, Beauvais, SFR Condorcet 3417, 19 Rue Pierre Waguet, BP 30313, F-60026 Beauvais CEDEX, France

² Current address: JS Consulting, 17c Avenue Jean Jaurès, 31290 Villefranche de Lauragais, France

³ Current address: University of Technology of Compiègne (UTC), Centre Pierre Guillaumat, Rue du Docteur Schweitzer, F-60203 Compiègne CEDEX, France

⁴ Laboratoire des Polysaccharides Microbiens et Végétaux, Université de Picardie Jules Verne, Avenue des Facultés, Le Bailly, F-80025 Amiens CEDEX, France

Molecules 2017, 22(6), 1017; https://doi.org/10.3390/molecules22061017 - 19 Jun 2017

Cited by 29 | Viewed by 8385

Abstract

Oligogalacturonides (OGs) are known for their powerful ability to stimulate the plant immune system but little is known about their mode of action in pea (Pisum sativum). In the present study, we investigated the elicitor activity of two fractions of OGs, [...] Read more.

Oligogalacturonides (OGs) are known for their powerful ability to stimulate the plant immune system but little is known about their mode of action in pea (Pisum sativum). In the present study, we investigated the elicitor activity of two fractions of OGs, with polymerization degrees (DPs) of 2–25, in pea against Aphanomyces euteiches. One fraction was nonacetylated (OGs − Ac) whereas the second one was 30% acetylated (OGs + Ac). OGs were applied by injecting the upper two rachises of the plants at three- and/or four-weeks-old. Five-week-old roots were inoculated with 10⁵ zoospores of A. euteiches. The root infection level was determined at 7, 10 and 14 days after inoculation using the quantitative real-time polymerase chain reaction (qPCR). Results showed significant root infection reductions namely 58, 45 and 48% in the plants treated with 80 µg OGs + Ac and 59, 56 and 65% with 200 µg of OGs − Ac. Gene expression results showed the upregulation of genes involved in the antifungal defensins, lignans and the phytoalexin pisatin pathways and a priming effect in the basal defense, SA and ROS gene markers as a response to OGs. The reduction of the efficient dose in OGs + Ac is suggesting that acetylation is necessary for some specific responses. Our work provides the first evidence for the potential of OGs in the defense induction in pea against Aphanomyces root rot. Full article

(This article belongs to the Special Issue Structure, Chemical Analysis, Biosynthesis, Metabolism, Molecular Engineering and Biological Functions of Phytoalexins)

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30 pages, 3378 KB

Open AccessPerspective

Photophysics and Photochemistry of Canonical Nucleobases’ Thioanalogs: From Quantum Mechanical Studies to Time Resolved Experiments

by Serra Arslancan¹, Lara Martínez-Fernández^2,*

and Inés Corral^1,3,*

¹ Departamento de Química, Módulo 13, Universidad Autónoma de Madrid, Madrid 28049, Spain

² Istituto Biostrutture e Bioimmagini-Consiglio Nazionale delle Ricerche, Via Mezzocannone 16, Napoli I-80134, Italy

³ Institute for Advanced Research in Chemical Sciences (IADCHEM), Universidad Autónoma de Madrid, Madrid 28049, Spain

Molecules 2017, 22(6), 998; https://doi.org/10.3390/molecules22060998 - 18 Jun 2017

Cited by 65 | Viewed by 8160

Abstract

Interest in understanding the photophysics and photochemistry of thiated nucleobases has been awakened because of their possible involvement in primordial RNA or their potential use as photosensitizers in medicinal chemistry. The interpretation of the photodynamics of these systems, conditioned by their intricate potential [...] Read more.

Interest in understanding the photophysics and photochemistry of thiated nucleobases has been awakened because of their possible involvement in primordial RNA or their potential use as photosensitizers in medicinal chemistry. The interpretation of the photodynamics of these systems, conditioned by their intricate potential energy surfaces, requires the powerful interplay between experimental measurements and state of the art molecular simulations. In this review, we provide an overview on the photophysics of natural nucleobases’ thioanalogs, which covers the last 30 years and both experimental and computational contributions. For all the canonical nucleobase’s thioanalogs, we have compiled the main steady state absorption and emission features and their interpretation in terms of theoretical calculations. Then, we revise the main topographical features, including stationary points and interstate crossings, of their potential energy surfaces based on quantum mechanical calculations and we conclude, by combining the outcome of different spectroscopic techniques and molecular dynamics simulations, with the mechanism by which these nucleobase analogs populate their triplet excited states, which are at the origin of their photosensitizing properties. Full article

(This article belongs to the Special Issue Experimental and Computational Photochemistry of Bioorganic Molecules)

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10 pages, 1406 KB

Open AccessArticle

Structural Characterization of a Rhamnogalacturonan I Domain from Ginseng and Its Inhibitory Effect on Galectin-3

by Huimin Shi, Li Yu, Yun Shi, Jiaojiao Lu, He Teng, Yifa Zhou and Lin Sun^*

Jilin Province Key Laboratory on Chemistry and Biology of Natural Drugs in Changbai Mountain, School of Life Sciences, Northeast Normal University, Changchun 130024, China

Molecules 2017, 22(6), 1016; https://doi.org/10.3390/molecules22061016 - 18 Jun 2017

Cited by 35 | Viewed by 7426

Abstract

A rhamnogalacturonan I domain, named RG-I-3A, was prepared from ginseng pectin by pectinase digestion and chromatography separation. Monosaccharide composition analysis revealed that it was mainly composed of galacturonic acid, rhamnose, galactose, and arabinose in a molar ratio of 32.5:11.2:31.9:16.5, with a molecular weight [...] Read more.

A rhamnogalacturonan I domain, named RG-I-3A, was prepared from ginseng pectin by pectinase digestion and chromatography separation. Monosaccharide composition analysis revealed that it was mainly composed of galacturonic acid, rhamnose, galactose, and arabinose in a molar ratio of 32.5:11.2:31.9:16.5, with a molecular weight of 50 kDa. Partial acid hydrolysis, monoclonal antibody detection, and NMR spectra analysis suggested RG-I-3A was composed of →4)-α-GalpA-(1→2)-α-Rhap-(1→disaccharide repeating units as backbone, with β-1,4-galactan, α-1,5-arabinan, AG-I, and AG-II side chains substituted via the O-4 of Rhap. Galectin-3-mediated hemagglutination and biolayer interferometry assay indicated that RG-I-3A had inhibitory activity on galectin-3. These findings suggest the potential use of this ginseng RG-I domain as a galectin-3 inhibitor in drug development applications. Full article

(This article belongs to the Special Issue Natural Polysaccharides)

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14 pages, 13733 KB

Open AccessArticle

Repositioning FDA Drugs as Potential Cruzain Inhibitors from Trypanosoma cruzi: Virtual Screening, In Vitro and In Vivo Studies

by Isidro Palos¹

, Edgar E. Lara-Ramirez², Julio Cesar Lopez-Cedillo³, Carlos Garcia-Perez⁴, Muhammad Kashif⁴

, Virgilio Bocanegra-Garcia⁴, Benjamin Nogueda-Torres³ and Gildardo Rivera^4,*

¹ Unidad Académica Multidisciplinaria Reynosa-Rodhe, Universidad Autónoma de Tamaulipas, Carr. Reynosa-San Fernando, s/n, Reynosa 88779, México

² Unidad de Investigación Biomédica de Zacatecas, Instituto Mexicano del Seguro Social (IMSS), Alameda Trinidad García de la Cadena, s/n, Zacatecas 98000, México

³ Departamento de Parasitología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prolongación de Carpio y Plan de Ayala, s/n, Ciudad de México 11340, México

⁴ Laboratory of Pharmaceutical Biothecnology, Centro de Biotecnología Genómica, Instituto Politécnico Nacional, Boulevard del Maestro, s/n, Esq. Elías Piña, Reynosa 88710, México

Molecules 2017, 22(6), 1015; https://doi.org/10.3390/molecules22061015 - 18 Jun 2017

Cited by 41 | Viewed by 7759

Abstract

Chagas disease (CD) is a neglected disease caused by the parasite Trypanosoma cruzi, which affects underdeveloped countries. The current drugs of choice are nifurtimox and benznidazole, but both have severe adverse effects and less effectivity in chronic infections; therefore, the need to [...] Read more.

Chagas disease (CD) is a neglected disease caused by the parasite Trypanosoma cruzi, which affects underdeveloped countries. The current drugs of choice are nifurtimox and benznidazole, but both have severe adverse effects and less effectivity in chronic infections; therefore, the need to discover new drugs is essential. A computer-guided drug repositioning method was applied to identify potential FDA drugs (approved and withdrawn) as cruzain (Cz) inhibitors and trypanocidal effects were confirmed by in vitro and in vivo studies. 3180 FDA drugs were virtually screened using a structure-based approach. From a first molecular docking analysis, a set of 33 compounds with the best binding energies were selected. Subsequent consensus affinity binding, ligand amino acid contact clustering analysis, and ranked position were used to choose four known pharmacological compounds to be tested in vitro. Mouse blood samples infected with trypomastigotes from INC-5 and NINOA strains were used to test the trypanocidal effect of four selected compounds. Among these drugs, one fibrate antilipemic (etofyllin clofibrate) and three β-lactam antibiotics (piperacillin, cefoperazone, and flucloxacillin) showed better trypanocidal effects (LC₅₀ range 15.8–26.1 μg/mL) in comparison with benznidazole and nifurtimox (LC₅₀ range 33.1–46.7 μg/mL). A short-term in vivo evaluation of these compounds showed a reduction of parasitemia in infected mice (range 90–60%) at 6 h, but this was low compared to benznidazole (50%). This work suggests that four known FDA drugs could be used to design and obtain new trypanocidal agents. Full article

(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)

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24 pages, 3073 KB

Open AccessReview

Cancer Chemoprevention by Resveratrol: The p53 Tumor Suppressor Protein as a Promising Molecular Target

by Danielly C. Ferraz da Costa¹, Eliane Fialho^2,* and Jerson L. Silva^3,*

¹ Instituto de Nutrição, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, 20550-013, Brazil

² Instituto de Nutrição Josué de Castro, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

³ Instituto de Bioquímica Médica Leopoldo de Meis & Instituto Nacional de Ciência e Tecnologia de Biologia Estrutural e Bioimagem, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, 21941-902, Brazil

Molecules 2017, 22(6), 1014; https://doi.org/10.3390/molecules22061014 - 18 Jun 2017

Cited by 58 | Viewed by 20185

Abstract

Increasing epidemiological and experimental evidence has demonstrated an inverse relationship between the consumption of plant foods and the incidence of chronic diseases, including cancer. Microcomponents that are naturally present in such foods, especially polyphenols, are responsible for the benefits to human health. Resveratrol [...] Read more.

Increasing epidemiological and experimental evidence has demonstrated an inverse relationship between the consumption of plant foods and the incidence of chronic diseases, including cancer. Microcomponents that are naturally present in such foods, especially polyphenols, are responsible for the benefits to human health. Resveratrol is a diet-derived cancer chemopreventive agent with high therapeutic potential, as demonstrated by different authors. The aim of this review is to collect and present recent evidence from the literature regarding resveratrol and its effects on cancer prevention, molecular signaling (especially regarding the involvement of p53 protein), and therapeutic perspectives with an emphasis on clinical trial results to date. Full article

(This article belongs to the Special Issue Improvements for Resveratrol Efficacy)

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12 pages, 4018 KB

Open AccessArticle

Mechanistic Explanation of the Weak Carbonic Anhydrase’s Esterase Activity

by Paolo Piazzetta^*, Tiziana Marino

and Nino Russo^*

Dipartimento di Chimica e Tecnologie Chimiche (CTC), Università della Calabria, 87036 Arcavacata di Rende (CS), Italy

Molecules 2017, 22(6), 1009; https://doi.org/10.3390/molecules22061009 - 18 Jun 2017

Cited by 8 | Viewed by 6653

Abstract

In order to elucidate the elementary mechanism of the promiscuous esterase activity of human carbonic anhydrase (h-CA), we present an accurate theoretical investigation on the hydrolysis of fully-acetylated d-glucose functionalized as sulfamate. This h-CA’s inhibitor is of potential relevance in cancer therapy. [...] Read more.

In order to elucidate the elementary mechanism of the promiscuous esterase activity of human carbonic anhydrase (h-CA), we present an accurate theoretical investigation on the hydrolysis of fully-acetylated d-glucose functionalized as sulfamate. This h-CA’s inhibitor is of potential relevance in cancer therapy. The study has been performed within the framework of three-layer ONIOM (QM-high:QM’-medium:MM-low) hybrid approach. The computations revealed that the hydrolysis process is not energetically favored, in agreement with the observed weak carbonic anhydrase’s esterase activity. Full article

(This article belongs to the Special Issue Metallopeptides)

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16 pages, 2868 KB

Open AccessArticle

Metabolomics Characterization of Two Apocynaceae Plants, Catharanthus roseus and Vinca minor, Using GC-MS and LC-MS Methods in Combination

by Qi Chen¹

, Xueyan Lu¹, Xiaorui Guo², Qingxi Guo^1,* and Dewen Li^2,*

¹ Center for Ecological Research, Northeast Forestry University, Harbin 150040, China

² Key Laboratory of Plant Ecology, Northeast Forestry University, Harbin 150040, China

Molecules 2017, 22(6), 997; https://doi.org/10.3390/molecules22060997 - 17 Jun 2017

Cited by 48 | Viewed by 9681

Abstract

Catharanthus roseus (C. roseus) and Vinca minor (V. minor) are two common important medical plants belonging to the family Apocynaceae. In this study, we used non-targeted GC-MS and targeted LC-MS metabolomics to dissect the metabolic profile of two plants [...] Read more.

Catharanthus roseus (C. roseus) and Vinca minor (V. minor) are two common important medical plants belonging to the family Apocynaceae. In this study, we used non-targeted GC-MS and targeted LC-MS metabolomics to dissect the metabolic profile of two plants with comparable phenotypic and metabolic differences. A total of 58 significantly different metabolites were present in different quantities according to PCA and PLS-DA score plots of the GC-MS analysis. The 58 identified compounds comprised 16 sugars, eight amino acids, nine alcohols and 18 organic acids. We subjected these metabolites into KEGG pathway enrichment analysis and highlighted 27 metabolic pathways, concentrated on the TCA cycle, glycometabolism, oligosaccharides, and polyol and lipid transporter (RFOS). Among the primary metabolites, trehalose, raffinose, digalacturonic acid and gallic acid were revealed to be the most significant marker compounds between the two plants, presumably contributing to species-specific phenotypic and metabolic discrepancy. The profiling of nine typical alkaloids in both plants using LC-MS method highlighted higher levels of crucial terpenoid indole alkaloid (TIA) intermediates of loganin, serpentine, and tabersonine in V. minor than in C. roseus. The possible underlying process of the metabolic flux from primary metabolism pathways to TIA synthesis was discussed and proposed. Generally speaking, this work provides a full-scale comparison of primary and secondary metabolites between two medical plants and a metabolic explanation of their TIA accumulation and phenotype differences. Full article

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14 pages, 884 KB

Open AccessArticle

Sensory Characteristics and Volatile Components of Dry Dog Foods Manufactured with Sorghum Fractions

by Brizio Di Donfrancesco and Kadri Koppel^*

Center for Sensory Analysis and Consumer Behavior, Kansas State University, 1310 Research Park Dr, Manhattan, KS 66502, USA

Molecules 2017, 22(6), 1012; https://doi.org/10.3390/molecules22061012 - 17 Jun 2017

Cited by 15 | Viewed by 7202

Abstract

Descriptive sensory analysis and gas chromatography-mass spectrometry (GC-MS) with a modified headspace solid-phase microextraction (SPME) method was performed on three extruded dry dog food diets manufactured with different fractions of red sorghum and a control diet containing corn, brewer’s rice, and wheat as [...] Read more.

Descriptive sensory analysis and gas chromatography-mass spectrometry (GC-MS) with a modified headspace solid-phase microextraction (SPME) method was performed on three extruded dry dog food diets manufactured with different fractions of red sorghum and a control diet containing corn, brewer’s rice, and wheat as a grain source in order to determine the effect of sorghum fractions on dry dog food sensory properties. The aroma compounds and flavor profiles of samples were similar with small differences, such as higher toasted aroma notes, and musty and dusty flavor in the mill-feed sample. A total of 37 compounds were tentatively identified and semi-quantified. Aldehydes were the major group present in the samples. The total volatile concentration was low, reflecting the mild aroma of the samples. Partial least squares regression was performed to identify correlations between sensory characteristics and detected aroma compounds. Possible relationships, such as hexanal and oxidized oil, and broth aromatics were identified. Volatile compounds were also associated with earthy, musty, and meaty aromas and flavor notes. This study showed that extruded dry dog foods manufactured with different red sorghum fractions had similar aroma, flavor, and volatile profiles. Full article

(This article belongs to the Collection Recent Advances in Flavors and Fragrances)

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13 pages, 1828 KB

Open AccessArticle

Synthesis and Evaluation of Phenylxanthine Derivatives as Potential Dual A2AR Antagonists/MAO-B Inhibitors for Parkinson’s Disease

by Xuebao Wang

, Chao Han, Yong Xu, Kaiqi Wu, Shuangya Chen, Mangsha Hu, Luyao Wang, Yun Ye and Faqing Ye^*

School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China

Molecules 2017, 22(6), 1010; https://doi.org/10.3390/molecules22061010 - 17 Jun 2017

Cited by 18 | Viewed by 6579

Abstract

The aim of this research was to prove the speculation that phenylxanthine (PX) derivatives possess adenosine A2A receptor (A2AR)-blocking properties and to screening and evaluate these PX derivatives as dual A2AR antagonists/MAO-B inhibitors for Parkinson′s disease. To explore this hypothesis, two series of [...] Read more.

The aim of this research was to prove the speculation that phenylxanthine (PX) derivatives possess adenosine A2A receptor (A2AR)-blocking properties and to screening and evaluate these PX derivatives as dual A2AR antagonists/MAO-B inhibitors for Parkinson′s disease. To explore this hypothesis, two series of PX derivatives were prepared and their antagonism against A2AR and inhibition against MAO-B were determined in vitro. In order to evaluate further the antiparkinsonian properties, pharmacokinetic and haloperidol-induced catalepsy experiments were carried out in vivo. The PX-D and PX-E analogues acted as potent A2AR antagonists with Ki values ranging from 0.27 to 10 μM, and these analogues displayed relatively mild MAO-B inhibition potencies, with inhibitor dissociation constants (Ki values) ranging from 0.25 to 10 μM. Further, the compounds PX-D-P6 and PX-E-P8 displayed efficacious antiparkinsonian properties in haloperidol-induced catalepsy experiments, verifying that these two compounds were potent A2AR antagonists and MAO-B inhibitors. We conclude that PX-D and PX-E analogues are a promising candidate class of dual-acting compounds for treating Parkinson′s disease. Full article

(This article belongs to the Special Issue Polypharmacology and Multitarget Drug Discovery)

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13 pages, 2888 KB

Open AccessArticle

Cholinesterase Inhibitory Activities of Adamantyl-Based Derivatives and Their Molecular Docking Studies

by Huey Chong Kwong¹, Siau Hui Mah^2,*

, Tze Shyang Chia³, Ching Kheng Quah³, Gin Keat Lim¹ and C. S. Chidan Kumar⁴

¹ School of Chemical Sciences, Universiti Sains Malaysia, Penang 11800 USM, Malaysia

² School of Biosciences, Taylor’s University, Lakeside Campus, 47500 Subang Jaya, Selangor, Malaysia

³ X-ray Crystallography Unit, School of Physics, Universiti Sains Malaysia, Penang 11800 USM, Malaysia

⁴ Department of Engineering Chemistry, Vidya Vikas Institute of Engineering & Technology, Visvesvaraya Technological University, Alanahalli, Mysuru 570028, Karnataka, India

Molecules 2017, 22(6), 1005; https://doi.org/10.3390/molecules22061005 - 17 Jun 2017

Cited by 9 | Viewed by 5702

Abstract

Adamantyl-based compounds are clinically important for the treatments of type 2 diabetes and for their antiviral abilities, while many more are under development for other pharmaceutical uses. This study focused on the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities of adamantyl-based ester derivatives [...] Read more.

Adamantyl-based compounds are clinically important for the treatments of type 2 diabetes and for their antiviral abilities, while many more are under development for other pharmaceutical uses. This study focused on the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities of adamantyl-based ester derivatives with various substituents on the phenyl ring using Ellman’s colorimetric method. Compound 2e with a 2,4-dichloro electron-withdrawing substituent on the phenyl ring exhibited the strongest inhibition effect against AChE, with an IC₅₀ value of 77.15 µM. Overall, the adamantyl-based ester with the mono-substituent at position 3 of the phenyl ring exhibited good AChE inhibition effects with an ascending order for the substituents: Cl < NO₂ < CH₃ < OCH₃. Furthermore, compounds with electron-withdrawing groups (Cl and NO₂) substituted at position 3 on their phenyl rings demonstrated stronger AChE inhibition effects, in comparison to their respective positional isomers. On the other hand, compound 2j with a 3-methoxyphenyl ring showed the highest inhibition effect against BChE, with an IC₅₀ value of 223.30 µM. Molecular docking analyses were conducted for potential AChE and BChE inhibitors, and the results demonstrated that the peripheral anionic sites of target proteins were predominant binding sites for these compounds through hydrogen bonds and halogen interactions instead of hydrophobic interactions in the catalytic active site. Full article

(This article belongs to the Special Issue The Cholinesterases—Structure, Mechanism, Function and Drug Design: The 25th Anniversary of the Solution of the Crystal Structure of Acetylcholinesterase by Joel L. Sussman and Israel Silman)

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12 pages, 4010 KB

Open AccessArticle

In Vitro Comparative Study of the Inhibitory Effects of Mangiferin and Its Aglycone Norathyriol towards UDP-Glucuronosyl Transferase (UGT) Isoforms

by Dan Sun^1,†, Chun-Ze Zhang^2,†, Rui-Xue Ran³, Yun-Feng Cao⁴, Zuo Du^4,5, Zhi-Wei Fu^4,5, Chun-Ting Huang^4,5, Zhen-Ying Zhao⁶, Wei-Hua Zhang^2,* and Zhong-Ze Fang^4,5,*

¹ College of Life Sciences, Nankai University, Tianjin 300071, China

² Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin 300121, China

³ Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnosis, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China

⁴ Key Laborotary of Liaoning Tumor Clinical Metabolomics (KLLTCM), Jinzhou 121001, Liaoning, China

⁵ Department of Toxicology, School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin 300070, China

⁶ Tianjin Union Medical Center, 190 Jieyuan Road, Hongqiao District, Tianjin 300121, China

^† These two authors equally contributed to this work.

Molecules 2017, 22(6), 1008; https://doi.org/10.3390/molecules22061008 - 16 Jun 2017

Cited by 28 | Viewed by 5659

Abstract

Mangiferin (MGF), the predominant constituent of extracts of the mango plant Mangifera Indica L., has been investigated extensively because of its remarkable pharmacological effects. In vitro recombinant UGTs-catalyzed glucuronidation of 4-methylumbelliferone (4-MU) was used to investigate the inhibition of mangiferin and aglycone norathyriol [...] Read more.

Mangiferin (MGF), the predominant constituent of extracts of the mango plant Mangifera Indica L., has been investigated extensively because of its remarkable pharmacological effects. In vitro recombinant UGTs-catalyzed glucuronidation of 4-methylumbelliferone (4-MU) was used to investigate the inhibition of mangiferin and aglycone norathyriol towards various isoforms of UGTs in our study, which evaluated the inhibitory capacity of MGF and its aglycone norathyriol (NTR) towards UDP-glucuronosyltransferase (UGT) isoforms. Initial screening experiment showed that deglycosylation of MGF into NTR strongly increased the inhibitory effects towards almost all the tested UGT isoforms at a concentration of 100 μM. Kinetic experiments were performed to further characterize the inhibition of UGT1A3, UGT1A7 and UGT1A9 by NTR. NTR competitively inhibited UGT1A3, UGT1A7 and UGT1A9, with an IC₅₀ value of 8.2, 4.4, and 12.3 μM, and a Ki value of 1.6, 2.0, and 2.8 μM, respectively. In silico docking showed that only NTR could dock into the activity cavity of UGT1A3, UGT1A7 and UGT1A9. The binding free energy of NTR to UGT1A3, 1A7, 1A9 were −7.4, −7.9 and −4.0 kcal/mol, respectively. Based on the inhibition evaluation standard ([I]/Ki < 0.1, low possibility; 0.1 < [I]/Ki < 1, medium possibility; [I]/Ki > 1, high possibility), an in vivo herb–drug interaction between MGF/NTR and drugs mainly undergoing UGT1A3-, UGT1A7- or UGT1A9-catalyzed metabolism might occur when the plasma concentration of NTR is above 1.6, 2.0 and 2.8 μM, respectively. Full article

(This article belongs to the Section Metabolites)

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28 pages, 4081 KB

Open AccessArticle

Comprehensive Identification of Guan-Xin-Shu-Tong Capsule via a Mass Defect and Fragment Filtering Approach by High Resolution Mass Spectrometry: In Vitro and In Vivo Study

by Xun Gao¹, Jingqing Mu², Qing Li², Shaoyi Guan³, Ran Liu², Yiyang Du², Huifen Zhang^2,* and Kaishun Bi^2,*

¹ School of Traditional Chinese Medicine, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China

² School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China

³ The General Hospital of Shenyang Military, 83 Wenhua Road, Shenyang 110016, China

Molecules 2017, 22(6), 1007; https://doi.org/10.3390/molecules22061007 - 16 Jun 2017

Cited by 12 | Viewed by 6537

Abstract

The Guan-Xin-Shu-Tong capsule (GXSTC) is a well-known traditional Chinese medicine that is used for the treatment of coronary heart disease. Despite its common use in China, basic pharmacological research on its active components is limited. A comprehensive analytical method using quadrupole-time-of-flight mass spectrometry [...] Read more.

The Guan-Xin-Shu-Tong capsule (GXSTC) is a well-known traditional Chinese medicine that is used for the treatment of coronary heart disease. Despite its common use in China, basic pharmacological research on its active components is limited. A comprehensive analytical method using quadrupole-time-of-flight mass spectrometry (Q-TOF/MS), specifically with the Triple TOF 5600 platform, was developed to characterize the compounds in the GXSTC powder itself (in vitro) as well as the active components in healthy and heart disease model rats after its oral administration (in vivo). The 5600 platform was operated in both positive and negative ion modes, before the raw data were processed using the extracted ion chromatography (EIC), mass defect filtering (MDF) and fragment filtering (FF) techniques. With the aid of reference compounds for retention time and fragment ion comparisons, 18 compounds were unambiguously identified in vitro. An additional 56 other compounds were tentatively characterized using the accurate quasi-molecular ion mass and Tandem mass spectrometry (MS/MS) fragmentation pattern strategies. Among them, 30 compounds were characterized based on the MDF and FF approaches. Normal rats in addition to hyperlipidemic (HL) and acute blood stasis (ABS) model rats were given a single oral dose of GXSTC solution for subsequent blood analysis at 1 and 2 h after administration. A total of 24 prototypecomponents and 20 metabolites derived from GXSTC were differentially detected across the three animal groups, including the absence of four phase II phenolic acid metabolites in the ABS group and the presence of three diterpenoid-related metabolites exclusive to the HL group. The use of reference compounds as well as the mass defect and fragment-filtering strategies were critical to identify GXSTC compounds in vitro and in vivo. This can be used for further quality control and pharmacological studies aimed at characterizing the active and potential beneficial compounds of this ancient medicine. Full article

(This article belongs to the Section Natural Products Chemistry)

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22 pages, 1976 KB

Open AccessArticle

Novel Tacrine-Scutellarin Hybrids as Multipotent Anti-Alzheimer’s Agents: Design, Synthesis and Biological Evaluation

by Katarina Spilovska^1,2, Jan Korabecny^1,3

, Vendula Sepsova^1,3

, Daniel Jun^1,3, Martina Hrabinova^1,3, Petr Jost¹, Lubica Muckova¹, Ondrej Soukup^2,3

, Jana Janockova³

, Tomas Kucera¹, Rafael Dolezal³, Eva Mezeiova^2,3, Daniel Kaping² and Kamil Kuca^3,*

¹ Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic

² National Institute of Mental Health, Topolova 748, 250 67 Klecany, Czech Republic

³ Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic

Molecules 2017, 22(6), 1006; https://doi.org/10.3390/molecules22061006 - 16 Jun 2017

Cited by 45 | Viewed by 8533

Abstract

A novel series of 6-chlorotacrine-scutellarin hybrids was designed, synthesized and the biological activity as potential anti-Alzheimer’s agents was assessed. Their inhibitory activity towards human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE), antioxidant activity, ability to cross the blood-brain barrier (BBB) [...] Read more.

A novel series of 6-chlorotacrine-scutellarin hybrids was designed, synthesized and the biological activity as potential anti-Alzheimer’s agents was assessed. Their inhibitory activity towards human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE), antioxidant activity, ability to cross the blood-brain barrier (BBB) and hepatotoxic profile were evaluated in vitro. Among these compounds, hybrid K1383, bearing two methylene tether between two basic scaffolds, was found to be very potent hAChE inhibitor (IC₅₀ = 1.63 nM). Unfortunately, none of the hybrids displayed any antioxidant activity (EC₅₀ ≥ 500 μM). Preliminary data also suggests a comparable hepatotoxic profile with 6-Cl-THA (established on a HepG2 cell line). Kinetic studies performed on hAChE with the most active compound in the study, K1383, pointed out to a mixed, non-competitive enzyme inhibition. These findings were further corroborated by docking studies. Full article

(This article belongs to the Special Issue Polypharmacology and Multitarget Drug Discovery)

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8 pages, 529 KB

Open AccessArticle

Hydronopylformamides: Modification of the Naturally Occurring Compound (-)-β-Pinene to Produce Insect Repellent Candidates against Blattella germanica

by Shengliang Liao¹, Yan Liu², Hongyan Si¹, Zhuanquan Xiao³, Guorong Fan¹, Shangxing Chen¹, Peng Wang¹ and Zongde Wang^1,*

¹ College of Forestry, Jiangxi Agricultural University, Camphor Tree Engineering and Technology Research Center of State Forestry Administration and Jiangxi Province, Nanchang 330045, Jiangxi, China

² Yichun Hydrological Bureau of Jiangxi Province, Yichun 336000, Jiangxi, China

³ College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330027, China

Molecules 2017, 22(6), 1004; https://doi.org/10.3390/molecules22061004 - 16 Jun 2017

Cited by 11 | Viewed by 5486

Abstract

The development of a novel repellent plays an important role in the integrated control of Blattella germanica. A series of novel hydronopylformamides derivatives were synthesized from a naturally occurring compound (-)-β-pinene. The structures of these hydronopylformamides derivatives were characterized by Fourier transform [...] Read more.

The development of a novel repellent plays an important role in the integrated control of Blattella germanica. A series of novel hydronopylformamides derivatives were synthesized from a naturally occurring compound (-)-β-pinene. The structures of these hydronopylformamides derivatives were characterized by Fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance spectroscopy (¹H-NMR and ¹³C-NMR), and electron impact mass spectrometry (EI-MS). Repellency of these hydronopylformamides derivatives against Blattella germanica was evaluated by the using petri dish arena method. The results showed that four derivatives (compounds 8a, 8b, 8c and 8e) exhibited repellency against Blattella germanica at a concentration of 20 mg/mL. Compound 8a was the most active compound among these derivatives, where the repelling ratios of compound 8a against Blattella germanica were 66.10%, 50.46%, 48.26%, at concentrations of 20 mg/mL, 10 mg/mL, and 5 mg/mL, respectively. In addition, compound 8a showed better repellency than the traditional insect repellent N, N-diethyl-3-methylbenzamide (DEET), which indicated that compound 8a had a good application prospect in the prevention of Blattella germanica. This research hopes to promote the value-added utilization of (-)-β-pinene and the development of novel German cockroach repellents. Full article

(This article belongs to the Special Issue Natural Product Inspired Scaffolds Designs)

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13 pages, 1847 KB

Open AccessArticle

Anti-Inflammatory and Anti-Oxidant Potential of the Root Extract and Constituents of Doronicum austriacum

by Stefania Marzocco¹

, Simona Adesso^1,2, Mostafa Alilou³, Hermann Stuppner³ and Stefan Schwaiger^3,*

¹ Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, I-84084 Fisciano SA, Italy

² PhD Program in Drug Discovery and Development, University of Salerno, Via Giovanni Paolo II 132, I-84084 Fisciano SA, Italy

³ Institute of Pharmacy, Pharmacognosy, Member of the CMBI, University of Innsbruck, CCB, Innrain 80-82, 6020 Innsbruck, Austria

Molecules 2017, 22(6), 1003; https://doi.org/10.3390/molecules22061003 - 16 Jun 2017

Cited by 25 | Viewed by 4974

Abstract

Background: Doronicum austriacum Jacq., Asteraceae, is a plant which is used in traditional alpine medicine. Historical sources describe the medical use of the root, but up until now only a few studies evaluated its pharmacological properties. The evaluation of the dichloromethane extract, and [...] Read more.

Background: Doronicum austriacum Jacq., Asteraceae, is a plant which is used in traditional alpine medicine. Historical sources describe the medical use of the root, but up until now only a few studies evaluated its pharmacological properties. The evaluation of the dichloromethane extract, and its major compounds for their anti-inflammatory and anti-oxidant potential was performed in macrophages J774A.1 and C6 astrocytes. Nitric oxide (NO) and reactive oxygen species (ROS) release, as well as nitrotyrosine formation, were evaluated. Moreover, in order to evaluate the potential anti-proliferative activity, under the same experimental conditions, 3-(4,5-dimethyltiazol-2yl)-2,5-phenyl-2H-tetrazolium bromide (MTT) assay was also performed. Our results indicate that Doronicum austriacum has a significant effect in inhibiting both pro-inflammatory and pro-oxidative mediators. All isolated compounds were able to significantly inhibit NO and ROS release both in macrophage and in astrocytes cells, even if the effect was more pronounced in macrophage. In particular, among the tested compounds, 6,12-dihydroxy-(−)-2S-tremetone exerted stronger activity. Both extract and single compounds did not affect cellular viability. This study provides evidence for the pharmacological anti-inflammatory and anti-oxidant potential of Doronicum austriacum extract. These effects could be due to the activity of its major constituents and subsequent identification of benzofurans as a promising compound class to combat inflammation and related diseases. Full article

(This article belongs to the Section Natural Products Chemistry)

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14 pages, 580 KB

Open AccessArticle

Identification of Onosma visianii Roots Extract and Purified Shikonin Derivatives as Potential Acaricidal Agents against Tetranychus urticae

by Stefania Sut^1,†, Roman Pavela^2,†, Vladislav Kolarčik³, Loredana Cappellacci⁴

, Riccardo Petrelli⁴

, Filippo Maggi^4,*

, Stefano Dall’Acqua^1,*

and Giovanni Benelli⁵

¹ Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo, 35121 Padova, Italy

² Crop Research Institute, Drnovska 507, 161 06, Prague 6, Czech Republic

³ Department of Botany, Institute of Biology and Ecology, Faculty of Science, P.J. Šafárik University, Mánesova 23, 04154 Košice, Slovakia

⁴ School of Pharmacy, University of Camerino, Via Sant’Agostino 1, 62032 Camerino, Italy

⁵ Department of Agriculture, Food and Environment, University of Pisa, via del Borghetto 80, 56124 Pisa, Italy

^† These authors contributed equally to the work.

Molecules 2017, 22(6), 1002; https://doi.org/10.3390/molecules22061002 - 16 Jun 2017

Cited by 32 | Viewed by 6536

Abstract

There is an increasing need for the discovery of reliable and eco-friendly pesticides and natural plant-derived products may play a crucial role as source of new active compounds. In this research, a lipophilic extract of Onosma visianii roots extract containing 12% of shikonin [...] Read more.

There is an increasing need for the discovery of reliable and eco-friendly pesticides and natural plant-derived products may play a crucial role as source of new active compounds. In this research, a lipophilic extract of Onosma visianii roots extract containing 12% of shikonin derivatives demonstrated significant toxicity and inhibition of oviposition against Tetranychus urticae mites. Extensive chromatographic separation allowed the isolation of 11 naphthoquinone derivatives that were identified by spectral techniques and were tested against Tetranychus urticae. All the isolated compounds presented effects against the considered mite and isobutylshikonin (1) and isovalerylshikonin (2) were the most active, being valuable model compounds for the study of new anti-mite agents. Full article

(This article belongs to the Section Natural Products Chemistry)

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15 pages, 2274 KB

Open AccessArticle

Discovery of Indeno[1,2-c]quinoline Derivatives as Potent Dual Antituberculosis and Anti-Inflammatory Agents

by Chih-Hua Tseng^1,2,3,4,5

, Chun-Wei Tung^1,5,6

, Chen-Hsin Wu⁷, Cherng-Chyi Tzeng^3,5,7, Yen-Hsu Chen^8,9,10,11,*

, Tsong-Long Hwang^12,13,14,*

and Yeh-Long Chen^4,5,7,*

¹ School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan

² Department of Fragrance and Cosmetic Science, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan

³ Research Center for Natural Products and Drug Development, Kaohsiung Medical University, Kaohsiung 807, Taiwan

⁴ Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan

⁵ Department of Medical Research, Kaohsiung Medical University-Hospital, Kaohsiung 807, Taiwan

⁶ Ph.D. Program in Toxicology, Kaohsiung Medical University, Kaohsiung City 807, Taiwan

⁷ Department of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung 807, Taiwan

⁸ Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Medical University-Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan

⁹ School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan

¹⁰ Department of Laboratory Medicine, Kaohsiung Medical University-Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan

¹¹ Center for Dengue Fever Control and Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan

¹² Graduate Institute of Natural Products, College of Medicine, and Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Taoyuan 333, Taiwan

¹³ Research Center for Chinese Herbal Medicine, Research Center for Food and Cosmetic Safety, and Graduate Institute of Health Industry Technology, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan

¹⁴ Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan

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Molecules 2017, 22(6), 1001; https://doi.org/10.3390/molecules22061001 - 16 Jun 2017

Cited by 38 | Viewed by 6590

Abstract

A series of indeno[1,2-c]quinoline derivatives were designed, synthesized and evaluated for their anti-tuberculosis (anti-TB) and anti-inflammatory activities. The minimum inhibitory concentration (MIC) of the newly synthesized compound was tested against Mycobacterium tuberculosis H₃₇R_V. Among the tested compounds, [...] Read more.

A series of indeno[1,2-c]quinoline derivatives were designed, synthesized and evaluated for their anti-tuberculosis (anti-TB) and anti-inflammatory activities. The minimum inhibitory concentration (MIC) of the newly synthesized compound was tested against Mycobacterium tuberculosis H₃₇R_V. Among the tested compounds, (E)-N′-[6-(4-hydroxypiperidin-1-yl)-11H-indeno[1,2-c]quinolin-11-ylidene]isonicotino-hydrazide (12), exhibited significant activities against the growth of M. tuberculosis (MIC values of 0.96 μg/mL) with a potency approximately equal to that of isoniazid (INH), an anti-TB drug. Important structure features were analyzed by quantitative structure–activity relationship (QSAR) analysis to give better insights into the structure determinants for predicting the anti-TB activity. The anti-inflammatory activity was induced by superoxide anion generation and neutrophil elastase (NE) release using the formyl-l-methionyl-l-leucyl-l-phenylalanine (fMLF)-activated human neutrophils method. Results indicated that compound 12 demonstrated a potent dual inhibitory effect on NE release and superoxide anion generation with IC₅₀ values of 1.76 and 1.72 μM, respectively. Our results indicated that compound 12 is a potential lead compound for the discovery of dual anti-TB and anti-inflammatory drug candidates. In addition, 6-[3-(hydroxymethyl)piperidin-1-yl]-9-methoxy-11H-indeno[1,2-c]quinolin-11-one (4g) showed a potent dual inhibitory effect on NE release and superoxide anion generation with IC₅₀ values of 0.46 and 0.68 μM, respectively, and is a potential lead compound for the discovery of anti-inflammatory drug candidates. Full article

(This article belongs to the Special Issue Frontiers in Antimicrobial Drug Discovery and Design)

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Molecules, Volume 22, Issue 6 (June 2017) – 171 articles

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