Molecules

11 pages, 3666 KiB

Open AccessArticle

Exploring the Self-Assembled Tacticity in Aurophilic Polymeric Arrangements of Diphosphanegold(I) Fluorothiolates

by Guillermo Moreno-Alcántar, Laura Salazar, Guillermo Romo-Islas, Marcos Flores-Álamo and Hugo Torrens

Molecules 2019, 24(23), 4422; https://doi.org/10.3390/molecules24234422 - 3 Dec 2019

Cited by 5 | Viewed by 3206

Abstract

Despite the recurrence of aurophilic interactions in the solid-state structures of gold(I) compounds, its rational control, modulation, and application in the generation of functional supramolecular structures is an area that requires further development. The ligand effects over the aurophilic-based supramolecular structures need to [...] Read more.

Despite the recurrence of aurophilic interactions in the solid-state structures of gold(I) compounds, its rational control, modulation, and application in the generation of functional supramolecular structures is an area that requires further development. The ligand effects over the aurophilic-based supramolecular structures need to be better understood. This paper presents the supramolecular structural diversity of a series of new 1,3-bis(diphenylphosphane)propane (dppp) gold(I) fluorinated thiolates with the general formula [Au₂(SR_F)₂(μ-dppp)] (SR_F = SC₆F₅ (1); SC₆HF₄-4 (2); SC₆H₃(CF₃)₂-3,5 (3); SC₆H₄CF₃-2 (4); SC₆H₄CF₃-4 (5); SC₆H₃F₂-3,4 (6); SC₆H₃F₂-3,5 (7); SC₆H₄F-2 (8); SC₆H₄F-3 (9); SC₆H₄F-4 (10)). These compounds were synthesized and characterized, and six of their solid-state crystalline structures were determined using single-crystal X-ray diffraction. In the crystalline arrangement, they form aurophilic-bridged polymers. In these systems, the changes in the fluorination patterns of the thiolate ligands tune the aurophilic-induced self-assembly of the compounds causing tacticity and chiral differentiation of the monomers. This is an example of the use of ligand effects on the tune of the supramolecular association of gold complexes. Full article

(This article belongs to the Special Issue Advances in Supramolecular Chemistry)

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16 pages, 479 KiB

Open AccessArticle

Antiprotozoal Activity of Turkish Origanum onites Essential Oil and Its Components

by Deniz Tasdemir, Marcel Kaiser, Betül Demirci, Fatih Demirci and K. Hüsnü Can Baser

Molecules 2019, 24(23), 4421; https://doi.org/10.3390/molecules24234421 - 3 Dec 2019

Cited by 43 | Viewed by 7395

Abstract

Essential oil of Origanum species is well known for antimicrobial activity, but only a few have been evaluated in narrow spectrum antiprotozoal assays. Herein, we assessed the antiprotozoal potential of Turkish Origanum onites L. oil and its major constituents against a panel of [...] Read more.

Essential oil of Origanum species is well known for antimicrobial activity, but only a few have been evaluated in narrow spectrum antiprotozoal assays. Herein, we assessed the antiprotozoal potential of Turkish Origanum onites L. oil and its major constituents against a panel of parasitic protozoa. The essential oil was obtained by hydrodistillation from the dried herbal parts of O. onites and analyzed by Gas Chromatography-Flame Ionization Detector (GC-FID) and Gas Chromatography coupled with Mass Spectrometry (GC-MS). The in vitro activity of the oil and its major components were evaluated against Trypanosoma brucei rhodesiense, T. cruzi, Leishmania donovani, and Plasmodium falciparum. The main component of the oil was identified as carvacrol (70.6%), followed by linalool (9.7%), p-cymene (7%), γ-terpinene (2.1%), and thymol (1.8%). The oil showed significant in vitro activity against T. b. rhodesiense (IC₅₀ 180 ng/mL), and moderate antileishmanial and antiplasmodial effects, without toxicity to mammalian cells. Carvacrol, thymol, and 10 additional abundant oil constituents were tested against the same panel; carvacrol and thymol retained the oil’s in vitro antiparasitic potency. In the T. b. brucei mouse model, thymol, but not carvacrol, extended the mean survival of animals. This study indicates the potential of the essential oil of O. onites and its constituents in the treatment of protozoal infections. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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32 pages, 3761 KiB

Open AccessArticle

Optimizing Water-Based Extraction of Bioactive Principles of Hawthorn: From Experimental Laboratory Research to Homemade Preparations

by Phu Cao Ngoc, Laurent Leclercq, Jean-Christophe Rossi, Isabelle Desvignes, Jasmine Hertzog, Anne-Sylvie Fabiano-Tixier, Farid Chemat, Philippe Schmitt-Kopplin and Hervé Cottet

Molecules 2019, 24(23), 4420; https://doi.org/10.3390/molecules24234420 - 3 Dec 2019

Cited by 14 | Viewed by 5580

Abstract

Hawthorn (Crataegus) is used for its cardiotonic, hypotensive, vasodilative, sedative, antiatherosclerotic, and antihyperlipidemic properties. One of the main goals of this work was to find a well-defined optimized extraction protocol usable by each of us that would lead to repeatable, controlled, and quantified [...] Read more.

Hawthorn (Crataegus) is used for its cardiotonic, hypotensive, vasodilative, sedative, antiatherosclerotic, and antihyperlipidemic properties. One of the main goals of this work was to find a well-defined optimized extraction protocol usable by each of us that would lead to repeatable, controlled, and quantified daily uptake of active components from hawthorn at a drinkable temperature (below 60 °C). A thorough investigation of the extraction mode in water (infusion, maceration, percolation, ultrasounds, microwaves) on the yield of extraction and the amount of phenolic compounds, flavonoids, and proanthocyanidin oligomers as well as on the Ultra High Performance Liquid Chromatography (UHPLC) profiles of the extracted compounds was carried out. High-resolution Fourier transform ion cyclotron resonance mass spectrometry was also implemented to discriminate the different samples and conditions of extraction. The quantitative and qualitative aspects of the extraction as well as the kinetics of extraction were studied, not only according to the part (flowers or leaves), the state (fresh or dried), and the granulometry of the dry plant, but also the stirring speed, the temperature, the extraction time, the volume of the container (cup, mug or bowl) and the use of infusion bags. Full article

(This article belongs to the Special Issue From Green to Democratic Analytical Chemistry)

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31 pages, 2136 KiB

Open AccessReview

Anti-Infective and Anti-Cancer Properties of the Annona Species: Their Ethnomedicinal Uses, Alkaloid Diversity, and Pharmacological Activities

by Ari Satia Nugraha, Yuvita Dian Damayanti, Phurpa Wangchuk and Paul A. Keller

Molecules 2019, 24(23), 4419; https://doi.org/10.3390/molecules24234419 - 3 Dec 2019

Cited by 54 | Viewed by 9601

Abstract

Annona species have been a valuable source of anti-infective and anticancer agents. However, only limited evaluations of their alkaloids have been carried out. This review collates and evaluates the biological data from extracts and purified isolates for their anti-infective and anti-cancer activities. An [...] Read more.

Annona species have been a valuable source of anti-infective and anticancer agents. However, only limited evaluations of their alkaloids have been carried out. This review collates and evaluates the biological data from extracts and purified isolates for their anti-infective and anti-cancer activities. An isoquinoline backbone is a major structural alkaloid moiety of the Annona genus, and more than 83 alkaloids have been isolated from this genus alone. Crude extracts of Annona genus are reported with moderate activities against Plasmodium falciparum showing larvicidal activities. However, no pure compounds from the Annona genus were tested against the parasite. The methanol extract of Annona muricata showed apparent antimicrobial activities. The isolated alkaloids from this genus including liriodenine, anonaine, asimilobine showed sensitivity against Staphylococcus epidermidis. Other alkaloids such as (+)-Xylopine and isocoreximine indicated significant anti-cancer activity against A549 and K-562 cell lines, respectively. This review revealed that the alkaloids from Annona genus are rich in structural diversity and pharmacological activities. Further exploration of this genus and their alkaloids has potential for developing novel anti-infective and anticancer drugs. Full article

(This article belongs to the Special Issue From Ethnobotany to Ecopharmacognosy: Chemical Characterization and Bioactivity Evaluation of Medicinal and Aromatic Plants)

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12 pages, 780 KiB

Open AccessCommunication

Composition of Essential Oils from Roots and Aerial Parts of Carpesium divaricatum, a Traditional Herbal Medicine and Wild Edible Plant from South-East Asia, Grown in Poland

by Anna Wajs-Bonikowska, Janusz Malarz and Anna Stojakowska

Molecules 2019, 24(23), 4418; https://doi.org/10.3390/molecules24234418 - 3 Dec 2019

Cited by 10 | Viewed by 4556

Abstract

Carpesium divaricatum Sieb. and Zucc. has long been used both as traditional medicine and seasonal food. The most extensively studied specialized metabolites synthesized by the plant are sesquiterpene lactones of germacrane-type. Low-molecular and volatile terpenoids produced by C. divaricatum, however, have never [...] Read more.

Carpesium divaricatum Sieb. and Zucc. has long been used both as traditional medicine and seasonal food. The most extensively studied specialized metabolites synthesized by the plant are sesquiterpene lactones of germacrane-type. Low-molecular and volatile terpenoids produced by C. divaricatum, however, have never been explored. In this work, compositions of essential oils distilled from roots and shoots of C. divaricatum plants, cultivated either in the open field or in the glasshouse have been studied by GC-MS-FID supported by NMR spectroscopy. The analyses led to the identification of 145 compounds in all, 112 of which were localized in aerial parts and 80 in roots of the plants grown in the open field. Moreover, remarkable differences in composition of oils produced by aerial and underground parts of C. divaricatum have been observed. The major volatiles found in the shoots were: α-pinene (40%), nerol (4%) and neryl-isobutyrate (3%), whereas predominant components of the root oil were 10-isobutyryloxy-8,9-epoxythymyl-isobutyrate (29%), thymyl-isobutyrate (6%) and 9-isobutyryloxythymyl-isobutyrate (6%). In the analyzed oils, seventeen thymol derivatives were identified. Among them eight compounds were specific for roots. Roots of the plants cultivated in the glasshouse were, in general, a poor source of essential oil in comparison with those of the plants grown in the open field. Chemophenetic relationships with other taxa of the Inuleae-Inulineae were also briefly discussed. Full article

(This article belongs to the Special Issue Progress in Volatile Organic Compounds Research)

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25 pages, 4581 KiB

Open AccessArticle

Conformational Investigations in Flexible Molecules Using Orientational NMR Constraints in Combination with ³J-Couplings and NOE Distances

by Christophe Farès, Julia B. Lingnau, Cornelia Wirtz and Ulrich Sternberg

Molecules 2019, 24(23), 4417; https://doi.org/10.3390/molecules24234417 - 3 Dec 2019

Cited by 12 | Viewed by 4995

Abstract

The downscaling of NMR tensorial interactions, such as dipolar couplings, from tens of kilohertz to a few hertz in low-order media is the result of dynamics spanning several orders of magnitudes, including vibrational modes (~ns-fs), whole-molecule reorientation (~ns) and higher barrier internal conformational [...] Read more.

The downscaling of NMR tensorial interactions, such as dipolar couplings, from tens of kilohertz to a few hertz in low-order media is the result of dynamics spanning several orders of magnitudes, including vibrational modes (~ns-fs), whole-molecule reorientation (~ns) and higher barrier internal conformational exchange (<ms). In this work, we propose to employ these dynamically averaged interactions to drive an “alignment-tensor-free” molecular dynamic simulation with orientation constraints (MDOC) in order to efficiently access the conformational space sampled by flexible small molecules such as natural products. Key to this approach is the application of tensorial pseudo-force restraints which simultaneously guide the overall reorientation and conformational fluctuations based on defined memory function over the running trajectory. With the molecular mechanics force-field, which includes bond polarization theory (BPT), and complemented with other available NMR parameters such as NOEs and scalar J-couplings, MDOC efficiently arrives at dynamic ensembles that reproduce the entire NMR dataset with exquisite accuracy and theoretically reveal the systems conformational space and equilibrium. The method as well as its potential towards configurational elucidation is presented on diastereomeric pairs of flexible molecules: a small 1,4-diketone 1 with a single rotatable bond as well as a 24-ring macrolide related to the natural product mandelalide A 2. Full article

(This article belongs to the Special Issue NMR Spectroscopy in Natural Product Structure Elucidation)

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13 pages, 4109 KiB

Open AccessArticle

Sal B Alleviates Myocardial Ischemic Injury by Inhibiting TLR4 and the Priming Phase of NLRP3 Inflammasome

by Yang Hu, Qingju Li, Yunzheng Pan and Li Xu

Molecules 2019, 24(23), 4416; https://doi.org/10.3390/molecules24234416 - 3 Dec 2019

Cited by 18 | Viewed by 3644

Abstract

Salvianolic acid B is one of the main water-soluble components of Salvia miltiorrhiza Bge. Many reports have shown that it has significant anti-myocardial ischemia effect. However, the underlying mechanism remains unclear. Our present study demonstrated that Sal B could alleviate myocardial ischemic injury [...] Read more.

Salvianolic acid B is one of the main water-soluble components of Salvia miltiorrhiza Bge. Many reports have shown that it has significant anti-myocardial ischemia effect. However, the underlying mechanism remains unclear. Our present study demonstrated that Sal B could alleviate myocardial ischemic injury by inhibiting the priming phase of NLRP3 inflammasome. In vivo, serum c-troponin I (cTn), lactate dehydrogenase (LDH) levels, the cardiac function and infract size were examined. We found that Sal B could notably reduce the myocardial ischemic injury caused by ligation of the left anterior descending coronary artery. In vitro, Sal B down-regulated the TLR4/NF-κB signaling cascades in lipopolysaccharide (LPS)-stimulated H9C2 cells. Furthermore, Sal B reduced the expression levels of IL-1β and NLRP3 inflammasome in a dose-dependent manner. In short, our study provided evidence that Sal B could attenuate myocardial ischemic injury via inhibition of TLR4/NF-κB/NLRP3 signaling pathway. And in an upstream level, MD-2 may be the potential target. Full article

(This article belongs to the Special Issue Natural Product Pharmacology and Medicinal Chemistry)

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19 pages, 3524 KiB

Open AccessArticle

7-epi-Clusianone, a Multi-Targeting Natural Product with Potential Chemotherapeutic, Immune-Modulating, and Anti-Angiogenic Properties

by Wesley F. Taylor, Maria Yanez, Sara E. Moghadam, Mahdi Moridi Farimani, Sara Soroury, Samad N. Ebrahimi, Marzieh Tabefam and Ehsan Jabbarzadeh

Molecules 2019, 24(23), 4415; https://doi.org/10.3390/molecules24234415 - 3 Dec 2019

Cited by 19 | Viewed by 3297

Abstract

Targeted therapies have changed the treatment of cancer, giving new hope to many patients in recent years. The shortcomings of targeted therapies including acquired resistance, limited susceptible patients, high cost, and high toxicities, have led to the necessity of combining these therapies with [...] Read more.

Targeted therapies have changed the treatment of cancer, giving new hope to many patients in recent years. The shortcomings of targeted therapies including acquired resistance, limited susceptible patients, high cost, and high toxicities, have led to the necessity of combining these therapies with other targeted or chemotherapeutic treatments. Natural products are uniquely capable of synergizing with targeted and non-targeted anticancer regimens due to their ability to affect multiple cellular pathways simultaneously. Compounds which provide an additive effect to the often combined immune therapies and cytotoxic chemotherapies, are exceedingly rare. These compounds would however provide a strengthening bridge between the two treatment modalities, increasing their effectiveness and improving patient prognoses. In this study, 7-epi-clusianone was investigated for its anticancer properties. While previous studies have suggested clusianone and its conformational isomers, including 7-epi-clusianone, are chemotherapeutic, few cancer types have been demonstrated to exhibit sensitivity to these compounds and little is known about the mechanism. In this study, 7-epi-clusianone was shown to inhibit the growth of 60 cancer cell types and induce significant cell death in 25 cancer cell lines, while simultaneously modulating the immune system, inhibiting angiogenesis, and inhibiting cancer cell invasion, making it a promising lead compound for cancer drug discovery. Full article

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32 pages, 1677 KiB

Open AccessReview

Forty Years Since the Structural Elucidation of Platelet-Activating Factor (PAF): Historical, Current, and Future Research Perspectives

by Ronan Lordan, Alexandros Tsoupras, Ioannis Zabetakis and Constantinos A. Demopoulos

Molecules 2019, 24(23), 4414; https://doi.org/10.3390/molecules24234414 - 3 Dec 2019

Cited by 104 | Viewed by 8897

Abstract

In the late 1960s, Barbaro and Zvaifler described a substance that caused antigen induced histamine release from rabbit platelets producing antibodies in passive cutaneous anaphylaxis. Henson described a ‘soluble factor’ released from leukocytes that induced vasoactive amine release in platelets. Later observations by [...] Read more.

In the late 1960s, Barbaro and Zvaifler described a substance that caused antigen induced histamine release from rabbit platelets producing antibodies in passive cutaneous anaphylaxis. Henson described a ‘soluble factor’ released from leukocytes that induced vasoactive amine release in platelets. Later observations by Siraganuan and Osler observed the existence of a diluted substance that had the capacity to cause platelet activation. In 1972, the term platelet-activating factor (PAF) was coined by Benveniste, Henson, and Cochrane. The structure of PAF was later elucidated by Demopoulos, Pinckard, and Hanahan in 1979. These studies introduced the research world to PAF, which is now recognised as a potent phospholipid mediator. Since its introduction to the literature, research on PAF has grown due to interest in its vital cell signalling functions and more sinisterly its role as a pro-inflammatory molecule in several chronic diseases including cardiovascular disease and cancer. As it is forty years since the structural elucidation of PAF, the aim of this review is to provide a historical account of the discovery of PAF and to provide a general overview of current and future perspectives on PAF research in physiology and pathophysiology. Full article

(This article belongs to the Section Medicinal Chemistry)

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14 pages, 1284 KiB

Open AccessArticle

Identification and Quantitation of Ursolic and Oleanolic Acids in Ilex aquifolium L. Leaf Extracts Using ¹³C and ¹H-NMR Spectroscopy

by Doreen Palu, Ange Bighelli, Joseph Casanova and Mathieu Paoli

Molecules 2019, 24(23), 4413; https://doi.org/10.3390/molecules24234413 - 3 Dec 2019

Cited by 17 | Viewed by 5748

Abstract

Leaves of Ilex aquifolium L. have been used for their therapeutic properties. In previous studies, components contained in the leaves were first isolated by various chromatographic techniques. Then, quantitation of oleanolic and ursolic acids, which are responsible for the biological and therapeutic activities [...] Read more.

Leaves of Ilex aquifolium L. have been used for their therapeutic properties. In previous studies, components contained in the leaves were first isolated by various chromatographic techniques. Then, quantitation of oleanolic and ursolic acids, which are responsible for the biological and therapeutic activities of the plant, was performed by HPLC, HPTLC, and somewhat by GC-MS. Our objective was to develop a simple method that allows the identification of compounds contained in the leaves of Corsican I. aquifolium and to quantify ursolic and oleanolic acids. Leaves were successively extracted with hexane and dichloromethane. The extracts were chromatographed on silica gel and the fractions of column chromatography submitted to ¹³C-NMR analysis, following a computerized method developed in the laboratory. ¹³C-NMR allowed the identification of various triterpenes including ursolic acid and oleanolic acid. Quantitation of both acids was achieved, for the first time, by ¹H-NMR after validation of the method (accuracy, precision, linearity, limit of detection and limit of quantitation). Ursolic and oleanolic acids accounted for 55.3% and 20.8% of the dichloromethane extract, respectively. This represents 1.3% and 0.5% of the mass of dried leaves. ¹H-NMR spectroscopy appeared as a powerful tool for a rapid quantitation of biologically active compounds from I. aquifolium. Full article

(This article belongs to the Special Issue NMR Spectroscopy as a Structural and Analytical Probe of Natural Products: Emerging Advancements and Future Insights)

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10 pages, 855 KiB

Open AccessArticle

Cytotoxic Stilbenes and Canthinone Alkaloids from Brucea antidysenterica (Simaroubaceae)

by Yves Salomon Makong, Gervais Mouthé Happi, Judith Liliane Djouaka Bavoua, Jean Duplex Wansi, Lutfun Nahar, Alain François Kamdem Waffo, Claire Martin, Norbert Sewald and Satyajit Dey Sarker

Molecules 2019, 24(23), 4412; https://doi.org/10.3390/molecules24234412 - 3 Dec 2019

Cited by 16 | Viewed by 4061

Abstract

A phytochemical study of the root and bark of Brucea antidysenterica J. F. Mill. (Simaroubaceae) afforded three new compounds, including a stilbene glycoside bruceanoside A (1), and two canthinone alkaloids bruceacanthinones A (3) and B (4), along [...] Read more.

A phytochemical study of the root and bark of Brucea antidysenterica J. F. Mill. (Simaroubaceae) afforded three new compounds, including a stilbene glycoside bruceanoside A (1), and two canthinone alkaloids bruceacanthinones A (3) and B (4), along with ten known secondary metabolites, rhaponticin (2), 1,11-dimethoxycanthin-6-one (5), canthin-6-one (6), 1-methoxycanthin-6-one (7), 2-methoxycanthin-6-one (8), 2-hydroxy-1,11-dimethoxycanthin-6-one (9), β-carboline-1-propionic acid (10), cleomiscosin C (11), cleomiscosin A (12), and hydnocarpin (13). The structures of all the compounds were determined using spectrometric and spectroscopic methods including 1D and 2D NMR, and HRSEIMS. The identities of the known compounds were further confirmed by comparison of their data with those reported in the literature. The root and bark methanolic extracts, the dichloromethane and ethyl acetate soluble fractions, and the isolated compounds (3–13), were assessed for their cytotoxicity against the cancer cell lines A-549, MCF-7, and PC-3. The results suggested that compounds in the extracts might possess a synergic action in their cytotoxicity. Full article

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20 pages, 1232 KiB

Open AccessArticle

2-Arylidene-1-indandiones as Pleiotropic Agents with Antioxidant and Inhibitory Enzymes Activities

by Olympia Kouzi, Eleni Pontiki and Dimitra Hadjipavlou-Litina

Molecules 2019, 24(23), 4411; https://doi.org/10.3390/molecules24234411 - 3 Dec 2019

Cited by 16 | Viewed by 3662

Abstract

Indandiones are a relatively new group of compounds presenting a wide range of biological activities. The synthesis of these compounds was performed via a Knoevenagel reaction between an aldehyde and 1,3-indandione and were obtained with a yield up to 54%. IR, ¹H-Nucleic [...] Read more.

Indandiones are a relatively new group of compounds presenting a wide range of biological activities. The synthesis of these compounds was performed via a Knoevenagel reaction between an aldehyde and 1,3-indandione and were obtained with a yield up to 54%. IR, ¹H-Nucleic Magnetic Resonance (NMR), ¹³C-NMR, LC/MS ESI⁺ and elemental analysis were used for the confirmation of the structures of the novel derivatives. Lipophilicity values of compounds were calculated theoretically and experimentally by reversed chromatography method as values R_M. The novel derivatives were studied through in vitro and in vivo experiments for their activity as anti-inflammatory and antioxidant agents and as inhibitors of lipoxygenase, trypsin, and thrombin. The inhibition of the carrageenin-induced paw edema (CPE) was also determined for representative structures. In the above series of experiments, we find that all the compounds showed moderate to satisfying interaction with the stable DPPH free radical in relation to the concentration and the time 2-arylidene-1-indandione (10) was the strongest. We observed moderate or very low antioxidant activities for selected compounds in the decolorization assay with ABTS^+•. Most of the compounds showed high anti-lipid peroxidation of linoleic acid induced by AAPH.2-arylidene-1-indandione (7) showed a strongly inhibited soybean LOX. Only 2-arylidene-1-indandione (3) showed moderate scavenging activity of superoxide anion, whereas 2-arylidene-1-indandione (8) and 2-arylidene-1-indandione (9) showed very strong inhibition on proteolysis. 2-arylidene-1-indandione (8) highly inhibited serine protease thrombin. 2-arylidene-1-indandiones (7, 8 and 9) can be used as lead multifunctional molecules. The compounds were active for the inhibition of the CPE (30–57%) with 2-arylidene-1-indandione (1) being the most potent (57%). According to the predicted results a great number of the derivatives can cross the Blood–Brain Barrier (BBB), act in CNS and easily transported, diffused, and absorbed. Efforts are conducted a) to correlate quantitatively the in vitro/in vivo results with the most important physicochemical properties of the structural components of the molecules and b) to clarify the correlation of actions among them to propose a possible mechanism of action. Hydration energy as E_HYDR and highest occupied molecular orbital (HOMO) better describe their antioxidant profile whereas the lipophilicity as R_M values governs the in vivo anti-inflammatory activity. Docking studies are performed and showed that soybean LOX oxidation was prevented by blocking into the hydrophobic domain the substrates to the active site. Full article

(This article belongs to the Special Issue Design, Synthesis, and Biological Evaluation of Enzyme Inhibitors)

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17 pages, 1832 KiB

Open AccessReview

Future Therapeutic Perspectives into the Alzheimer’s Disease Targeting the Oxidative Stress Hypothesis

by Jéssika P. Teixeira, Alexandre A. de Castro, Flávia V. Soares, Elaine F. F. da Cunha and Teodorico C. Ramalho

Molecules 2019, 24(23), 4410; https://doi.org/10.3390/molecules24234410 - 3 Dec 2019

Cited by 83 | Viewed by 6376

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease that is usually accompanied by aging, increasingly being the most common cause of dementia in the elderly. This disorder is characterized by the accumulation of beta amyloid plaques (Aβ) resulting from impaired amyloid precursor protein (APP) [...] Read more.

Alzheimer’s disease (AD) is a neurodegenerative disease that is usually accompanied by aging, increasingly being the most common cause of dementia in the elderly. This disorder is characterized by the accumulation of beta amyloid plaques (Aβ) resulting from impaired amyloid precursor protein (APP) metabolism, together with the formation of neurofibrillary tangles and tau protein hyperphosphorylation. The exacerbated production of reactive oxygen species (ROS) triggers the process called oxidative stress, which increases neuronal cell abnormalities, most often followed by apoptosis, leading to cognitive dysfunction and dementia. In this context, the development of new therapies for the AD treatment is necessary. Antioxidants, for instance, are promising species for prevention and treatment because they are capable of disrupting the radical chain reaction, reducing the production of ROS. These species have also proven to be adjunctive to conventional treatments making them more effective. In this sense, several recently published works have focused their attention on oxidative stress and antioxidant species. Therefore, this review seeks to show the most relevant findings of these studies. Full article

(This article belongs to the Special Issue Development of Novel Drugs for Alzheimer´s Disease)

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9 pages, 1286 KiB

Open AccessArticle

Gas-Dynamic Kinetics of Vapour Sampling in the Detection of Explosives

by Vladimir M. Gruznov and Alexander B. Vorozhtsov

Molecules 2019, 24(23), 4409; https://doi.org/10.3390/molecules24234409 - 3 Dec 2019

Cited by 2 | Viewed by 2428

Abstract

The dynamic sorption concentration of explosive vapours on concentrators made of a metal mesh, and the transportation of explosive vapours through the extended metal channels are considered. The efficiency of the concentration and transportation is determined by the breakthrough of the substance’s molecules [...] Read more.

The dynamic sorption concentration of explosive vapours on concentrators made of a metal mesh, and the transportation of explosive vapours through the extended metal channels are considered. The efficiency of the concentration and transportation is determined by the breakthrough of the substance’s molecules through the channels. The research methods we used were breakthrough calculation theory and experiment. When calculating the breakthrough, a mesh was presented as a set of parallel identical channels. Wire mesh and extended channels were made of stainless steel. The breakthrough is determined through the specific frequency of the collisions between the molecules and the channel’s surface. This is presented as a function of the ratio of the substance diffusion flow to the channel’s surface to the airflow through the channel. The conditions for high-speed concentration, complete capture of explosive vapours, and low vapour losses during their transportation through the extended channels were determined theoretically and experimentally. For a concentrator made of a mesh, the condition of a high concentration rate at a high breakthrough (up to 80%) was determined. The described sorption concentration is used in portable gas chromatographic detectors of explosive vapours of the EKHO series. Full article

(This article belongs to the Section Analytical Chemistry)

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16 pages, 4320 KiB

Open AccessReview

The Amyloid as a Ribbon-Like Micelle in Contrast to Spherical Micelles Represented by Globular Proteins

by Mateusz Banach, Leszek Konieczny and Irena Roterman

Molecules 2019, 24(23), 4395; https://doi.org/10.3390/molecules24234395 - 3 Dec 2019

Cited by 15 | Viewed by 3562

Abstract

Selected amyloid structures available in the Protein Data Bank have been subjected to a comparative analysis. Classification is based on the distribution of hydrophobicity in amyloids that differ with respect to sequence, chain length, the distribution of beta folds, protofibril structure, and the [...] Read more.

Selected amyloid structures available in the Protein Data Bank have been subjected to a comparative analysis. Classification is based on the distribution of hydrophobicity in amyloids that differ with respect to sequence, chain length, the distribution of beta folds, protofibril structure, and the arrangement of protofibrils in each superfibril. The study set includes the following amyloids: Aβ (1–42), which is listed as Aβ (15–40) and carries the D23N mutation, and Aβ (11–42) and Aβ (1–40), both of which carry the E22Δ mutation, tau amyloid, and α-synuclein. Based on the fuzzy oil drop model (FOD), we determined that, despite their conformational diversity, all presented amyloids adopt a similar structural pattern that can be described as a ribbon-like micelle. The same model, when applied to globular proteins, results in structures referred to as “globular micelles,” emerging as a result of interactions between the proteins’ constituent residues and the aqueous solvent. Due to their composition, amyloids are unable to attain entropically favorable globular forms and instead attempt to limit contact between hydrophobic residues and water by producing elongated structures. Such structures typically contain quasi hydrophobic cores that stretch along the fibril’s long axis. Similar properties are commonly found in ribbon-like micelles, with alternating bands of high and low hydrophobicity emerging as the fibrils increase in length. Thus, while globular proteins are generally consistent with a 3D Gaussian distribution of hydrophobicity, the distribution instead conforms to a 2D Gaussian distribution in amyloid fibrils. Full article

(This article belongs to the Special Issue Amyloids in Neurodegenerative Diseases)

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8 pages, 1650 KiB

Open AccessArticle

Synthesis and Biological Evaluation of BODIPY-PF-543

by Jitendra Shrestha, Gil Tae Hwang, Taeho Lee, Seon Woong Kim, Yoon Sin Oh, Yongseok Kwon, Seung Woo Hong, Sanghee Kim, Hong Seop Moon, Dong Jae Baek and Eun-Young Park

Molecules 2019, 24(23), 4408; https://doi.org/10.3390/molecules24234408 - 2 Dec 2019

Cited by 7 | Viewed by 4109

Abstract

Sphingosine-1-phosphate (S1P) regulates the proliferation of various cells and promotes the growth of cancer cells. Sphingosine kinase (SK), which transforms sphingosine into S1P, has two isotypes: SK1 and SK2. To date, both isotypes are known to be involved in the proliferation of cancer [...] Read more.

Sphingosine-1-phosphate (S1P) regulates the proliferation of various cells and promotes the growth of cancer cells. Sphingosine kinase (SK), which transforms sphingosine into S1P, has two isotypes: SK1 and SK2. To date, both isotypes are known to be involved in the proliferation of cancer cells. PF-543, an SK1 inhibitor developed by Pfizer, strongly inhibits SK1. However, despite its strong SK1 inhibitory effect, PF-543 shows low anticancer activity in vitro. Therefore, additional biological evidence on the anticancer activity of SK1 inhibitor is required. The present study aimed to investigate the intracellular localization of PF-543 and identify its association with anticancer activity by introducing a fluoroprobe into PF-543. Boron–dipyrromethene (BODIPY)-introduced PF-543 has a similar SK1 inhibitory effect as PF-543. These results indicate that the introduction of BODIPY does not significantly affect the inhibitory effect of SK1. In confocal microscopy after BODIPY-PF-543 treatment, the compound was mainly located in the cytosol of the cells. This study demonstrated the possibility of introducing fluorescent material into an SK inhibitor and designing a synthesized compound that is permeable to cells while maintaining the SK inhibitory effect. Full article

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16 pages, 1666 KiB

Open AccessArticle

Spectrophotometric and Smartphone-Assisted Determination of Phenolic Compounds Using Crude Eggplant Extract

by M.A. Morosanova, A.S. Bashkatova and E.I. Morosanova

Molecules 2019, 24(23), 4407; https://doi.org/10.3390/molecules24234407 - 2 Dec 2019

Cited by 7 | Viewed by 4133

Abstract

In order to develop a simple, reliable and low cost enzymatic method for the determination of phenolic compounds we studied polyphenol oxidase activity of crude eggplant (S. melongena) extract using 13 phenolic compounds. Catechol, caffeic and chlorogenic acids, and L-DOPA have [...] Read more.

In order to develop a simple, reliable and low cost enzymatic method for the determination of phenolic compounds we studied polyphenol oxidase activity of crude eggplant (S. melongena) extract using 13 phenolic compounds. Catechol, caffeic and chlorogenic acids, and L-DOPA have been rapidly oxidized with the formation of colored products. Monophenolic compounds have been oxidized at a much slower speed. Ferulic acid, quercetin, rutin, and dihydroquercetin have been found to inhibit polyphenol oxidase activity of crude eggplant extract. The influence of pH, temperature, crude eggplant extract amount, and 3-methyl-2-benzothiazolinone hydrazone (MBTH) concentration on the oxidation of catechol, caffeic acid, chlorogenic acid, and L-DOPA has been investigated spectrophotometrically. Michaelis constants values decrease by a factor of 2 to 3 in the presence of MBTH. Spectrophotometric (cuvette and microplate variants) and smartphone-assisted procedures for phenolic compounds determination have been proposed. Average saturation values (HSV color model) of the images of the microplate wells have been chosen as the analytical signal for smartphone-assisted procedure. LOD values for catechol, caffeic acid, chlorogenic acid, and L-DOPA equaled 5.1, 6.3, 5.8 and 30.0 µM (cuvette procedure), 12.2, 13.2, 13.2 and 80.4 µM (microplate procedure), and 23.5, 26.4, 20.8 and 120.6 µM (smartphone procedure). All the variants have been successfully applied for fast (4-5 min) and simple TPC determination in plant derived products and L-DOPA determination in model biological fluids. The values found with smartphone procedure are in good agreement with both spectrophotometric procedures values and reference values. Using crude eggplant extract- mediated reactions combined with smartphone camera detection has allowed creating low-cost, reliable and environmentally friendly analytical method for the determination of phenolic compounds. Full article

(This article belongs to the Special Issue From Green to Democratic Analytical Chemistry)

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18 pages, 4657 KiB

Open AccessFeature PaperArticle

Synthesis and Optoelectronic Characterization of Perylene Diimide-Quinoline Based Small Molecules

by Stefania Aivali, Loukia Tsimpouki, Charalampos Anastasopoulos and Joannis K. Kallitsis

Molecules 2019, 24(23), 4406; https://doi.org/10.3390/molecules24234406 - 2 Dec 2019

Cited by 18 | Viewed by 5712

Abstract

Perylene diimide (PDI) is one of the most studied functional dyes due to their structural versatility and fine tuning of the materials properties. Core substituted PDIs are prominent n-type semiconductor materials that could be used as non-fullerene acceptors in organic photovoltaics. Herein, we [...] Read more.

Perylene diimide (PDI) is one of the most studied functional dyes due to their structural versatility and fine tuning of the materials properties. Core substituted PDIs are prominent n-type semiconductor materials that could be used as non-fullerene acceptors in organic photovoltaics. Herein, we develop versatile organic building blocks based on PDI by decorating the PDI core with quinoline groups. Styryl and hydroxy phenyl mono and difunctionalized molecules were prepared using mono-nitro and dibromo bay substituted PDIs by Suzuki coupling with the respective boronic acid derivatives. A novel methodology using nitro-PDI under Suzuki coupling conditions as an electrophile partner was successfully tested. Furthermore, the PDI derivatives were used for the synthesis of soluble, electron accepting small molecules combining PDI with weak electron withdrawing quinoline derivatives. The new molecules presented wide absorbance in the visible spectrum from 450 to almost 700 nm while their LUMO levels and their energy levels are in the range of −3.8 to −4.2 eV. Full article

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16 pages, 2930 KiB

Open AccessFeature PaperArticle

Insights into the Discovery of Novel Neuroprotective Agents: A Comparative Study between Sulfanylcinnamic Acid Derivatives and Related Phenolic Analogues

by Daniel Chavarria, Carlos Fernandes, Brandon Aguiar, Tiago Silva, Jorge Garrido, Fernando Remião, Paulo J. Oliveira, Eugenio Uriarte and Fernanda Borges

Molecules 2019, 24(23), 4405; https://doi.org/10.3390/molecules24234405 - 2 Dec 2019

Cited by 11 | Viewed by 3628

Abstract

Exogenous antioxidants may be beneficial therapeutic tools to tackle the oxidative damage in neurodegenerative diseases by regulation of the redox state that is critical for cell viability and organ function. Inspired by natural plant polyphenols, a series of cinnamic acid-based thiophenolic and phenolic [...] Read more.

Exogenous antioxidants may be beneficial therapeutic tools to tackle the oxidative damage in neurodegenerative diseases by regulation of the redox state that is critical for cell viability and organ function. Inspired by natural plant polyphenols, a series of cinnamic acid-based thiophenolic and phenolic compounds were synthesized and their antioxidant and neuroprotective properties were studied. In general, our results showed that the replacement of the hydroxyl group (OH) by a sulfhydryl group (SH) increased the radical scavenging activity and enhanced the reaction rate with 1,1-diphenyl-2-picrylhydrazyl radical (DPPH^{^•}) and galvinoxyl radical (GO^{^•}). These results correlated well with the lower oxidation potential (E_p) values of thiophenols. However, a lower peroxyl radical (ROO^{^•}) scavenging activity was observed for thiophenols in oxygen radical absorbance capacity (ORAC-FL) assay. Furthermore, the introduction of 5-methoxy and 5-phenyl groups in the aromatic ring of 4-thioferulic acid (TFA) 2 and ferulic acid (FA) 1 did not significantly improve their antioxidant activity, despite the slight decrease of E_p observed for compounds 5, 6, and 9. Concerning cinnamic acid amides, the antioxidant profile was similar to the parent compounds. None of the compounds under study presented significant cytotoxic effects in human differentiated neuroblastoma cells. Thiophenolic amide 3 stands out as the most promising thiophenol-based antioxidant, showing cellular neuroprotective effects against oxidative stress inducers (hydrogen peroxide and iron). Full article

(This article belongs to the Special Issue Cinnamic Acids and Analogs: Food and Health Applications)

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16 pages, 1542 KiB

Open AccessReview

Microalgae Biomass as a Potential Feedstock for the Carboxylate Platform

by Jose Antonio Magdalena and Cristina González-Fernández

Molecules 2019, 24(23), 4404; https://doi.org/10.3390/molecules24234404 - 2 Dec 2019

Cited by 14 | Viewed by 3950

Abstract

Volatile fatty acids (VFAs) are chemical building blocks for industries, and are mainly produced via the petrochemical pathway. However, the anaerobic fermentation (AF) process gives a potential alternative to produce these organic acids using renewable resources. For this purpose, waste streams, such as [...] Read more.

Volatile fatty acids (VFAs) are chemical building blocks for industries, and are mainly produced via the petrochemical pathway. However, the anaerobic fermentation (AF) process gives a potential alternative to produce these organic acids using renewable resources. For this purpose, waste streams, such as microalgae biomass, might constitute a cost-effective feedstock to obtain VFAs. The present review is intended to summarize the inherent potential of microalgae biomass for VFA production. Different strategies, such as the use of pretreatments to the inoculum and the manipulation of operational conditions (pH, temperature, organic loading rate or hydraulic retention time) to promote VFA production from different microalgae strains, are discussed. Microbial structure analysis using microalgae biomass as a substrate is pointed out in order to further comprehend the roles of bacteria and archaea in the AF process. Finally, VFA applications in different industry fields are reviewed. Full article

(This article belongs to the Special Issue Microalgae for Production of Bioproducts and Biofuels)

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15 pages, 1872 KiB

Open AccessFeature PaperArticle

Heparanase as an Additional Tool for Detecting Structural Peculiarities of Heparin Oligosaccharides

by Anna Alekseeva, Elena Urso, Giulia Mazzini and Annamaria Naggi

Molecules 2019, 24(23), 4403; https://doi.org/10.3390/molecules24234403 - 2 Dec 2019

Cited by 8 | Viewed by 3160

Abstract

Due to the biological properties of heparin and low-molecular-weight heparin (LMWH), continuous advances in elucidation of their microheterogeneous structure and discovery of novel structural peculiarities are crucial. Effective strategies for monitoring manufacturing processes and assessment of more restrictive specifications, as imposed by the [...] Read more.

Due to the biological properties of heparin and low-molecular-weight heparin (LMWH), continuous advances in elucidation of their microheterogeneous structure and discovery of novel structural peculiarities are crucial. Effective strategies for monitoring manufacturing processes and assessment of more restrictive specifications, as imposed by the current regulatory agencies, need to be developed. Hereby, we apply an efficient heparanase-based strategy to assert the structure of two major isomeric octasaccharides of dalteparin and investigate the tetrasaccharides arising from antithrombin binding region (ATBR) of bovine mucosal heparin. Heparanase, especially when combined with other sample preparation methods (e.g., size exclusion, affinity chromatography, heparinase depolymerization), was shown to be a powerful tool providing relevant information about heparin structural peculiarities. The applied approach provided direct evidence that oligomers bearing glucuronic acid–glucosamine-3-O-sulfate at their nonreducing end represent an important structural signature of dalteparin. When extended to ATBR-related tetramers of bovine heparin, the heparanase-based approach allowed for elucidation of the structure of minor sequences that have not been reported yet. The obtained results are of high importance in the view of the growing interest of regulatory agencies and manufacturers in the development of low-molecular-weight heparin generics as well as bovine heparin as alternative source. Full article

(This article belongs to the Special Issue Emerging Frontiers in Glycosaminoglycans and Mimetics)

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28 pages, 5028 KiB

Open AccessFeature PaperArticle

Radiation Induced One-Electron Oxidation of 2-Thiouracil in Aqueous Solutions

by Konrad Skotnicki, Katarzyna Taras-Goslinska, Ireneusz Janik and Krzysztof Bobrowski

Molecules 2019, 24(23), 4402; https://doi.org/10.3390/molecules24234402 - 2 Dec 2019

Cited by 5 | Viewed by 3601

Abstract

Oxidative damage to 2-thiouracil (2-TU) by hydroxyl (^•OH) and azide (^●N₃) radicals produces various primary reactive intermediates. Their optical absorption spectra and kinetic characteristics were studied by pulse radiolysis with UV-vis spectrophotometric and conductivity detection and by [...] Read more.

Oxidative damage to 2-thiouracil (2-TU) by hydroxyl (^•OH) and azide (^●N₃) radicals produces various primary reactive intermediates. Their optical absorption spectra and kinetic characteristics were studied by pulse radiolysis with UV-vis spectrophotometric and conductivity detection and by time-dependent density functional theory (TD-DFT) method. The transient absorption spectra recorded in the reactions of ^•OH with 2-TU depend on the concentration of 2-TU, however, only slightly on pH. At low concentrations, they are characterized by a broad absorption band with a weakly pronounced maxima located at λ = 325, 340 and 385 nm, whereas for high concentrations, they are dominated by an absorption band with λ_max ≈ 425 nm. Based on calculations using TD-DFT method, the transient absorption spectra at low concentration of 2-TU were assigned to the ^●OH-adducts to the double bond at C5 and C6 carbon atoms (3^●, 4^●) and 2c-3e bonded ^●OH adduct to sulfur atom (1…^●OH) and at high concentration of 2-TU also to the dimeric 2c-3e S-S-bonded radical in neutral form (2^●). The dimeric radical (2^●) is formed in the reaction of thiyl-type radical (6^●) with 2-TU and both radicals are in an equilibrium with K_eq = 4.2 × 10³ M⁻¹. Similar equilibrium (with K_eq = 4.3 × 10³ M⁻¹) was found for pH above the pK_a of 2-TU which involves admittedly the same radical (6^●) but with the dimeric 2c-3e S-S bonded radical in anionic form (2^●−). In turn, ^●N₃-induced oxidation of 2-TU occurs via radical cation with maximum spin location on the sulfur atom which subsequently undergoes deprotonation at N1 atom leading again to thiyl-type radical (6^●). This radical is a direct precursor of dimeric radical (2^●). Full article

(This article belongs to the Special Issue Biomimetic Radical Chemistry and Applications)

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15 pages, 3014 KiB

Open AccessArticle

Some Properties of Electron Beam-Irradiated Sheep Wool Linked to Cr(III) Sorption

by Jana Braniša, Angela Kleinová, Klaudia Jomová, Radka Malá, Volodymyr Morgunov and Mária Porubská

Molecules 2019, 24(23), 4401; https://doi.org/10.3390/molecules24234401 - 2 Dec 2019

Cited by 13 | Viewed by 3189

Abstract

We examined the characteristics of an electron beam irradiated wool with an absorbed dose of (21–410) kGy in comparison with natural wool with respect to the determination of the isoelectric point (IEP), zero charge point (ZCP), mechanism of Cr(III) sorption from higher concentrated [...] Read more.

We examined the characteristics of an electron beam irradiated wool with an absorbed dose of (21–410) kGy in comparison with natural wool with respect to the determination of the isoelectric point (IEP), zero charge point (ZCP), mechanism of Cr(III) sorption from higher concentrated solutions, and the modelling of the wool-Cr(III) interaction. The data of ZPC and IEP differed between natural and irradiated samples. Increasing the dose shifted the pH of ZPC from 6.85 for natural wool to 6.20 for the highest dosed wool, while the natural wool IEP moved very little, from pH = 3.35 to 3.40 for all of the irradiated samples. The sorption experiments were performed in a pH bath set at 3.40, and the determination of the residual Cr(III) in the bath was performed by VIS spectrometry under optimized conditions. The resulting sorptivity showed a monotonically rising trend with increasing Cr(III) concentration in the bath. Lower doses, unlike higher doses, showed better sorptivity than the natural wool. FTIR data indicated the formation of complex chromite salts of carboxylates and cysteinates. Crosslinks via ligands coming from different keratin chains were predicted, preferably on the surface of the fibers, but to a degree that did not yet inhibit the diffusion of Cr(III)-cations into the fiber volume. We also present a concept of a complex octahedral structure. Full article

(This article belongs to the Section Materials Chemistry)

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14 pages, 2249 KiB

Open AccessArticle

Simultaneous Use of Stimulatory Agents to Enhance the Production and Hypoglycaemic Activity of Polysaccharides from Inonotus obliquus by Submerged Fermentation

by Mengya Wang, Zhezhen Zhao, Xia Zhou, Jinrong Hu, Jiao Xue, Xiao Liu, Jingsheng Zhang, Ping Liu and Shisheng Tong

Molecules 2019, 24(23), 4400; https://doi.org/10.3390/molecules24234400 - 2 Dec 2019

Cited by 21 | Viewed by 3118

Abstract

This study aimed to determine the effect of applying stimulatory agents to liquid cultured Inonotus obliquus on the simultaneous accumulation of exo-polysaccharides (EPS) and their monosaccharide composition. Different stimulatory agents (VB₆, VB₁, betulin and birch extract) were investigated for [...] Read more.

This study aimed to determine the effect of applying stimulatory agents to liquid cultured Inonotus obliquus on the simultaneous accumulation of exo-polysaccharides (EPS) and their monosaccharide composition. Different stimulatory agents (VB₆, VB₁, betulin and birch extract) were investigated for their effects on active exo-polysaccharides by submerged fermentation of I. obliquus. The mycelial biomass, reducing sugar content, EPS yield and α-glucosidase inhibition rate were determined, and the EPS obtained was analyzed for monosaccharide composition. The results showed that the addition of all the four stimulatory agents could significantly increase the inhibitory activity against α-glucosidase of EPS than the control, whereas EPS from 4 μg/mL VB₁-containing medium had the best effect with an estimated IC₅₀ value 24.34 μg/mL. Among the four stimulatory agents, VB₆ gave maximum production of mycelial biomass and EPS at the concentration of 4 μg/mL with a increase of 50.79% and 114.46%, respectively. In addition, betulin had a significant effect on increasing the EPS yield and activity, and birch extract had a significantly stimulatory effect on the mycelial growth and the polysaccharides activity, only slightly worse than VB₆ and VB₁. Moreover, the addition of different stimulatory agents changed the monosaccharide composition of polysaccharides, which had a correlation with polysaccharide activity. Full article

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15 pages, 2044 KiB

Open AccessArticle

Relativistic Effects on NMR Parameters of Halogen-Bonded Complexes

by Ibon Alkorta, José Elguero, Manuel Yáñez, Otilia Mó and M. Merced Montero-Campillo

Molecules 2019, 24(23), 4399; https://doi.org/10.3390/molecules24234399 - 2 Dec 2019

Cited by 10 | Viewed by 3282

Abstract

Relativistic effects are found to be important for the estimation of NMR parameters in halogen-bonded complexes, mainly when they involve the heavier elements, iodine and astatine. A detailed study of 60 binary complexes formed between dihalogen molecules (XY with X, Y = F, [...] Read more.

Relativistic effects are found to be important for the estimation of NMR parameters in halogen-bonded complexes, mainly when they involve the heavier elements, iodine and astatine. A detailed study of 60 binary complexes formed between dihalogen molecules (XY with X, Y = F, Cl, Br, I and At) and four Lewis bases (NH₃, H₂O, PH₃ and SH₂) was carried out at the MP2/aug-cc-pVTZ/aug-cc-pVTZ-PP computational level to show the extent of these effects. The NMR parameters (shielding and nuclear quadrupolar coupling constants) were computed using the relativistic Hamiltonian ZORA and compared to the values obtained with a non-relativistic Hamiltonian. The results show a mixture of the importance of the relativistic corrections as both the size of the halogen atom and the proximity of this atom to the basic site of the Lewis base increase. Full article

(This article belongs to the Special Issue Halogen Bonding: Insights from Computational Tools)

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18 pages, 1921 KiB

Open AccessArticle

2-Unsubstituted Imidazole N-Oxides as Novel Precursors of Chiral 3-Alkoxyimidazol-2-ylidenes Derived from trans-1,2-Diaminocyclohexane and Other Chiral Amino Compounds

by Grzegorz Mlostoń, Małgorzata Celeda, Marcin Jasiński, Katarzyna Urbaniak, Przemysław J. Boratyński, Peter R. Schreiner and Heinz Heimgartner

Molecules 2019, 24(23), 4398; https://doi.org/10.3390/molecules24234398 - 2 Dec 2019

Cited by 11 | Viewed by 4084

Abstract

‘Desymmetrization’ of trans-1,2-diaminocyclohexane by treatment with α,ω-dihalogenated alkylation reagents leads to mono-NH₂ derivatives (‘primary-tertiary diamines’). Upon reaction with formaldehyde, these products formed monomeric formaldimines. Subsequently, reactions of the formaldimines with α-hydroxyiminoketones led to the corresponding 2-unsubstituted imidazole N-oxide derivatives, which [...] Read more.

‘Desymmetrization’ of trans-1,2-diaminocyclohexane by treatment with α,ω-dihalogenated alkylation reagents leads to mono-NH₂ derivatives (‘primary-tertiary diamines’). Upon reaction with formaldehyde, these products formed monomeric formaldimines. Subsequently, reactions of the formaldimines with α-hydroxyiminoketones led to the corresponding 2-unsubstituted imidazole N-oxide derivatives, which were used here as new substrates for the in situ generation of chiral imidazol-2-ylidenes. Upon O-selective benzylation, new chiral imidazolium salts were obtained, which were deprotonated by treatment with triethylamine in the presence of elemental sulfur. Under these conditions, the intermediate imidazol-2-ylidenes were trapped by elemental sulfur, yielding the corresponding chiral non-enolizable imidazole-2-thiones in good yields. Analogous reaction sequences, starting with imidazole N-oxides derived from enantiopure primary amines, amino alcohols, and amino acids, leading to the corresponding 3-alkoxyimidazole-2-thiones were also studied. Full article

(This article belongs to the Special Issue Stereochemistry in Action)

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15 pages, 5354 KiB

Open AccessArticle

Poly(Dopamine) Coating on 3D-Printed Poly-Lactic-Co-Glycolic Acid/β-Tricalcium Phosphate Scaffolds for Bone Tissue Engineering

by Zhimin Xu, Ningning Wang, Peng Liu, Yidan Sun, Yumeng Wang, Fan Fei, Shichen Zhang, Jianying Zheng and Bing Han

Molecules 2019, 24(23), 4397; https://doi.org/10.3390/molecules24234397 - 2 Dec 2019

Cited by 43 | Viewed by 5999

Abstract

Bone defects caused by osteoporosis, bone malignant tumors, and trauma are very common, but there are many limiting factors in the clinical treatment of them. Bone tissue engineering is the most promising treatment and is considered to be the main strategy for bone [...] Read more.

Bone defects caused by osteoporosis, bone malignant tumors, and trauma are very common, but there are many limiting factors in the clinical treatment of them. Bone tissue engineering is the most promising treatment and is considered to be the main strategy for bone defect repair. We prepared polydopamine-coated poly-(lactic-co-glycolic acid)/β-tricalcium phosphate composite scaffolds via 3D printing, and a series of characterization and biocompatibility tests were carried out. The results show that the mechanical properties and pore-related parameters of the composite scaffolds are not affected by the coatings, and the hydrophilicities of the surface are obviously improved. Scanning electron microscopy and micro-computed tomography display the nanoscale microporous structure of the bio-materials. Biological tests demonstrate that this modified surface can promote cell adhesion and proliferation and improve osteogenesis through the increase of polydopamine (PDA) concentrations. Mouse cranial defect experiments are conducted to further verify the conclusion that scaffolds with a higher content of PDA coatings have a better effect on the formation of new bones. In the study, the objective of repairing critical-sized defects is achieved by simply adding PDA as coatings to obtain positive results, which can suggest that this modification method with PDA has great potential. Full article

(This article belongs to the Section Materials Chemistry)

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13 pages, 3725 KiB

Open AccessArticle

Influence of Storage Time and Temperature on the Toxicity, Endocrine Potential, and Migration of Epoxy Resin Precursors in Extracts of Food Packaging Materials

by Błażej Kudłak, Natalia Jatkowska, Paweł Kubica, Galina Yotova and Stefan Tsakovski

Molecules 2019, 24(23), 4396; https://doi.org/10.3390/molecules24234396 - 2 Dec 2019

Cited by 5 | Viewed by 3055

Abstract

The aim of the present study was to establish a standard methodology for the extraction of epoxy resin precursors from several types of food packages (cans, multi-layered composite material, and cups) with selected simulation media (distilled water, 5% ethanol, 3% dimethyl sulfoxide, 5% [...] Read more.

The aim of the present study was to establish a standard methodology for the extraction of epoxy resin precursors from several types of food packages (cans, multi-layered composite material, and cups) with selected simulation media (distilled water, 5% ethanol, 3% dimethyl sulfoxide, 5% acetic acid, artificial saliva) at different extraction times and temperatures (factors). Biological analyses were conducted to determine the acute toxicity levels of the extracts (with Vibrio fischeri bacteria) and their endocrine potential (with Saccharomyces cerevisiae yeasts). In parallel, liquid chromatography-tandem mass spectrometry was performed to determine levels of bisphenol A diglycidyl ether (BADGE), bisphenol F diglycidyl ether (mixture of isomers, BFDGE), ring novolac glycidyl ether (3-ring NOGE), and their derivatives. The variation induced by the different experimental factors was statistically evaluated with analysis of variance simultaneous component analysis (ASCA). Our findings demonstrate the value of using a holistic approach to best partition the effects contributing to the end points of these assessments, and offer further guidance for adopting such a methodology, thus being a broadly useful reference for understanding the phenomena related to the impacts of food packaging materials on quality for long- and short-term storage, while offering a general method for analysis. Full article

(This article belongs to the Special Issue Using Modern Bioanalytics and Chemometric Tools in Environmental and Diagnostic Applications)

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53 pages, 3833 KiB

Open AccessReview

Effects of Propolis Extract and Propolis-Derived Compounds on Obesity and Diabetes: Knowledge from Cellular and Animal Models

by Hiroshi Kitamura

Molecules 2019, 24(23), 4394; https://doi.org/10.3390/molecules24234394 - 1 Dec 2019

Cited by 47 | Viewed by 12152

Abstract

Propolis is a natural product resulting from the mixing of bee secretions with botanical exudates. Since propolis is rich in flavonoids and cinnamic acid derivatives, the application of propolis extracts has been tried in therapies against cancer, inflammation, and metabolic diseases. As metabolic [...] Read more.

Propolis is a natural product resulting from the mixing of bee secretions with botanical exudates. Since propolis is rich in flavonoids and cinnamic acid derivatives, the application of propolis extracts has been tried in therapies against cancer, inflammation, and metabolic diseases. As metabolic diseases develop relatively slowly in patients, the therapeutic effects of propolis in humans should be evaluated over long periods of time. Moreover, several factors such as medical history, genetic inheritance, and living environment should be taken into consideration in human studies. Animal models, especially mice and rats, have some advantages, as genetic and microbiological variables can be controlled. On the other hand, cellular models allow the investigation of detailed molecular events evoked by propolis and derivative compounds. Taking advantage of animal and cellular models, accumulating evidence suggests that propolis extracts have therapeutic effects on obesity by controlling adipogenesis, adipokine secretion, food intake, and energy expenditure. Studies in animal and cellular models have also indicated that propolis modulates oxidative stress, the accumulation of advanced glycation end products (AGEs), and adipose tissue inflammation, all of which contribute to insulin resistance or defects in insulin secretion. Consequently, propolis treatment may mitigate diabetic complications such as nephropathy, retinopathy, foot ulcers, and non-alcoholic fatty liver disease. This review describes the beneficial effects of propolis on metabolic disorders. Full article

(This article belongs to the Special Issue Bee Products: From Molecules to Human Health)

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20 pages, 971 KiB

Open AccessArticle

Construction of Quantitative Structure Activity Relationship (QSAR) Models to Predict Potency of Structurally Diversed Janus Kinase 2 Inhibitors

by Saw Simeon and Nathjanan Jongkon

Molecules 2019, 24(23), 4393; https://doi.org/10.3390/molecules24234393 - 1 Dec 2019

Cited by 17 | Viewed by 6017

Abstract

Janus kinase 2 (JAK2) inhibitors represent a promising therapeutic class of anticancer agents against many myeloproliferative disorders. Bioactivity data on pIC

_{50}

of 2229 JAK2 inhibitors were employed in the construction of quantitative structure-activity relationship (QSAR) models. The models were built from 100 [...] Read more.

Janus kinase 2 (JAK2) inhibitors represent a promising therapeutic class of anticancer agents against many myeloproliferative disorders. Bioactivity data on pIC

_{50}

of 2229 JAK2 inhibitors were employed in the construction of quantitative structure-activity relationship (QSAR) models. The models were built from 100 data splits using decision tree (DT), support vector machine (SVM), deep neural network (DNN) and random forest (RF). The predictive power of RF models were assessed via 10-fold cross validation, which afforded excellent predictive performance with

R^{2}

and RMSE of 0.74 ± 0.05 and 0.63 ± 0.05, respectively. Moreover, test set has excellent performance of

R^{2}

(0.75 ± 0.03) and RMSE (0.62 ± 0.04). In addition, Y-scrambling was utilized to evaluate the possibility of chance correlation of the predictive model. A thorough analysis of the substructure fingerprint count was conducted to provide insights on the inhibitory properties of JAK2 inhibitors. Molecular cluster analysis revealed that pyrazine scaffolds have nanomolar potency against JAK2. Full article

(This article belongs to the Special Issue Recent Advances in Computational Drug Discovery: From In Silico Screening to Multiscale De Novo Drug Design)

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