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Molecules, Volume 25, Issue 7 (April-1 2020) – 285 articles

Cover Story (view full-size image): As drug carriers, nanoparticles are powerful weapons in the fight against cancer. Their passive accumulation in tumoral tissues in combination with cell targeting and stimuli-responsive properties allow them to deliver therapeutic agents to tumoral cells in a selective and controlled manner. However, recent studies report that only a low number of injected nanomedicines reach solid tumors, which challenges the concept of eradicating this disease by only targeting malignant cells. An possible strategy involves engineering nanocarriers able to interact with the immune cell population present in the malignant tissue to trigger a potent and sustained immune response against the cancerous cells. In this review, the recent advances toward this goal are presented. View this paper.
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Article
Biophysical Screens Identify Fragments That Bind to the Viral DNA-Binding Proteins EBNA1 and LANA
Molecules 2020, 25(7), 1760; https://doi.org/10.3390/molecules25071760 - 10 Apr 2020
Cited by 3 | Viewed by 1337
Abstract
The human gamma-herpesviruses Epstein–Barr virus (EBV) (HHV-4) and Kaposi’s sarcoma-associated herpesvirus (KSHV) (HHV-8) are responsible for a number of diseases, including various types of cancer. Epstein–Barr nuclear antigen 1 (EBNA1) from EBV and latency-associated nuclear antigen (LANA) from KSHV are viral-encoded DNA-binding proteins [...] Read more.
The human gamma-herpesviruses Epstein–Barr virus (EBV) (HHV-4) and Kaposi’s sarcoma-associated herpesvirus (KSHV) (HHV-8) are responsible for a number of diseases, including various types of cancer. Epstein–Barr nuclear antigen 1 (EBNA1) from EBV and latency-associated nuclear antigen (LANA) from KSHV are viral-encoded DNA-binding proteins that are essential for the replication and maintenance of their respective viral genomes during latent, oncogenic infection. As such, EBNA1 and LANA are attractive targets for the development of small-molecule inhibitors. To this end, we performed a biophysical screen of EBNA1 and LANA using a fragment library by saturation transfer difference (STD)–NMR spectroscopy and surface plasmon resonance (SPR). We identified and validated a number of unique fragment hits that bind to EBNA1 or LANA. We also determined the high-resolution crystal structure of one fragment bound to EBNA1. Results from this screening cascade provide new chemical starting points for the further development of potent inhibitors for this class of viral proteins. Full article
(This article belongs to the Special Issue Fragment Based Drug Discovery)
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Article
Ultrasonically-Assisted and Conventional Extraction from Erodium Glaucophyllum Roots Using Ethanol:Water Mixtures: Phenolic Characterization, Antioxidant, and Anti-Inflammatory Activities
Molecules 2020, 25(7), 1759; https://doi.org/10.3390/molecules25071759 - 10 Apr 2020
Cited by 2 | Viewed by 1056
Abstract
The paper presents experimental results concerning the ultrasonically-assisted extraction of bioactive compounds from Erodium glaucophyllum roots. A comparison with conventional methodology is presented, and thereby the phytochemical composition and the antioxidant and anti-inflammatory activities of extracts are evaluated. The phenolic profile of Erodium [...] Read more.
The paper presents experimental results concerning the ultrasonically-assisted extraction of bioactive compounds from Erodium glaucophyllum roots. A comparison with conventional methodology is presented, and thereby the phytochemical composition and the antioxidant and anti-inflammatory activities of extracts are evaluated. The phenolic profile of Erodium extracts was analyzed by TOF–LC–MS–MS. The identification of phenolic compounds revealed that the major component was (+)-gallocatechin in the aqueous extracts obtained for the different extraction methodologies. The highest quantity of phenolic compounds and antioxidant capacity was found in the hydroethanolic extract obtained by conventional extraction (29.22–25.50 mg GAE/g DM; 21.174 mM Trolox equivalent). The highest content of carotenoids, varying from 0.035 to 0.114 mg/g dry matter, was reached by ultrasonic-assisted extraction. Furthermore, Erodium extracts showed a potent inhibition of the inflammatory reaction by means of the inhibition of tumor necrosis factor-alpha (TNF-α). The extracts obtained when ultrasound extraction was combined with ethanol:water (50:50, v/v) presented the greatest inhibition (92%). Full article
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Review
Tri(boryl)alkanes and Tri(boryl)alkenes: The Versatile Reagents
Molecules 2020, 25(7), 1758; https://doi.org/10.3390/molecules25071758 - 10 Apr 2020
Cited by 3 | Viewed by 1094
Abstract
The interest of organoboron chemistry in organic synthesis is growing, together with the development of new and versatile polyborated reagents. Here, the preparation of 1,1,1-tri(boryl)alkanes, 1,2,3-tri(boryl)alkanes, 1,1,2-tri(boryl)alkanes, as well as 1,1,2-tri(boryl)alkenes as suitable and accessible polyborated systems is demonstrated as being easily applied [...] Read more.
The interest of organoboron chemistry in organic synthesis is growing, together with the development of new and versatile polyborated reagents. Here, the preparation of 1,1,1-tri(boryl)alkanes, 1,2,3-tri(boryl)alkanes, 1,1,2-tri(boryl)alkanes, as well as 1,1,2-tri(boryl)alkenes as suitable and accessible polyborated systems is demonstrated as being easily applied in the construction of new carbon-carbon and carbon-heteroatom bonds. Synthetic procedures and limitations have been collected to demonstrate the powerful strategies to construct selective molecules, taking advantages of the easy transformation of carbon-boron bond in multiple functionalities, under the total control of chemo- and stereoselectivity. Full article
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Review
Molecular and Cellular Mechanisms of Cytotoxic Activity of Vanadium Compounds against Cancer Cells
Molecules 2020, 25(7), 1757; https://doi.org/10.3390/molecules25071757 - 10 Apr 2020
Cited by 14 | Viewed by 1145
Abstract
Discovering that metals are essential for the structure and function of biomolecules has given a completely new perspective on the role of metal ions in living organisms. Nowadays, the design and synthesis of new metal-based compounds, as well as metal ion binding components, [...] Read more.
Discovering that metals are essential for the structure and function of biomolecules has given a completely new perspective on the role of metal ions in living organisms. Nowadays, the design and synthesis of new metal-based compounds, as well as metal ion binding components, for the treatment of human diseases is one of the main aims of bioinorganic chemistry. One of the areas in vanadium-based compound research is their potential anticancer activity. In this review, we summarize recent molecular and cellular mechanisms in the cytotoxic activity of many different synthetic vanadium complexes as well as inorganic salts. Such mechanisms shall include DNA binding, oxidative stress, cell cycle regulation and programed cell death. We focus mainly on cellular studies involving many type of cancer cell lines trying to highlight some new significant advances. Full article
(This article belongs to the Special Issue Advances in Anticancer Drug Discovery)
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Review
How Computational Chemistry and Drug Delivery Techniques Can Support the Development of New Anticancer Drugs
Molecules 2020, 25(7), 1756; https://doi.org/10.3390/molecules25071756 - 10 Apr 2020
Cited by 5 | Viewed by 1411
Abstract
The early and late development of new anticancer drugs, small molecules or peptides can be slowed down by some issues such as poor selectivity for the target or poor ADME properties. Computer-aided drug design (CADD) and target drug delivery (TDD) techniques, although apparently [...] Read more.
The early and late development of new anticancer drugs, small molecules or peptides can be slowed down by some issues such as poor selectivity for the target or poor ADME properties. Computer-aided drug design (CADD) and target drug delivery (TDD) techniques, although apparently far from each other, are two research fields that can give a significant contribution to overcome these problems. Their combination may provide mechanistic understanding resulting in a synergy that makes possible the rational design of novel anticancer based therapies. Herein, we aim to discuss selected applications, some also from our research experience, in the fields of anticancer small organic drugs and peptides. Full article
(This article belongs to the Special Issue Peptides and Small Molecules as Anti-Cancer Agents)
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Article
Sensitive Detection of Nucleic Acids Using Subzyme Feedback Cascades
Molecules 2020, 25(7), 1755; https://doi.org/10.3390/molecules25071755 - 10 Apr 2020
Cited by 1 | Viewed by 1087
Abstract
The development of Subzymes demonstrates how the catalytic activity of DNAzymes can be controlled for detecting nucleic acids; however, Subzymes alone lack the sensitivity required to detect low target concentrations. To improve sensitivity, we developed a feedback system using a pair of cross-catalytic [...] Read more.
The development of Subzymes demonstrates how the catalytic activity of DNAzymes can be controlled for detecting nucleic acids; however, Subzymes alone lack the sensitivity required to detect low target concentrations. To improve sensitivity, we developed a feedback system using a pair of cross-catalytic Subzymes. These were individually tethered to microparticles (MP) and separated by a porous membrane rendering them unable to interact. In the presence of a target, active PlexZymes® cleave a first Subzyme, which separates a first DNAzyme from its MP, allowing the DNAzyme to migrate through the membrane, where it can cleave a second Subzyme. This releases a second DNAzyme which can now migrate through the membrane and cleave more of the first Subzyme, thus initiating a cross-catalytic cascade. Activated DNAzymes can additionally cleave fluorescent substrates, generating a signal, and thereby, indicating the presence of the target. The method detected 1 fM of DNA homologous to the ompA gene of Chlamydia trachomatis within 30 min, demonstrating a 10,000-fold increase in sensitivity over PlexZyme detection alone. The Subzyme cascade is universal and can be triggered by any target by modifying the target sensing arms of the PlexZymes. Further, it is isothermal, protein-enzyme-free and shows great potential for rapid and affordable biomarker detection. Full article
(This article belongs to the Special Issue Advances in Catalytic DNA)
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Article
One-Pot Iridium Catalyzed C–H Borylation/Sonogashira Cross-Coupling: Access to Borylated Aryl Alkynes
Molecules 2020, 25(7), 1754; https://doi.org/10.3390/molecules25071754 - 10 Apr 2020
Cited by 3 | Viewed by 1638
Abstract
Borylated aryl alkynes have been synthesized via one-pot iridium catalyzed C–H borylation (CHB)/Sonogashira cross-coupling of aryl bromides. Direct borylation of aryl alkynes encountered problems related to the reactivity of the alkyne under CHB conditions. However, tolerance of aryl bromides to CHB made possible [...] Read more.
Borylated aryl alkynes have been synthesized via one-pot iridium catalyzed C–H borylation (CHB)/Sonogashira cross-coupling of aryl bromides. Direct borylation of aryl alkynes encountered problems related to the reactivity of the alkyne under CHB conditions. However, tolerance of aryl bromides to CHB made possible a subsequent Sonogashira cross-coupling to access the desired borylated aryl alkynes. Full article
(This article belongs to the Special Issue Advances in Cross-Coupling Reactions)
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Article
In Silico Screening for Novel Leucine Aminopeptidase Inhibitors with 3,4-Dihydroisoquinoline Scaffold
Molecules 2020, 25(7), 1753; https://doi.org/10.3390/molecules25071753 - 10 Apr 2020
Cited by 1 | Viewed by 1113
Abstract
Cancers are the leading cause of deaths worldwide. In 2018, an estimated 18.1 million new cancer cases and 9.6 million cancer-related deaths occurred globally. Several previous studies have shown that the enzyme, leucine aminopeptidase is involved in pathological conditions such as cancer. On [...] Read more.
Cancers are the leading cause of deaths worldwide. In 2018, an estimated 18.1 million new cancer cases and 9.6 million cancer-related deaths occurred globally. Several previous studies have shown that the enzyme, leucine aminopeptidase is involved in pathological conditions such as cancer. On the basis of the knowledge that isoquinoline alkaloids have antiproliferative activity and inhibitory activity towards leucine aminopeptidase, the present study was conducted a study which involved database search, virtual screening, and design of new potential leucine aminopeptidase inhibitors with a scaffold based on 3,4-dihydroisoquinoline. These compounds were then filtered through Lipinski’s “rule of five,” and 25 081 of them were then subjected to molecular docking. Next, three-dimensional quantitative structure-activity relationship (3D-QSAR) study was performed for the selected group of compounds with the best binding score results. The developed model, calculated by leave-one-out method, showed acceptable predictive and descriptive capability as represented by standard statistical parameters r2 (0.997) and q2 (0.717). Further, 35 compounds were identified to have an excellent predictive reliability. Finally, nine selected compounds were evaluated for drug-likeness and different pharmacokinetics parameters such as absorption, distribution, metabolism, excretion, and toxicity. Our methodology suggested that compounds with 3,4-dihydroisoquinoline moiety were potentially active in inhibiting leucine aminopeptidase and could be used for further in-depth in vitro and in vivo studies. Full article
(This article belongs to the Special Issue Structure-Based Design of Biologically Active Compounds)
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Review
Recent Advances in the Application of Antibacterial Complexes Using Essential Oils
Molecules 2020, 25(7), 1752; https://doi.org/10.3390/molecules25071752 - 10 Apr 2020
Cited by 4 | Viewed by 1193
Abstract
Although antibacterial spectrum of essential oils (EOs) has been analyzed along with consumers’ needs on natural biocides, singular treatments generally require high concentration of EOs and long-term exposures to eliminate target bacteria. To overcome these limitations, antibacterial complex has been developed and this [...] Read more.
Although antibacterial spectrum of essential oils (EOs) has been analyzed along with consumers’ needs on natural biocides, singular treatments generally require high concentration of EOs and long-term exposures to eliminate target bacteria. To overcome these limitations, antibacterial complex has been developed and this review analyzed previous reports regarding the combined antibacterial effects of EOs. Since unexpectable combined effects (synergism or antagonism) can be derived from the treatment of antibacterial complex, synergistic and antagonistic combinations have been identified to improve the treatment efficiency and to avoid the overestimation of bactericidal efficacy, respectively. Although antibacterial mechanism of EOs is not yet clearly revealed, mode of action regarding synergistic effects especially for the elimination of pathogens by using low quantity of EOs with short-term exposure was reported. Whereas comprehensive analysis on previous literatures for EO-based disinfectant products implies that the composition of constituents in antibacterial complexes is variable and thus analyzing the impact of constituting substances (e.g., surfactant, emulsifier) on antibacterial effects is further needed. This review provides practical information regarding advances in the EO-based combined treatment technologies and highlights the importance of following researches on the interaction of constituents in antibacterial complex to clarify the mechanisms of antibacterial synergism and/or antagonism. Full article
(This article belongs to the Special Issue Essential Oils as Antimicrobial and Anti-infectious Agents II)
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Article
Arylaminopropanone Derivatives as Potential Cholinesterase Inhibitors: Synthesis, Docking Study and Biological Evaluation
Molecules 2020, 25(7), 1751; https://doi.org/10.3390/molecules25071751 - 10 Apr 2020
Cited by 2 | Viewed by 788
Abstract
Neurodegenerative diseases in which the decrease of the acetylcholine is observed are growing worldwide. In the present study, a series of new arylaminopropanone derivatives with N-phenylcarbamate moiety (1–16) were prepared as potential acetylcholinesterase and butyrylcholinesterase inhibitors. In vitro enzyme assays [...] Read more.
Neurodegenerative diseases in which the decrease of the acetylcholine is observed are growing worldwide. In the present study, a series of new arylaminopropanone derivatives with N-phenylcarbamate moiety (1–16) were prepared as potential acetylcholinesterase and butyrylcholinesterase inhibitors. In vitro enzyme assays were performed; the results are expressed as a percentage of inhibition and the IC50 values. The inhibitory activities were compared with reference drugs galantamine and rivastigmine showing piperidine derivatives (1–3) as the most potent. A possible mechanism of action for these compounds was determined from a molecular modelling study by using combined techniques of docking, molecular dynamics simulations and quantum mechanics calculations. Full article
(This article belongs to the Section Medicinal Chemistry)
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Article
Characterization of 18F-PM-PBB3 (18F-APN-1607) Uptake in the rTg4510 Mouse Model of Tauopathy
Molecules 2020, 25(7), 1750; https://doi.org/10.3390/molecules25071750 - 10 Apr 2020
Cited by 5 | Viewed by 1251
Abstract
Misfolding, aggregation, and cerebral accumulation of tau deposits are hallmark features of Alzheimer’s disease. Positron emission tomography study of tau can facilitate the development of anti-tau treatment. Here, we investigated a novel tau tracer 18F-PM-PBB3 (18F-APN-1607) in a mouse model [...] Read more.
Misfolding, aggregation, and cerebral accumulation of tau deposits are hallmark features of Alzheimer’s disease. Positron emission tomography study of tau can facilitate the development of anti-tau treatment. Here, we investigated a novel tau tracer 18F-PM-PBB3 (18F-APN-1607) in a mouse model of tauopathy. Dynamic PET scans were collected in groups of rTg4510 transgenic mice at 2–11 months of age. Associations between distribution volume ratios (DVR) and standardized uptake value ratios (SUVR) with cerebellum reference were used to determine the optimal scanning time and uptake pattern for each age. Immunohistochemistry staining of neurofibrillary tangles and autoradiography study was performed for ex vivo validation. An SUVR 40–70 min was most consistently correlated with DVR and was used in further analyses. Significant increased 18F-PM-PBB3 uptake in the brain cortex was found in six-month-old mice (+28.9%, p < 0.05), and increased further in the nine-month-old group (+38.8%, p < 0.01). The trend of increased SUVR value remained evident in the hippocampus and striatum regions except for cortex where uptake becomes slightly reduced in 11-month-old animals (+37.3%, p < 0.05). Radioactivity distributions from autoradiography correlate well to the presence of human tau (HT7 antibody) and hyperphosphorylated tau (antibody AT8) from the immunohistochemistry study of the adjacent brain sections. These findings supported that the 40–70 min 18F-PM-PBB3 PET scan with SUVR measurement can detect significantly increased tau deposits in a living rTg4510 transgenic mouse models as early as six-months-old. The result exhibited promising dynamic imaging capability of this novel tau tracer, and the above image characteristics should be considered in the design of longitudinal preclinical tau image studies. Full article
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Article
Phenolic Composition of the Leaves of Pyrola rotundifolia L. and Their Antioxidant and Cytotoxic Activity
Molecules 2020, 25(7), 1749; https://doi.org/10.3390/molecules25071749 - 10 Apr 2020
Cited by 8 | Viewed by 1005
Abstract
The leaves of Pyrola rotundifolia L. were extracted in the mixed solvent of methanol/acetone/water (2:2:1, v/v/v) and investigated for their phytochemical analysis and biological activity. Total phenolic and flavonoid contents were determined spectrophotometrically. A high content of phenols [...] Read more.
The leaves of Pyrola rotundifolia L. were extracted in the mixed solvent of methanol/acetone/water (2:2:1, v/v/v) and investigated for their phytochemical analysis and biological activity. Total phenolic and flavonoid contents were determined spectrophotometrically. A high content of phenols (208.35 mg GAE/g of dry extract), flavonoids (38.90 mg QE/g of dry extract) and gallotannins (722.91 GAE/g of dry extract) was obtained. Ultra-high performance liquid chromatography diode array detector tandem mass spectrometry (UHPLC–DAD–MS) allowed for the detection of 23 major peaks at 254 nm. The extract was analyzed for its antioxidant capacity using 2,2-diphenyl-1-picryl-hydrazyl (DPPH) and 2,2′-azinobis[3-ethylbenzthiazoline]-6-sulfonic acid (ABTS•+) radical scavenging, metal chelating power and β-carotene-linoleic acid bleaching assays. The examined extract showed moderate radical scavenging and chelating activity, and good inhibiting ability of linoleic acid oxidation (EC50 = 0.05 mg/mL) in comparison to standards. The cytotoxic effect in increasing concentration on five types of leukemic cell lines was also investigated using trypan blue vital staining. It was found that the analyzed extract induced the apoptosis of all the tested cell lines. Our findings suggest that the leaves of P. rotundifolia are a source of valuable compounds providing protection against oxidative damage, hence their use in traditional medicine is justified. Full article
(This article belongs to the Special Issue Chromatographic Science of Natural Products)
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Article
Dual P-Glycoprotein and CA XII Inhibitors: A New Strategy to Reverse the P-gp Mediated Multidrug Resistance (MDR) in Cancer Cells
Molecules 2020, 25(7), 1748; https://doi.org/10.3390/molecules25071748 - 10 Apr 2020
Cited by 5 | Viewed by 914
Abstract
A new series of N,N-bis(alkanol)amine aryl diesters was synthesized and studied as dual P-glycoprotein (P-gp) and carbonic anhydrase XII inhibitors (CA XII). These hybrids should be able to synergistically overcome P-gp mediated multidrug resistance (MDR) in cancer cells. It was reported that [...] Read more.
A new series of N,N-bis(alkanol)amine aryl diesters was synthesized and studied as dual P-glycoprotein (P-gp) and carbonic anhydrase XII inhibitors (CA XII). These hybrids should be able to synergistically overcome P-gp mediated multidrug resistance (MDR) in cancer cells. It was reported that the efflux activity of P-gp could be modulated by CA XII, as the pH reduction caused by CA XII inhibition produces a significant decrease in P-gp ATPase activity. The new compounds reported here feature both P-gp and CA XII binding moieties. These hybrids contain a N,N-bis(alkanol)amine diester scaffold found in P-glycoprotein ligands and a coumarin or benzene sulfonamide moiety to target CA XII. Many compounds displayed a dual activity against P-gp and CA XII being active in the Rhd 123 uptake test on K562/DOX cells and in the hCA XII inhibition test. On LoVo/DOX cells, that overexpress both P-gp and CA XII, some coumarin derivatives showed a high MDR reversal effect in Rhd 123 uptake and doxorubicin cytotoxicity enhancement tests. In particular, compounds 7 and 8 showed higher activity than verapamil and were more potent on LoVo/DOX than on K562/DOX cells overexpressing only P-gp. They can be considered as valuable candidates for selective P-gp/CA XII inhibition in MDR cancer cells. Full article
(This article belongs to the Special Issue Multitarget Ligands)
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Article
Flame-Made Calcium Phosphate Nanoparticles with High Drug Loading for Delivery of Biologics
Molecules 2020, 25(7), 1747; https://doi.org/10.3390/molecules25071747 - 10 Apr 2020
Cited by 5 | Viewed by 1360
Abstract
Nanoparticles exhibit potential as drug carriers in biomedicine due to their high surface-to-volume ratio that allows for facile drug loading. Nanosized drug delivery systems have been proposed for the delivery of biologics facilitating their transport across epithelial layers and maintaining their stability against [...] Read more.
Nanoparticles exhibit potential as drug carriers in biomedicine due to their high surface-to-volume ratio that allows for facile drug loading. Nanosized drug delivery systems have been proposed for the delivery of biologics facilitating their transport across epithelial layers and maintaining their stability against proteolytic degradation. Here, we capitalize on a nanomanufacturing process famous for its scalability and reproducibility, flame spray pyrolysis, and produce calcium phosphate (CaP) nanoparticles with tailored properties. The as-prepared nanoparticles are loaded with bovine serum albumin (model protein) and bradykinin (model peptide) by physisorption and the physicochemical parameters influencing their loading capacity are investigated. Furthermore, we implement the developed protocol by formulating CaP nanoparticles loaded with the LL-37 antimicrobial peptide, which is a biological drug currently involved in clinical trials. High loading values along with high reproducibility are achieved. Moreover, it is shown that CaP nanoparticles protect LL-37 from proteolysis in vitro. We also demonstrate that LL-37 retains its antimicrobial activity against Escherichia coli and Streptococcus pneumoniae when loaded on nanoparticles in vitro. Therefore, we highlight the potential of nanocarriers for optimization of the therapeutic profile of existing and emerging biological drugs. Full article
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Article
Chemical Constituents with GNMT-Promoter-Enhancing and NRF2-Reduction Activities from Taiwan Agarwood Excoecaria formosana
Molecules 2020, 25(7), 1746; https://doi.org/10.3390/molecules25071746 - 10 Apr 2020
Cited by 2 | Viewed by 921
Abstract
Hepatocellular carcinoma (HCC) is considered to be a silent killer, and was the fourth leading global cause of cancer deaths in 2018. For now, sorafenib is the only approved drug for advanced HCC treatment. The introduction of additional chemopreventive agents and/or adjuvant therapies [...] Read more.
Hepatocellular carcinoma (HCC) is considered to be a silent killer, and was the fourth leading global cause of cancer deaths in 2018. For now, sorafenib is the only approved drug for advanced HCC treatment. The introduction of additional chemopreventive agents and/or adjuvant therapies may be helpful for the treatment of HCC. After screening 3000 methanolic extracts from the Formosan plant extract bank, Excoecaria formosana showed glycine N-methyltransferase (GNMT)-promoter-enhancing and nuclear factor erythroid 2-related factor 2 (NRF2)-suppressing activities. Further, the investigation of the whole plant of E. formosana led to the isolation of a new steroid, 7α-hydroperoxysitosterol-3-O-β-d-(6-O-palmitoyl)glucopyranoside (1); two new coumarinolignans, excoecoumarin A (2) and excoecoumarin B (3); a new diterpene, excoeterpenol A (4); and 40 known compounds (544). Among them, Compounds 38 and 4044 at a 100 μM concentration showed a 2.97 ± 0.27-, 3.17 ± 1.03-, 2.73 ± 0.23-, 2.63 ± 0.14-, 6.57 ± 0.13-, and 2.62 ± 0.05-fold increase in GNMT promoter activity, respectively. In addition, Compounds 40 and 43 could reduce NRF2 activity, a transcription factor associated with drug resistance, in Huh7 cells with relative activity of 33.1 ± 0.2% and 45.2 ± 2.5%. These results provided the basis for the utilization of Taiwan agarwood for the development of anti-HCC agents. Full article
(This article belongs to the Section Natural Products Chemistry)
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Review
Azides and Porphyrinoids: Synthetic Approaches and Applications. Part 2—Azides, Phthalocyanines, Subphthalocyanines and Porphyrazines
Molecules 2020, 25(7), 1745; https://doi.org/10.3390/molecules25071745 - 10 Apr 2020
Cited by 4 | Viewed by 1175
Abstract
The reaction between organic azides and alkyne derivatives via the Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) is an efficient strategy to combine phthalocyanines and analogues with different materials. As examples of such materials, it can be considered the following ones: graphene oxide, carbon nanotubes, silica [...] Read more.
The reaction between organic azides and alkyne derivatives via the Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) is an efficient strategy to combine phthalocyanines and analogues with different materials. As examples of such materials, it can be considered the following ones: graphene oxide, carbon nanotubes, silica nanoparticles, gold nanoparticles, and quantum dots. This approach is also being relevant to conjugate phthalocyanines with carbohydrates and to obtain new sophisticated molecules; in such way, new systems with significant potential applications become available. This review highlights recent developments on the synthesis of phthalocyanine, subphthalocyanine, and porphyrazine derivatives where CuAAC reactions are the key synthetic step. Full article
(This article belongs to the Special Issue Organic Azides 2019)
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Article
Nanoparticles Based on Novel Carbohydrate-Functionalized Polymers
Molecules 2020, 25(7), 1744; https://doi.org/10.3390/molecules25071744 - 10 Apr 2020
Viewed by 881
Abstract
Polymeric nanoparticles can be used for drug delivery systems in healthcare. For this purpose poly(lactic-co-glycolic acid) (PLGA) and poly(ethylene glycol) (PEG) offer an excellent polymeric matrix. In this work, PLGA and PEG polymers were functionalized with coumarin and carbohydrate moieties such as thymidine, [...] Read more.
Polymeric nanoparticles can be used for drug delivery systems in healthcare. For this purpose poly(lactic-co-glycolic acid) (PLGA) and poly(ethylene glycol) (PEG) offer an excellent polymeric matrix. In this work, PLGA and PEG polymers were functionalized with coumarin and carbohydrate moieties such as thymidine, glucose, galactose, and mannose that have high biological specificities. Using a single oil in water emulsion methodology, functionalized PLGA nanoparticles were prepared having a smooth surface and sizes ranging between 114–289 nm, a low polydispersity index and a zeta potential from −28.2 to −56.0 mV. However, for the corresponding PEG derivatives the polymers obtained were produced in the form of films due to the small size of the hydrophobic core. Full article
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Review
Targeted Radionuclide Therapy of Prostate Cancer—From Basic Research to Clinical Perspectives
Molecules 2020, 25(7), 1743; https://doi.org/10.3390/molecules25071743 - 10 Apr 2020
Cited by 15 | Viewed by 1711
Abstract
Prostate cancer is the most commonly diagnosed malignancy in men and the second leading cause of cancer-related deaths in Western civilization. Although localized prostate cancer can be treated effectively in different ways, almost all patients progress to the incurable metastatic castration-resistant prostate cancer. [...] Read more.
Prostate cancer is the most commonly diagnosed malignancy in men and the second leading cause of cancer-related deaths in Western civilization. Although localized prostate cancer can be treated effectively in different ways, almost all patients progress to the incurable metastatic castration-resistant prostate cancer. Due to the significant mortality and morbidity rate associated with the progression of this disease, there is an urgent need for new and targeted treatments. In this review, we summarize the recent advances in research on identification of prostate tissue-specific antigens for targeted therapy, generation of highly specific and selective molecules targeting these antigens, availability of therapeutic radionuclides for widespread medical applications, and recent achievements in the development of new-generation small-molecule inhibitors and antibody-based strategies for targeted prostate cancer therapy with alpha-, beta-, and Auger electron-emitting radionuclides. Full article
(This article belongs to the Section Medicinal Chemistry)
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Article
Influence of Instant Controlled Pressure Drop (DIC) on Allergenic Potential of Tree Nuts
Molecules 2020, 25(7), 1742; https://doi.org/10.3390/molecules25071742 - 10 Apr 2020
Cited by 2 | Viewed by 982
Abstract
Pistachio and cashew contain allergenic proteins, which causes them to be removed from the diet of allergic people. Previous studies have demonstrated that food processing (thermal and non-thermal) can produce structural and/or conformational changes in proteins by altering their allergenic capacity. In this [...] Read more.
Pistachio and cashew contain allergenic proteins, which causes them to be removed from the diet of allergic people. Previous studies have demonstrated that food processing (thermal and non-thermal) can produce structural and/or conformational changes in proteins by altering their allergenic capacity. In this study, the influence of instant controlled pressure drop (DIC) on pistachio and cashew allergenic capacity has been studied. Western blot was carried out using IgG anti-11S and anti-2S and IgE antibodies from sera of patients sensitized to pistachio and cashew. DIC processing causes changes in the electrophoretic pattern, reducing the number and intensity of protein bands, as the pressure and temperature treatment increment, which results in a remarkable decrease in detection of potentially allergenic proteins. The harshest conditions of DIC (7 bar, 120 s) markedly reduce the immunodetection of allergenic proteins, not only by using IgG (anti 11S and anti 2S) but also when IgE sera from sensitized patients were used for Western blots. Such immunodetection is more affected in pistachio than in cashew nuts, but is not completely removed. Therefore, cashew proteins are possibly more resistant than pistachio proteins. According these findings, instant controlled pressure drop (DIC) can be considered a suitable technique in order to obtain hypoallergenic tree nut flour to be used in the food industry. Full article
(This article belongs to the Special Issue Opportunities and Challenges in High Pressure Processing of Foods)
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Article
Efficacy of Topical Treatment with (−)-Epigallocatechin Gallate, A Green Tea Catechin, in Mice with Cutaneous Leishmaniasis
Molecules 2020, 25(7), 1741; https://doi.org/10.3390/molecules25071741 - 10 Apr 2020
Cited by 3 | Viewed by 892
Abstract
The treatment of leishmaniasis includes pentavalent antimony drugs but, because of the side effects, toxicity and cases of treatment failure or resistance, the search of new antileishmanial compounds are necessary. The aims of this study were to evaluate and compare the in vitro [...] Read more.
The treatment of leishmaniasis includes pentavalent antimony drugs but, because of the side effects, toxicity and cases of treatment failure or resistance, the search of new antileishmanial compounds are necessary. The aims of this study were to evaluate and compare the in vitro antileishmanial activity of four green tea catechins, and to assess the efficacy of topical (−)-epigallocatechin gallate in a cutaneous leishmaniasis model. The antileishmanial activity of green tea catechins was evaluated against intracellular amastigotes, and cytotoxicity was performed with human monocytic cell line. BALB/c mice were infected in the ear dermis with Leishmania (Leishmania) amazonensis and treated with topical 15% (−)-epigallocatechin gallate, intraperitoneal Glucantime, and control group. The efficacy of treatments was evaluated by quantifying the parasite burden and by measuring the lesions size. (−)-Epigallocatechin gallate and (−)-epigallocatechin were the most active compounds with IC50 values <59.6 µg/mL and with a selectivity index >1. Topical treatment with (−)-epigallocatechin gallate decreased significantly both lesion size and parasite burden (80.4% inhibition) compared to control group (p < 0.05), and moreover (−)-epigallocatechin gallate showed a similar efficacy to Glucantime (85.1% inhibition), the reference drug for leishmaniasis treatment. Full article
(This article belongs to the Special Issue Drug Discovery for Neglected Diseases)
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Article
Optical Textures and Orientational Structures in Cholesteric Droplets with Conical Boundary Conditions
Molecules 2020, 25(7), 1740; https://doi.org/10.3390/molecules25071740 - 10 Apr 2020
Cited by 3 | Viewed by 952
Abstract
Cholesteric droplets dispersed in polymer with conical boundary conditions have been studied. The director configurations are identified by the polarising microscopy technique. The axisymmetric twisted axial-bipolar configuration with the surface circular defect at the droplet’s equator is formed at the relative chirality parameter [...] Read more.
Cholesteric droplets dispersed in polymer with conical boundary conditions have been studied. The director configurations are identified by the polarising microscopy technique. The axisymmetric twisted axial-bipolar configuration with the surface circular defect at the droplet’s equator is formed at the relative chirality parameter N 0 2.9 . The intermediate director configuration with the deformed circular defect is realised at 2.9 < N 0 < 3.95 , and the layer-like structure with the twisted surface defect loop is observed at N 0 3.95 . The cholesteric layers in the layer-like structure are slightly distorted although the cholesteric helix is untwisted. Full article
(This article belongs to the Special Issue Current Advances in Liquid Crystals)
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Article
Vine-Canes Valorisation: Ultrasound-Assisted Extraction from Lab to Pilot Scale
Molecules 2020, 25(7), 1739; https://doi.org/10.3390/molecules25071739 - 10 Apr 2020
Cited by 8 | Viewed by 836
Abstract
Wine production generates large amounts of vine-canes, a devalued by-product that could be used for the recovery of bioactive compounds. In this work, two vine-canes varieties, namely Touriga Nacional (TN) and Tinta Roriz (TR), were submitted to different ultrasound-assisted extraction (UAE) conditions. The [...] Read more.
Wine production generates large amounts of vine-canes, a devalued by-product that could be used for the recovery of bioactive compounds. In this work, two vine-canes varieties, namely Touriga Nacional (TN) and Tinta Roriz (TR), were submitted to different ultrasound-assisted extraction (UAE) conditions. The highest phenolic and flavonoid content was observed for TR extract obtained at lab-scale without an ice bath and pilot-scale after 60 min of extraction (32.6 ± 2.1 and 26.0 ± 1.5 mg gallic acid equivalent/g dry weight (dw) and 9.5 ± 0.6 and 8.3 ± 0.8 mg epicatechin equivalents/g dw, respectively). Further, all extracts demonstrated a high antioxidant activity to scavenge DPPH free radicals with the best value reached by TR at the lab-scale without an ice bath after 30 min and pilot-scale extraction after 60 min (34.2 ± 2.4 and 33.4 ± 2.1 mg trolox equivalents/g dw, respectively). Extracts phenolic composition were also evaluated by HPLC, demonstrating that resveratrol, myricetin and catechin were the main compounds. According to our knowledge, this is the first time that a pilot scale of UAE of phenolic compounds from vine-canes was performed. This paper represents an important step to the use of UAE as an industrial process to recover bioactive compounds. Full article
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Review
New Frontiers for the Use of IP6 and Inositol Combination in Treating Diabetes Mellitus: A Review
Molecules 2020, 25(7), 1720; https://doi.org/10.3390/molecules25071720 - 10 Apr 2020
Cited by 6 | Viewed by 1447
Abstract
Inositol, or myo-inositol, and associated analog molecules, including myo-inositol hexakisphosphate, are known to possess beneficial biomedical properties and are now being widely studied. The impact of these compounds in improving diabetic indices is significant, especially in light of the high cost of treating [...] Read more.
Inositol, or myo-inositol, and associated analog molecules, including myo-inositol hexakisphosphate, are known to possess beneficial biomedical properties and are now being widely studied. The impact of these compounds in improving diabetic indices is significant, especially in light of the high cost of treating diabetes mellitus and associated disorders globally. It is theorized that, within ten years, the global population of people with the disease will reach 578 million individuals, with the cost of care projected to be approximately 2.5 trillion dollars. Natural alternatives to pharmaceuticals are being sought, and this has led to studies involving inositol, and myo-inositol-hexakisphosphate, also referred to as IP6. It has been reported that IP6 can improve diabetic indices and regulate the activities of some metabolic enzymes involved in lipid and carbohydrate metabolism. Current research activities have been focusing on the mechanisms of action of inositol and IP6 in the amelioration of the indices of diabetes mellitus. We demonstrated that an IP6 and inositol combination supplement may regulate insulin secretion, modulate serum leptin concentrations, food intake, and associated weight gain, which may be beneficial in both prediabetic and diabetic states. The supplement attenuates vascular damage by reducing red cell distribution width. Serum HDL is increased while serum triglycerides tend to decrease with consumption of the combination supplement, perhaps due to the modulation of lipogenesis involving reduced serum lipase activity. We also noted increased fecal lipid output following combination supplement consumption. Importantly, liver function was found to be preserved. Concurrently, serum reactive oxygen species production was reduced, indicating that inositol and IP6 supplement consumption may reduce free radical damage to tissues and organs as well as serum lipids and blood glucose by preserving liver function. This review provides an overview of the findings associated with inositol and IP6 supplementation in the effective treatment of diabetes with a view to proposing the potential mechanisms of action. Full article
(This article belongs to the Special Issue Bioactivity of Inositol Phosphates)
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Article
Design, Synthesis of Novel Tetrandrine-14-l-Amino Acid and Tetrandrine-14-l-Amino Acid-Urea Derivatives as Potential Anti-Cancer Agents
Molecules 2020, 25(7), 1738; https://doi.org/10.3390/molecules25071738 - 09 Apr 2020
Viewed by 919
Abstract
Tetrandrine, a dibenzyltetrahydroisoquinoline alkaloid isolated from the root of the traditional Chinese medicinal plant Stephania tetrandra S. Moore, a member of the Menispermaceae, showed anti-cancer activity by inhibiting cell proliferation, preventing cell cycle progress and induction of cell death and autophagy. In this [...] Read more.
Tetrandrine, a dibenzyltetrahydroisoquinoline alkaloid isolated from the root of the traditional Chinese medicinal plant Stephania tetrandra S. Moore, a member of the Menispermaceae, showed anti-cancer activity by inhibiting cell proliferation, preventing cell cycle progress and induction of cell death and autophagy. In this study, twelve tetrandrine-l-amino acid derivatives and twelve tetrandrine-14-l-amino acid-urea derivatives were designed and synthesized, using C14-aminotetrandrine as raw material. Then the preliminary in vitro anti-cancer activities of these derivatives against human breast cancer cell line MDA-MB-231, human leukemia cell lines HEL and K562 were evaluated. The in vitro cytotoxicity results showed that these derivatives exhibited potent inhibitory effects on cancer cell growth, and the primary structure-activity relationships were evaluated. Notably, compound 3f exhibited satisfactory anticancer activity against all three cancer cell lines, especially the HEL cell line, with the IC50 value of 0.23 µM. Further research showed that 3f could induce G1/S cycle arrest and apoptosis in a dose- and time- dependent manner on the leukemia cell line HEL. The results suggested that 3f may be used as a potential anti-cancer agent for human leukemia. Full article
(This article belongs to the Special Issue Design, Synthesis and Applications of New Anti-Cancer Agents)
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Article
Suppressive Effect of Arctium Lappa L. Leaves on Retinal Damage Against A2E-Induced ARPE-19 Cells and Mice
Molecules 2020, 25(7), 1737; https://doi.org/10.3390/molecules25071737 - 09 Apr 2020
Cited by 1 | Viewed by 936
Abstract
Age-related macular degeneration (AMD) is a major cause of irreversible loss of vision with 80–90% of patients demonstrating dry type AMD. Dry AMD could possibly be prevented by polyphenol-rich medicinal foods by the inhibition of N-retinylidene-N-retinylethanolamine (A2E)-induced oxidative stress and cell damage. Arctium [...] Read more.
Age-related macular degeneration (AMD) is a major cause of irreversible loss of vision with 80–90% of patients demonstrating dry type AMD. Dry AMD could possibly be prevented by polyphenol-rich medicinal foods by the inhibition of N-retinylidene-N-retinylethanolamine (A2E)-induced oxidative stress and cell damage. Arctium lappa L. (AL) leaves are medicinal and have antioxidant activity. The purpose of this study was to elucidate the protective effects of the extract of AL leaves (ALE) on dry AMD models, including in vitro A2E-induced damage in ARPE-19 cells, a human retinal pigment epithelial cell line, and in vivo light-induced retinal damage in BALB/c mice. According to the total phenolic contents (TPCs), total flavonoid contents (TFCs) and antioxidant activities, ALE was rich in polyphenols and had antioxidant efficacies on 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), ferric reducing antioxidant power (FRAP), and 2′,7′-dichlorofluorescin diacetate (DCFDA) assays. The effects of ALE on A2E accumulation and A2E-induced cell death were also monitored. Despite continued exposure to A2E (10 μM), ALE attenuated A2E accumulation in APRE-19 cells with levels similar to lutein. A2E-induced cell death at high concentration (25 μM) was also suppressed by ALE by inhibiting the apoptotic signaling pathway. Furthermore, ALE could protect the outer nuclear layer (ONL) in the retina from light-induced AMD in BALB/c mice. In conclusion, ALE could be considered a potentially valuable medicinal food for dry AMD. Full article
(This article belongs to the Section Natural Products Chemistry)
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Article
Estimation of Chemical Composition of Pork Trimmings by Use of Density Measurement—Hydrostatic Method
Molecules 2020, 25(7), 1736; https://doi.org/10.3390/molecules25071736 - 09 Apr 2020
Viewed by 637
Abstract
This study aims to determine the possibility of using density measurements by using the hydrostatic method for the estimation of the chemical composition of pork. The research material included 75 pork samples obtained during industrial butchering and cutting. The density measurements were performed [...] Read more.
This study aims to determine the possibility of using density measurements by using the hydrostatic method for the estimation of the chemical composition of pork. The research material included 75 pork samples obtained during industrial butchering and cutting. The density measurements were performed using the hydrostatic method based on Archimedes’ principle. The meat samples were minced, and the content of the basic chemical components in them was determined. The usefulness of density measurement using the hydrostatic method in chemical composition estimation was determined by analyzing the correlation for the entire population, and after grouping the samples with a low (<15%), medium (15–25%), and high (>25%) fat content. High (in absolute value) coefficients of correlation between the meat density and the content of water (0.96), protein (0.94), and fat (−0.96) were found based on the results obtained. In order to achieve higher accuracy of the estimation, the applied regression equations should be adjusted to the presumed fat content in the meat. The standard error of prediction (SEP) values ranged from 0.67% to 2.82%, which indicates that the calculated estimation accuracy may be sufficient for proper planning of the production. Higher SEP values were found in fat content estimation and the lowest ones were found in protein content estimation. Full article
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Article
Analysis of Total Thiols in the Urine of a Cystathionine β-Synthase-Deficient Mouse Model of Homocystinuria Using Hydrophilic Interaction Chromatography
Molecules 2020, 25(7), 1735; https://doi.org/10.3390/molecules25071735 - 09 Apr 2020
Cited by 1 | Viewed by 837
Abstract
Homocysteine and related thiols (cysteine, cysteinylglycine, and glutathione) in the urine of a cystathionine β-synthase (CBS)-deficient mouse model were quantified using hydrophilic interaction chromatography with fluorescence detection. Urine samples were incubated with tris(2-carboxyethyl) phosphine to reduce disulfide bonds into thiols. After deproteinization, thiols [...] Read more.
Homocysteine and related thiols (cysteine, cysteinylglycine, and glutathione) in the urine of a cystathionine β-synthase (CBS)-deficient mouse model were quantified using hydrophilic interaction chromatography with fluorescence detection. Urine samples were incubated with tris(2-carboxyethyl) phosphine to reduce disulfide bonds into thiols. After deproteinization, thiols were fluorescently derivatized with ammonium 7-fluoro-2,1,3-benzoxadiazole-4-sulfonate (SBD-F). Homocysteine, cysteine, cysteinylglycine, and glutathione in mouse urine were analyzed using an amide-type column with a mobile phase of acetonitrile/120 mM ammonium formate buffer (pH 3.0) (81:19). The developed method was well-validated. Thiol concentrations in the urine of CBS-wild type (-WT), -heterozygous (-Hetero), and -knockout (-KO) mice were quantified using the developed method. As expected, total homocysteine concentration in CBS-KO mice was significantly higher than that in CBS-WT and CBS-Hetero mice. The developed method shows promise for diagnoses in preclinical and clinical studies. Full article
(This article belongs to the Special Issue Biological Sample Analysis by Liquid Chromatography II)
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Review
Carbohydrates—Key Players in Tobacco Aroma Formation and Quality Determination
Molecules 2020, 25(7), 1734; https://doi.org/10.3390/molecules25071734 - 09 Apr 2020
Cited by 2 | Viewed by 1004
Abstract
Carbohydrates are important compounds in natural products where they primarily serve as a source of energy, but they have important secondary roles as precursors of aroma or bioactive compounds. They are present in fresh and dried (cured) tobacco leaves as well. The sugar [...] Read more.
Carbohydrates are important compounds in natural products where they primarily serve as a source of energy, but they have important secondary roles as precursors of aroma or bioactive compounds. They are present in fresh and dried (cured) tobacco leaves as well. The sugar content of tobacco depends on the tobacco variety, harvesting, and primarily on the curing conditions (temperature, time and moisture). If the process of curing employs high temperatures (flue-curing and sun-curing), final sugar content is high. In contrast, when air curing has a lower temperature, at the end of the process, sugar level is low. Beside simple sugars, other carbohydrates reported in tobacco are oligosaccharides, cellulose, starch, and pectin. Degradation of polysaccharides results in a higher yield of simple sugars, but at the same time reduces sugars oxidization and transfer into carbon dioxide and water. Loss of sugar producers will compensate with added sugars, to cover undesirable aroma properties and achieve a better, pleasant taste during smoking. However, tobacco carbohydrates can be precursors for many harmful compounds, including formaldehyde and 5-hydroxymethylfurfural. Keeping in mind that added sugars in tobacco production are unavoidable, it is important to understand all changes in carbohydrates from harvesting to consuming in order to achieve better product properties and avoid the formation of harmful compounds. This review summarizes current knowledge about tobacco carbohydrates, including changes during processing with special focus on carbohydrates as precursors of harmful compounds during smoking. Full article
(This article belongs to the Section Natural Products Chemistry)
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Communication
Towards Building Blocks for Supramolecular Architectures Based on Azacryptates
Molecules 2020, 25(7), 1733; https://doi.org/10.3390/molecules25071733 - 09 Apr 2020
Cited by 2 | Viewed by 784
Abstract
In this work, we report the synthesis of a new bis(tris(2-aminoethyl)amine) azacryptand L with triphenyl spacers. The binding properties of its dicopper complex for aromatic dicarboxylate anions (as TBA salts) were investigated, with the aim to obtain potential building blocks for supramolecular structures [...] Read more.
In this work, we report the synthesis of a new bis(tris(2-aminoethyl)amine) azacryptand L with triphenyl spacers. The binding properties of its dicopper complex for aromatic dicarboxylate anions (as TBA salts) were investigated, with the aim to obtain potential building blocks for supramolecular structures like rotaxanes and pseudo-rotaxanes. As expected, UV-Vis and emission studies of [Cu2L]4+ in water/acetonitrile mixture (pH = 7) showed a high affinity for biphenyl-4,4′-dicarboxylate (dfc2−), with a binding constant of 5.46 log units, due to the best match of the anion bite with the Cu(II)-Cu(II) distance in the cage’s cavity. Compared to other similar bistren cages, the difference of the affinity of [Cu2L]4+ for the tested anions was not so pronounced: conformational changes of L seem to promote a good interaction with both long (e.g., dfc2−) and short anions (e.g., terephthalate). The good affinity of [Cu2L]4+ for these dicarboxylates, together with hydrophobic interactions within the cage’s cavity, may promote the self-assembly of a stable 1:1 complex in water mixture. These results represent a good starting point for the application of these molecular systems as building units for the design of new supramolecular architectures based on non-covalent interactions, which could be of interest in all fields related to supramolecular devices. Full article
(This article belongs to the Special Issue Molecular Recognition and Self-Assembly in Chemistry and Medicine)
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Article
Synthesis and Evaluation of Artificial Nucleic Acid Bearing an Oxanorbornane Scaffold
Molecules 2020, 25(7), 1732; https://doi.org/10.3390/molecules25071732 - 09 Apr 2020
Cited by 1 | Viewed by 1003
Abstract
Natural oligonucleotides have many rotatable single bonds, and thus their structures are inherently flexible. Structural flexibility leads to an entropic loss when unwound oligonucleotides form a duplex with single-stranded DNA or RNA. An effective approach to reduce such entropic loss in the duplex-formation [...] Read more.
Natural oligonucleotides have many rotatable single bonds, and thus their structures are inherently flexible. Structural flexibility leads to an entropic loss when unwound oligonucleotides form a duplex with single-stranded DNA or RNA. An effective approach to reduce such entropic loss in the duplex-formation is the conformational restriction of the flexible phosphodiester linkage and/or sugar moiety. We here report the synthesis and biophysical properties of a novel artificial nucleic acid bearing an oxanorbornane scaffold (OxNorNA), where the adamant oxanorbornane was expected to rigidify the structures of both the linkage and sugar parts of nucleic acid. OxNorNA phosphoramidite with a uracil (U) nucleobase was successfully synthesized over 15 steps from a known sugar-derived cyclopentene. Thereafter, the given phosphoramidite was incorporated into the designed oligonucleotides. Thermal denaturation experiments revealed that oligonucleotides modified with the conformationally restricted OxNorNA-U properly form a duplex with the complementally DNA or RNA strands, although the Tm values of OxNorNA-U-modified oligonucleotides were lower than those of the corresponding natural oligonucleotides. As we had designed, entropic loss during the duplex-formation was reduced by the OxNorNA modification. Moreover, the OxNorNA-U-modified oligonucleotide was confirmed to have extremely high stability against 3′-exonuclease activity, and its stability was even higher than those of the phosphorothioate-modified counterparts (Sp and Rp). With the overall biophysical properties of OxNorNA-U, we expect that OxNorNA could be used for specialized applications, such as conformational fixation and/or bio-stability enhancement of therapeutic oligonucleotides (e.g., aptamers). Full article
(This article belongs to the Special Issue Recent Development of Nucleic Acid Analogs)
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