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Pharmaceuticals, Volume 13, Issue 11 (November 2020) – 90 articles

Cover Story (view full-size image): Lavandin essential oil (LEO) is mainly composed of terpene compounds endowed with the relevant anti-proliferative activity that can be enhanced by the application of nanotechnology. This study reports the chemical characterization and the anti-proliferative activity in different human cell lines of pure and nano-formulated lavandin EO. LEO and NanoLEO were analyzed by HS/GC-MS to compare their chemical volatile composition. The biological effects were investigated on SHSY5Y cells, MCF-7 cells, CCRF CEM cells, and Caco-2 cells by the MTT-assay. The antiproliferative activity of LEO was amplified when the essential oil was supplied as nanoformulation, mainly in Caco-2 cells. Scanning and transmission electron microscopy investigations were carried out on Caco-2 cells to outline, at the ultrastructural level, possible affections induced by LEO and NanoLEO treatments. View this paper
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Review
Logic Gates Based on DNA Aptamers
Pharmaceuticals 2020, 13(11), 417; https://doi.org/10.3390/ph13110417 - 23 Nov 2020
Cited by 2 | Viewed by 955
Abstract
DNA bio-computing is an emerging trend in modern science that is based on interactions among biomolecules. Special types of DNAs are aptamers that are capable of selectively forming complexes with target compounds. This review is devoted to a discussion of logic gates based [...] Read more.
DNA bio-computing is an emerging trend in modern science that is based on interactions among biomolecules. Special types of DNAs are aptamers that are capable of selectively forming complexes with target compounds. This review is devoted to a discussion of logic gates based on aptamers for the purposes of medicine and analytical chemistry. The review considers different approaches to the creation of logic gates and identifies the general algorithms of their creation, as well as describes the methods of obtaining an output signal which can be divided into optical and electrochemical. Aptameric logic gates based on DNA origami and DNA nanorobots are also shown. The information presented in this article can be useful when creating new logic gates using existing aptamers and aptamers that will be selected in the future. Full article
(This article belongs to the Special Issue Potential of the Aptamers to Fill Therapeutic and Diagnostic Gaps)
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Article
Association of 5-FU Therapeutic Drug Monitoring to DPD Phenotype Assessment May Reduce 5-FU Under-Exposure
Pharmaceuticals 2020, 13(11), 416; https://doi.org/10.3390/ph13110416 - 23 Nov 2020
Cited by 2 | Viewed by 772
Abstract
In order to limit 5-fluorouracil (5-FU) toxicity, some health agencies recommend evaluating dihydropyrimidine dehydrogenase (DPD) deficiency before any 5-FU treatment introduction. In our study, we investigated relationships between 5-FU clearance and markers of DPD activity such as uracilemia (U), dihydrouracilemia (UH2)/U [...] Read more.
In order to limit 5-fluorouracil (5-FU) toxicity, some health agencies recommend evaluating dihydropyrimidine dehydrogenase (DPD) deficiency before any 5-FU treatment introduction. In our study, we investigated relationships between 5-FU clearance and markers of DPD activity such as uracilemia (U), dihydrouracilemia (UH2)/U ratio, or genotype of the gene encoding DPD (DPYD). All patients with gastrointestinal cancers who received 5-FU-based regimens form March 2018 to June 2020 were included in our study. They routinely benefited of a pre-therapeutic DPYD genotyping and phenotyping. During 5-FU infusion, blood samples were collected to measure 5-FU steady-state concentration in order to adapt 5-FU doses at the following cycles. A total of 169 patients were included. Median age was 68 (40–88) years and main primary tumor sites were colorectal (40.8%) and pancreas (31.4%), metastatic in 76.3%. 5-FU was given as part of FOLFIRINOX (44.4%), simplified FOLFOX-6 (26.6%), or docetaxel/FOLFOX-4 (10.6%). Regarding DPD activity, median U and UH2/U were, respectively, 10.8 ng/mL and 10.1, and almost 15% harbored a heterozygous mutation. On the range of measured U and UH2/U, no correlation was observed with 5-FU clearance. Moreover, in patients with U < 16 ng/mL, 5-FU exposure was higher than in other patients, and most of them benefited of dose increase following 5-FU therapeutic drug monitoring (TDM). If recent guidelines recommend decreasing 5-FU dose in patients harboring U ≥ 16 ng/mL, our study highlights that those patients are at risk of under-exposure and that 5-FU TDM should be conducted in order to avoid loss of efficacy. Full article
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Article
Secretory Phospholipase A2-IIA Protein and mRNA Pools in Extracellular Vesicles of Bronchoalveolar Lavage Fluid from Patients with Early Acute Respiratory Distress Syndrome: A New Perception in the Dissemination of Inflammation?
Pharmaceuticals 2020, 13(11), 415; https://doi.org/10.3390/ph13110415 - 23 Nov 2020
Cited by 5 | Viewed by 777
Abstract
Secretory phospholipase-IIA A2 (sPLA2-IIA) is expressed in a variety of cell types under inflammatory conditions. Its presence in the bronchoalveolar lavage (BAL) fluid of patients with acute respiratory distress syndrome (ARDS) is associated with the severity of the injury. Exosomal [...] Read more.
Secretory phospholipase-IIA A2 (sPLA2-IIA) is expressed in a variety of cell types under inflammatory conditions. Its presence in the bronchoalveolar lavage (BAL) fluid of patients with acute respiratory distress syndrome (ARDS) is associated with the severity of the injury. Exosomal type extracellular vesicles, (EVs), are recognized to perform intercellular communication. They may alter the immune status of recipient target cells through cargo shuttling. In this work, we characterized the exosomal type EVs isolated from BAL fluid of patients with early and late ARDS as compared to control/non-ARDS patients, through morphological (confocal and electron microscopy) and biochemical (dynamic light scattering, qRT-PCR, immunoblotting) approaches. We provide evidence for the presence of an sPLA2-IIA-carrying EV pool that coprecipitates with exosomes in the BAL fluid of patients with ARDS. PLA2G2A mRNA was present in all the samples, although more prominently expressed in early ARDS. However, the protein was found only in EVs from early phase ARDS. Under both forms, sPLA2-IIA might be involved in inflammatory responses of recipient lung cells during ARDS. The perception of the association of sPLA2-IIA to the early diagnosis of ARDS or even with a mechanism of development and propagation of lung inflammation can help in the adoption of appropriate and innovative therapeutic strategies. Full article
(This article belongs to the Special Issue Lung Injury and Repair)
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Article
VEGF-Related Germinal Polymorphisms May Identify a Subgroup of Breast Cancer Patients with Favorable Outcome under Bevacizumab-Based Therapy—A Message from COMET, a French Unicancer Multicentric Study
Pharmaceuticals 2020, 13(11), 414; https://doi.org/10.3390/ph13110414 - 23 Nov 2020
Viewed by 810
Abstract
The prospective multicenter COMET trial followed a cohort of 306 consecutive metastatic breast cancer patients receiving bevacizumab and paclitaxel as first-line chemotherapy. This study was intended to identify and validate reliable biomarkers to better predict bevacizumab treatment outcomes and allow for a more [...] Read more.
The prospective multicenter COMET trial followed a cohort of 306 consecutive metastatic breast cancer patients receiving bevacizumab and paclitaxel as first-line chemotherapy. This study was intended to identify and validate reliable biomarkers to better predict bevacizumab treatment outcomes and allow for a more personalized use of this antiangiogenic agent. To that end, we aimed to establish risk scores for survival prognosis dichotomization based on classic clinico-pathological criteria combined or not with single nucleotide polymorphisms (SNPs). The genomic DNA of 306 patients was extracted and a panel of 13 SNPs, covering seven genes previously documented to be potentially involved in drug response, were analyzed by means of high-throughput genotyping. In receiver operating characteristic (ROC) analyses, the hazard model based on a triple-negative cancer phenotype variable, combined with specific SNPs in VEGFA (rs833061), VEGFR1 (rs9582036) and VEGFR2 (rs1870377), had the highest predictive value. The overall survival hazard ratio of patients assigned to the poor prognosis group based on this model was 3.21 (95% CI (2.33–4.42); p < 0.001). We propose that combining this pharmacogenetic approach with classical clinico-pathological characteristics could markedly improve clinical decision-making for breast cancer patients receiving bevacizumab-based therapy. Full article
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Review
Serum and Glucocorticoid-Inducible Kinase 1 (SGK1) in NSCLC Therapy
Pharmaceuticals 2020, 13(11), 413; https://doi.org/10.3390/ph13110413 - 22 Nov 2020
Viewed by 1026
Abstract
Non-small cell lung cancer (NSCLC) remains the most prevalent and one of the deadliest cancers worldwide. Despite recent success, there is still an urgent need for new therapeutic strategies. It is also becoming increasingly evident that combinatorial approaches are more effective than single [...] Read more.
Non-small cell lung cancer (NSCLC) remains the most prevalent and one of the deadliest cancers worldwide. Despite recent success, there is still an urgent need for new therapeutic strategies. It is also becoming increasingly evident that combinatorial approaches are more effective than single modality treatments. This review proposes that the serum and glucocorticoid-inducible kinase 1 (SGK1) may represent an attractive target for therapy of NSCLC. Although ubiquitously expressed, SGK1 deletion in mice causes only mild defects of ion physiology. The frequent overexpression of SGK1 in tumors is likely stress-induced and provides a therapeutic window to spare normal tissues. SGK1 appears to promote oncogenic signaling aimed at preserving the survival and fitness of cancer cells. Most importantly, recent investigations have revealed the ability of SGK1 to skew immune-cell differentiation toward pro-tumorigenic phenotypes. Future studies are needed to fully evaluate the potential of SGK1 as a therapeutic target in combinatorial treatments of NSCLC. However, based on what is currently known, SGK1 inactivation can result in anti-oncogenic effects both on tumor cells and on the immune microenvironment. A first generation of small molecules to inactivate SGK1 has already been already produced. Full article
(This article belongs to the Special Issue Treatment Options and Therapeutics for Non-small Cell Lung Cancer)
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Article
Simultaneous Determination of Isothiazolinones and Parabens in Cosmetic Products Using Solid-Phase Extraction and Ultra-High Performance Liquid Chromatography/Diode Array Detector
Pharmaceuticals 2020, 13(11), 412; https://doi.org/10.3390/ph13110412 - 22 Nov 2020
Viewed by 1047
Abstract
Isothiazolinones methylisothiazolinone (MI) and methylchloroisothiazolinone (MCI), and parabens methylparaben (MP), ethylparaben (EP), propylparaben (PP) and butylparaben (BP) are the most common synthetic preservatives. They are all known to be potential skin allergens that lead to contact dermatitis. Thus, the identification of these unsafe [...] Read more.
Isothiazolinones methylisothiazolinone (MI) and methylchloroisothiazolinone (MCI), and parabens methylparaben (MP), ethylparaben (EP), propylparaben (PP) and butylparaben (BP) are the most common synthetic preservatives. They are all known to be potential skin allergens that lead to contact dermatitis. Thus, the identification of these unsafe chemicals in cosmetic products is of high importance. In the present study, solid-phase extraction (SPE) based on HyperSep reversed-phase C8/benzene sulfonic acid ion exchanger (HyperSep C8/BSAIE) and Sep-Pak C18 sorbents, and ultra-high performance liquid chromatography/diode array detector (UHPLC/DAD) were optimized for the simultaneous determination of MI, MCI, MP, EP, PP and BP in cosmetic products. HyperSep C8/BSAIE and UHPLC/DAD with the eluting solvent mixture (acetonitrile/methanol, 2:1, v/v) and detection wavelength (255 nm) were found to be the optimal conditions, respectively. The method illustrates the excellent linearity range (0.008–20 μg/mL) with coefficient of determination (R2, 0.997–0.999), limits of detection (LOD, 0.001–0.002 μg/mL), precision in terms of relative standard deviation (RSD < 3%, intra-day and <6%, inter-day) when examining a standard mixture at low (0.07 µg/mL), medium (3 µg/mL) and high (15 µg/mL) concentrations. A total of 31 cosmetic samples were studied, achieving concentrations (MI, not detected (nd)-0.89 µg/g), (MCI, nd-0.62 µg/g), (MP, nd-6.53 µg/g), (EP, nd-0.90 µg/g), (PP, nd-9.69 µg/g) and (BP, nd-17.80 µg/g). Recovery values ranged from 92.33 to 101.43% depending on the types of sample. To our knowledge, this is the first specific method which covers the theme and describes background amounts of such preservatives in cosmetics. Full article
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Review
Atopic Dermatitis as a Multifactorial Skin Disorder. Can the Analysis of Pathophysiological Targets Represent the Winning Therapeutic Strategy?
Pharmaceuticals 2020, 13(11), 411; https://doi.org/10.3390/ph13110411 - 22 Nov 2020
Cited by 6 | Viewed by 1033
Abstract
Atopic dermatitis (AD) is a pathological skin condition with complex aetiological mechanisms that are difficult to fully understand. Scientific evidence suggests that of all the causes, the impairment of the skin barrier and cutaneous dysbiosis together with immunological dysfunction can be considered as [...] Read more.
Atopic dermatitis (AD) is a pathological skin condition with complex aetiological mechanisms that are difficult to fully understand. Scientific evidence suggests that of all the causes, the impairment of the skin barrier and cutaneous dysbiosis together with immunological dysfunction can be considered as the two main factors involved in this pathological skin condition. The loss of the skin barrier function is often linked to dysbiosis and immunological dysfunction, with an imbalance in the ratio between the pathogen Staphylococcus aureus and/or other microorganisms residing in the skin. The bibliographic research was conducted on PubMed, using the following keywords: ‘atopic dermatitis’, ‘bacterial therapy’, ‘drug delivery system’ and ‘alternative therapy’. The main studies concerning microbial therapy, such as the use of bacteria and/or part thereof with microbiota transplantation, and drug delivery systems to recover skin barrier function have been summarized. The studies examined show great potential in the development of effective therapeutic strategies for AD and AD-like symptoms. Despite this promise, however, future investigative efforts should focus both on the replication of some of these studies on a larger scale, with clinical and demographic characteristics that reflect the general AD population, and on the process of standardisation, in order to produce reliable data. Full article
(This article belongs to the Special Issue Novel Antibacterial Agents)
Review
Gastrointestinal Mechanisms Underlying the Cardiovascular Effect of Metformin
Pharmaceuticals 2020, 13(11), 410; https://doi.org/10.3390/ph13110410 - 22 Nov 2020
Cited by 1 | Viewed by 961
Abstract
Metformin, the most widely prescribed drug therapy for type 2 diabetes, has pleiotropic benefits, in addition to its capacity to lower elevated blood glucose levels, including mitigation of cardiovascular risk. The mechanisms underlying the latter remain unclear. Mechanistic studies have, hitherto, focused on [...] Read more.
Metformin, the most widely prescribed drug therapy for type 2 diabetes, has pleiotropic benefits, in addition to its capacity to lower elevated blood glucose levels, including mitigation of cardiovascular risk. The mechanisms underlying the latter remain unclear. Mechanistic studies have, hitherto, focused on the direct effects of metformin on the heart and vasculature. It is now appreciated that effects in the gastrointestinal tract are important to glucose-lowering by metformin. Gastrointestinal actions of metformin also have major implications for cardiovascular function. This review summarizes the gastrointestinal mechanisms underlying the action of metformin and their potential relevance to cardiovascular benefits. Full article
(This article belongs to the Special Issue Metformin: Mechanism and Application 2022)
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Perspective
A Multi-Objective Approach for Anti-Osteosarcoma Cancer Agents Discovery through Drug Repurposing
Pharmaceuticals 2020, 13(11), 409; https://doi.org/10.3390/ph13110409 - 22 Nov 2020
Cited by 2 | Viewed by 1224
Abstract
Osteosarcoma is the most common type of primary malignant bone tumor. Although nowadays 5-year survival rates can reach up to 60–70%, acute complications and late effects of osteosarcoma therapy are two of the limiting factors in treatments. We developed a multi-objective algorithm for [...] Read more.
Osteosarcoma is the most common type of primary malignant bone tumor. Although nowadays 5-year survival rates can reach up to 60–70%, acute complications and late effects of osteosarcoma therapy are two of the limiting factors in treatments. We developed a multi-objective algorithm for the repurposing of new anti-osteosarcoma drugs, based on the modeling of molecules with described activity for HOS, MG63, SAOS2, and U2OS cell lines in the ChEMBL database. Several predictive models were obtained for each cell line and those with accuracy greater than 0.8 were integrated into a desirability function for the final multi-objective model. An exhaustive exploration of model combinations was carried out to obtain the best multi-objective model in virtual screening. For the top 1% of the screened list, the final model showed a BEDROC = 0.562, EF = 27.6, and AUC = 0.653. The repositioning was performed on 2218 molecules described in DrugBank. Within the top-ranked drugs, we found: temsirolimus, paclitaxel, sirolimus, everolimus, and cabazitaxel, which are antineoplastic drugs described in clinical trials for cancer in general. Interestingly, we found several broad-spectrum antibiotics and antiretroviral agents. This powerful model predicts several drugs that should be studied in depth to find new chemotherapy regimens and to propose new strategies for osteosarcoma treatment. Full article
(This article belongs to the Collection Old Pharmaceuticals with New Applications)
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Article
In Vitro and Ex Vivo Evaluation of Penetratin as a Non-invasive Permeation Enhancer in the Penetration of Salmon Calcitonin through TR146 Buccal Cells and Porcine Buccal Tissues
Pharmaceuticals 2020, 13(11), 408; https://doi.org/10.3390/ph13110408 - 21 Nov 2020
Cited by 4 | Viewed by 759
Abstract
Buccal tissues are considered one of the potential alternative delivery route because of fast drug absorption and onset of action due to high vascularization and a non-keratinized epithelial membrane. In this study, the effect of Penetratin on the permeation of salmon calcitonin (sCT), [...] Read more.
Buccal tissues are considered one of the potential alternative delivery route because of fast drug absorption and onset of action due to high vascularization and a non-keratinized epithelial membrane. In this study, the effect of Penetratin on the permeation of salmon calcitonin (sCT), a model macromolecular peptide drug, through TR146 buccal cells and porcine buccal tissues has been evaluated. To observe permeation profile of sCT, TR146 buccal cells were treated with Alexa 647 conjugated sCT (Alexa 647-sCT) with different concentrations of fluorescein isothiocyanate -labeled Penetratin (FITC-Penetratin) ranging from 0 to 40 μM, and analyzed using flow cytometry and confocal laser scanning microscopy. Intracellular penetration of FITC-Penetratin rapidly increased at low concentrations from 0 to 15 μM and it gradually increased at concentrations above 15 μM. Intracellular penetration of Alexa 647-sCT enhanced with the increase of FITC-Penetratin concentration. When TR146 cell layers and buccal tissues were co-treated with sCT and Penetratin as permeation enhancer, the flux of sCT increased as per Penetratin concentration. Compared to the control, 12.2 μM of Penetratin enhanced the flux of sCT in TR146 cell layers and buccal tissues by 5.5-fold and 93.7-fold, respectively. These results strongly suggest that Penetratin may successfully act as a non-invasive permeation enhancer for macromolecular peptide drug delivery through buccal routes. Full article
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Article
Liraglutide Activates Glucagon-Like Peptide 1 Receptor to Attenuate Hyperglycemia through Endogenous Beta-Endorphin in Diabetic Rats
Pharmaceuticals 2020, 13(11), 407; https://doi.org/10.3390/ph13110407 - 20 Nov 2020
Viewed by 619
Abstract
Liraglutide, an acylated analog of glucagon-like peptide 1 (GLP-1), could improve glycemic control in diabetes. Moreover, endogenous opioid peptides play a role in blood sugar regulation. Since GLP-1 receptors are also expressed in extra-pancreatic tissues, this study investigates the effect of liraglutide on [...] Read more.
Liraglutide, an acylated analog of glucagon-like peptide 1 (GLP-1), could improve glycemic control in diabetes. Moreover, endogenous opioid peptides play a role in blood sugar regulation. Since GLP-1 receptors are also expressed in extra-pancreatic tissues, this study investigates the effect of liraglutide on endogenous opioid secretion in type 1-like diabetes. The endogenous opioid level was determined by enzyme-linked immunosorbent assay. The direct effect of liraglutide on endogenous opioid secretion was determined in the isolated adrenal medulla. Acute treatment with liraglutide dose-dependently attenuated hyperglycemia, and increased the plasma opioid neuropeptide, beta-endorphin (BER) levels in diabetic rats. These effects have been blocked by GLP-1 receptor antagonist, naloxone. Additionally, the effects of liraglutide were markedly reduced in adrenalectomized diabetic rats. In the isolated adrenal medulla, liraglutide induced BER secretion and increased the BER mRNA levels. Subcellular effects of liraglutide on the adrenal gland were further identified to mediate through the exchange proteins directly activated by cAMP, mainly using the pharmacological blockade. After repeatedly administering liraglutide, metabolic changes in diabetic rats were investigated, and genes associated with gluconeogenesis in the liver were downregulated. Naloxone pretreatment inhibited these effects of liraglutide, indicating the involvement of endogenous opioids. The present study indicated that liraglutide had an acute effect of reducing hyperglycemia by regulating endogenous opioid BER and modifying the glucose homeostasis. Full article
(This article belongs to the Section Pharmacology)
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Review
Contrasting Immunopathogenic and Therapeutic Roles of Granulocyte Colony-Stimulating Factor in Cancer
Pharmaceuticals 2020, 13(11), 406; https://doi.org/10.3390/ph13110406 - 20 Nov 2020
Cited by 1 | Viewed by 869
Abstract
Tumor cells are particularly adept at exploiting the immunosuppressive potential of neutrophils as a strategy to achieve uncontrolled proliferation and spread. Recruitment of neutrophils, particularly those of an immature phenotype, known as granulocytic myeloid-derived suppressor cells, is achieved via the production of tumor-derived [...] Read more.
Tumor cells are particularly adept at exploiting the immunosuppressive potential of neutrophils as a strategy to achieve uncontrolled proliferation and spread. Recruitment of neutrophils, particularly those of an immature phenotype, known as granulocytic myeloid-derived suppressor cells, is achieved via the production of tumor-derived granulocyte colony-stimulating factor (G-CSF) and neutrophil-selective chemokines. This is not the only mechanism by which G-CSF contributes to tumor-mediated immunosuppression. In this context, the G-CSF receptor is expressed on various cells of the adaptive and innate immune systems and is associated with induction of T cell polarization towards the Th2 and regulatory T cell (Treg) phenotypes. In contrast to the potentially adverse effects of sustained, endogenous production of G-CSF by tumor cells, stringently controlled prophylactic administration of recombinant (r) G-CSF is now a widely practiced strategy in medical oncology to prevent, and in some cases treat, chemotherapy-induced severe neutropenia. Following an overview of the synthesis, structure and function of G-CSF and its receptor, the remainder of this review is focused on: (i) effects of G-CSF on the cells of the adaptive and innate immune systems; (ii) mechanisms by which this cytokine promotes tumor progression and invasion; and (iii) current clinical applications and potential risks of the use of rG-CSF in medical oncology. Full article
(This article belongs to the Section Pharmacology)
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Article
Synthesis and Biological Evaluation of Carvacrol-Based Derivatives as Dual Inhibitors of H. pylori Strains and AGS Cell Proliferation
Pharmaceuticals 2020, 13(11), 405; https://doi.org/10.3390/ph13110405 - 19 Nov 2020
Cited by 5 | Viewed by 1074
Abstract
This study reports on the synthesis, structural assessment, microbiological screening against several strains of H. pylori and antiproliferative activity against human gastric adenocarcinoma (AGS) cells of a large series of carvacrol-based compounds. Structural analyses consisted of elemental analysis, 1H/13C/19 [...] Read more.
This study reports on the synthesis, structural assessment, microbiological screening against several strains of H. pylori and antiproliferative activity against human gastric adenocarcinoma (AGS) cells of a large series of carvacrol-based compounds. Structural analyses consisted of elemental analysis, 1H/13C/19F NMR spectra and crystallographic studies. The structure-activity relationships evidenced that among ether derivatives the substitution with specific electron-withdrawing groups (CF3 and NO2) especially in the para position of the benzyl ring led to an improvement of the antimicrobial activity, whereas electron-donating groups on the benzyl ring and ethereal alkyl chains were not tolerated with respect to the parent compound (MIC/MBC = 64/64 µg/mL). Ester derivatives (coumarin-carvacrol hybrids) displayed a slight enhancement of the inhibitory activity up to MIC values of 8–16 µg/mL. The most interesting compounds exhibiting the lowest MIC/MBC activity against H. pylori (among others, compounds 16 and 39 endowed with MIC/MBC values ranging between 2/2 to 32/32 µg/mL against all the evaluated strains) were also assayed for their ability to reduce AGS cell growth with respect to 5-Fluorouracil. Some derivatives can be regarded as new lead compounds able to reduce H. pylori growth and to counteract the proliferation of AGS cells, both contributing to the occurrence of gastric cancer. Full article
(This article belongs to the Special Issue Small Molecules as Antimicrobials)
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Article
Bornyl Derivatives of p-(Benzyloxy)Phenylpropionic Acid: In Vivo Evaluation of Antidiabetic Activity
Pharmaceuticals 2020, 13(11), 404; https://doi.org/10.3390/ph13110404 - 19 Nov 2020
Viewed by 726
Abstract
A series of bornyl derivatives of p-(benzyloxy)phenylpropionic acid were prepared, and their hypoglycemic activities were examined by an oral glucose tolerance test in mice. The results of this test revealed two compounds, 1 and 3, that can reduce the blood level [...] Read more.
A series of bornyl derivatives of p-(benzyloxy)phenylpropionic acid were prepared, and their hypoglycemic activities were examined by an oral glucose tolerance test in mice. The results of this test revealed two compounds, 1 and 3, that can reduce the blood level of glucose similarly to reference compound vildagliptin. Both compounds were tested in an experiment on mice with metabolic disorders: the C57BL/6Ay strain. Along with hypoglycemic properties, the two compounds showed different abilities to correct lipid metabolism disorders. In silico prediction revealed that the studied substances are most likely bifunctional multitarget hypoglycemic compounds whose mechanism of action is based on a pronounced reduction in insulin resistance and a strong incretin-mimetic effect. The difference in the size of effects of these compounds on biochemical parameters of blood in the experiment on C57BL/6Ay mice was in good agreement with the computational prediction of the priority ranking of biological targets for these compounds. These results indicate that bornyl derivatives of p-(benzyloxy)phenylpropionic acid have a good potential as new agents for diabetes mellitus treatment due to their hypoglycemic and lipid-normalizing properties. Full article
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Communication
Remyelination-Promoting DNA Aptamer Conjugate Myaptavin-3064 Binds to Adult Oligodendrocytes In Vitro
Pharmaceuticals 2020, 13(11), 403; https://doi.org/10.3390/ph13110403 - 19 Nov 2020
Viewed by 676
Abstract
We previously applied Systematic Evolution of Ligands by EXponential enrichment (SELEX) technology to identify myelin-specific DNA aptamers, using crude mouse central nervous system myelin as bait. This selection identified a 40-nucleotide aptamer (LJM-3064). Multiple biotinylated LJM-3064 molecules were conjugated to a streptavidin core [...] Read more.
We previously applied Systematic Evolution of Ligands by EXponential enrichment (SELEX) technology to identify myelin-specific DNA aptamers, using crude mouse central nervous system myelin as bait. This selection identified a 40-nucleotide aptamer (LJM-3064). Multiple biotinylated LJM-3064 molecules were conjugated to a streptavidin core to mimic a multimeric immunoglobulin M (IgM) antibody, generating 3064-BS-streptavidin (Myaptavin-3064). We previously showed that Myaptavin-3064 induces remyelination in the Theiler’s murine encephalomyelitis virus (TMEV) model of chronic spinal cord demyelination. While details of target binding and the mechanism of action remain unclear, we hypothesized that Myaptavin-3064 induces remyelination by binding to oligodendrocytes (OLs). We now report the results of binding assays using the human oligodendroglioma (HOG) cell line, applying both flow cytometry and immunocytochemistry (IC) to assay aptamer conjugate binding to cells. IC assays were applied to compare aptamer conjugate binding to primary embryonic mouse mixed cortical cultures and primary adult rat mixed glial cultures. We show that Myaptavin-3064 binds to HOG cells, with increased binding upon differentiation. In contrast, a negative control aptamer conjugate, 3060-BS, which did not promote central nervous system (CNS) remyelination, does not bind to HOG cells. Myaptavin-3064 did not bind to lung (L2) or kidney (BHK) cell lines. Total internal reflection fluorescence (TIRF) imaging indicates that Myaptavin-3064 binds at the cell membrane of live cells. In addition to HOG cells, Myaptavin-3064 binds to adult rat OLs, but not to embryonic mouse mixed cortical cultures. These data support the hypothesis that Myaptavin-3064 binds to a surface molecule on both rodent and human OLs in a manner that triggers a remyelination signal pathway. Full article
(This article belongs to the Special Issue Potential of the Aptamers to Fill Therapeutic and Diagnostic Gaps)
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Article
Availability of Guanitoxin in Water Samples Containing Sphaerospermopsis torques-reginae Cells Submitted to Dissolution Tests
Pharmaceuticals 2020, 13(11), 402; https://doi.org/10.3390/ph13110402 - 19 Nov 2020
Cited by 1 | Viewed by 851
Abstract
Guanitoxin (GNT) is a potent neurotoxin produced by freshwater cyanobacteria that can cause the deaths of wild and domestic animals. Through reports of animal intoxication by cyanobacteria cells that produce GNT, this study aimed to investigate the bio-accessibility of GNT in simulated solutions [...] Read more.
Guanitoxin (GNT) is a potent neurotoxin produced by freshwater cyanobacteria that can cause the deaths of wild and domestic animals. Through reports of animal intoxication by cyanobacteria cells that produce GNT, this study aimed to investigate the bio-accessibility of GNT in simulated solutions of the gastrointestinal content in order to understand the process of toxicosis promoted by GNT in vivo. Dissolution tests were conducted with a mixture of Sphaerospermopsis torques-reginae (Cyanobacteria; Nostocales) cultures (30%) and gastrointestinal solutions with and without proteolytic enzymes (70%) at a temperature of 37 °C and rotation at 100 rpm for 2 h. The identification of GNT was performed by LC-QqQ-MS/MS through the transitions [M + H]+m/z 253 > 58 and [M + H]+m/z 253 > 159, which showed high concentrations of GNT in simulated gastric fluid solutions (p-value < 0.001) in comparison to simulated solutions of intestinal content. The gastric solution with pepsin promoted the stability of GNT (p-value < 0.05) compared to the simulated solution of gastric fluid at the same pH without the enzyme. However, the results showed that GNT is also available in intestinal fluids for a period of 2 h, and solutions containing the pancreatin enzyme influenced the bio-accessibility of the toxin more compared to the intestinal medium without enzyme (p-value < 0.05). Therefore, the bio-accessibility of the toxin must be considered both in the stomach and in the intestine, and may help in the diagnosis and prediction of exposure and risk in vivo through the oral ingestion of GNT-producing cyanobacteria cells. Full article
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Article
Altered Brain Leptin and Leptin Receptor Expression in the 5XFAD Mouse Model of Alzheimer’s Disease
Pharmaceuticals 2020, 13(11), 401; https://doi.org/10.3390/ph13110401 - 18 Nov 2020
Cited by 1 | Viewed by 712
Abstract
Alzheimer’s disease (AD) is a complex neurodegenerative disorder characterized by the accumulation of amyloid plaques and neurofibrillary tangles. Interestingly, individuals with metabolic syndromes share some pathologies with those diagnosed with AD including neuroinflammation, insulin resistance and cognitive deficits. Leptin, an adipocyte-derived hormone, regulates [...] Read more.
Alzheimer’s disease (AD) is a complex neurodegenerative disorder characterized by the accumulation of amyloid plaques and neurofibrillary tangles. Interestingly, individuals with metabolic syndromes share some pathologies with those diagnosed with AD including neuroinflammation, insulin resistance and cognitive deficits. Leptin, an adipocyte-derived hormone, regulates metabolism, energy expenditure and satiety via its receptor, LepR. To investigate the possible involvement of leptin in AD, we examined the distribution of leptin and LepR in the brains of the 5XFAD mouse model of AD, utilizing immunofluorescent staining in young (10–12-weeks; n = 6) and old (48–52-weeks; n = 6) transgenic (Tg) mice, together with age-matched wild-type (WT) controls for both age groups (young-WT, n = 6; old-WT, n = 6). We also used double immunofluorescent staining to examine the distribution of leptin and leptin receptor expression in astrocytes. In young 5XFAD, young-WT and old-WT mice, we observed neuronal and endothelial expression of leptin and LepR throughout the brain. However, neuronal leptin and LepR expression in the old 5XFAD brain was significantly diminished. Reduced neuronal leptin and LepR expression was accompanied by plaque loading and neuroinflammation in the AD brain. A marked increase in astrocytic leptin and LepR was also observed in old 5XFAD mice compared to younger 5XFAD mice. We postulate that astrocytes may utilize LepR signalling to mediate and drive their metabolically active state when degrading amyloid in the AD brain. Overall, these findings provide evidence of impaired leptin and LepR signalling in the AD brain, supporting clinical and epidemiological studies performed in AD patients. Full article
(This article belongs to the Special Issue Therapeutic Agents for Neurological Disorders)
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Review
Sustainability of Biosimilars in Europe: A Delphi Panel Consensus with Systematic Literature Review
Pharmaceuticals 2020, 13(11), 400; https://doi.org/10.3390/ph13110400 - 17 Nov 2020
Cited by 1 | Viewed by 1015
Abstract
Introduction: Biosimilars have the potential to enhance the sustainability of evolving health care systems. A sustainable biosimilars market requires all stakeholders to balance competition and supply chain security. However, there is significant variation in the policies for pricing, procurement, and use of biosimilars [...] Read more.
Introduction: Biosimilars have the potential to enhance the sustainability of evolving health care systems. A sustainable biosimilars market requires all stakeholders to balance competition and supply chain security. However, there is significant variation in the policies for pricing, procurement, and use of biosimilars in the European Union. A modified Delphi process was conducted to achieve expert consensus on biosimilar market sustainability in Europe. Methods: The priorities of 11 stakeholders were explored in three stages: a brainstorming stage supported by a systematic literature review (SLR) and key materials identified by the participants; development and review of statements derived during brainstorming; and a facilitated roundtable discussion. Results: Participants argued that a sustainable biosimilar market must deliver tangible and transparent benefits to the health care system, while meeting the needs of all stakeholders. Key drivers of biosimilar market sustainability included: (i) competition is more effective than regulation; (ii) there should be incentives to ensure industry investment in biosimilar development and innovation; (iii) procurement processes must avoid monopolies and minimize market disruption; and (iv) principles for procurement should be defined by all stakeholders. However, findings from the SLR were limited, with significant gaps on the impact of different tender models on supply risks, savings, and sustainability. Conclusions: A sustainable biosimilar market means that all stakeholders benefit from appropriate and reliable access to biological therapies. Failure to care for biosimilar market sustainability may impoverish biosimilar development and offerings, eventually leading to increased cost for health care systems and patients, with fewer resources for innovation. Full article
(This article belongs to the Special Issue Biosimilars in Europe)
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Article
Using Carbomer-Based Hydrogels for Control the Release Rate of Diclofenac Sodium: Preparation and In Vitro Evaluation
Pharmaceuticals 2020, 13(11), 399; https://doi.org/10.3390/ph13110399 - 17 Nov 2020
Cited by 7 | Viewed by 806
Abstract
The aim of the current research work was to prepare Car934-g-poly(acrylic acid) hydrogels by the free-radical polymerization technique. Various concentrations of carbopol, acrylic acid and ethylene glycol dimethacrylate were employed for the fabrication of Car934-g-poly(acrylic acid) hydrogels. Fourier-transform infrared spectroscopy (FTIR), Thermogravimetric analysis [...] Read more.
The aim of the current research work was to prepare Car934-g-poly(acrylic acid) hydrogels by the free-radical polymerization technique. Various concentrations of carbopol, acrylic acid and ethylene glycol dimethacrylate were employed for the fabrication of Car934-g-poly(acrylic acid) hydrogels. Fourier-transform infrared spectroscopy (FTIR), Thermogravimetric analysis (TGA), Differential scanning calorimetry (DSC), Scanning electron microscope (SEM) and Powder X-ray diffractometry (PXRD) studies were performed to know the structural arrangement, thermal stability, physical appearance and amorphous network of developed hydrogels. FTIR analysis revealed that carbopol reacted with acrylic acid during the process of polymerization and confirmed the grafting of acrylic acid over the backbone of carbopol. TGA and DSC studies showed that developed hydrogels were thermally stable. Surface morphology was analyzed by SEM, which confirmed a porous network of hydrogels. PXRD analysis indicated that crystallinity of the drug was reduced by the amorphous network of hydrogels. Furthermore, swelling studies for all developed hydrogels were performed at both media, i.e., pH 1.2 and 7.4, and higher swelling was exhibited at pH 7.4. Sol–gel analysis was performed to evaluate the soluble unreacted part of the fabricated hydrogels. Similarly, an in-vitro study was conducted for all hydrogel formulations at both acidic (pH 1.2) and basic (pH 7.4) mediums, and a greater drug release was observed at pH 7.4. Different kinetics such as zero-order, first-order, the Higuchi model and the Korsmeyer–Peppas model were applied to know the mechanism of release order of drugs from the hydrogels. Full article
(This article belongs to the Section Pharmaceutical Technology)
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Article
Fungal Enzyme l-Lysine α-Oxidase Affects the Amino Acid Metabolism in the Brain and Decreases the Polyamine Level
Pharmaceuticals 2020, 13(11), 398; https://doi.org/10.3390/ph13110398 - 17 Nov 2020
Viewed by 657
Abstract
The fungal glycoprotein l-lysine α-oxidase (LO) catalyzes the oxidative deamination of l-lysine (l-lys). LO may be internalized in the intestine and shows antitumor, antibacterial, and antiviral effects in vivo. The main mechanisms of its effects have been shown to [...] Read more.
The fungal glycoprotein l-lysine α-oxidase (LO) catalyzes the oxidative deamination of l-lysine (l-lys). LO may be internalized in the intestine and shows antitumor, antibacterial, and antiviral effects in vivo. The main mechanisms of its effects have been shown to be depletion of the essential amino acid l-lys and action of reactive oxidative species produced by the reaction. Here, we report that LO penetrates into the brain and is retained there for up to 48 h after intravenous injection, which might be explained by specific pharmacokinetics. LO actively intervenes in amino acid metabolism in the brain. The most significant impact of LO was towards amino acids, which are directly exposed to its action (l-lys, l-orn, l-arg). In addition, the enzyme significantly affected the redistribution of amino acids directly associated with the tricarboxylic acid (TCA) cycle (l-asp and l-glu). We discovered that the depletion of l-orn, the precursor of polyamines (PA), led to a significant and long-term decrease in the concentration of polyamines, which are responsible for regulation of many processes including cell proliferation. Thus, LO may be used to reduce levels of l-lys and PA in the brain. Full article
(This article belongs to the Special Issue Amino Acids Metabolism and Cancer Therapy)
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Article
Small-Dose Sunitinib Modulates p53, Bcl-2, STAT3, and ERK1/2 Pathways and Protects against Adenine-Induced Nephrotoxicity
Pharmaceuticals 2020, 13(11), 397; https://doi.org/10.3390/ph13110397 - 17 Nov 2020
Cited by 1 | Viewed by 644
Abstract
The therapeutic use of numerous pharmacological agents may be limited due to their nephrotoxicity and associated kidney injury. The aim of our study is to test the hypothesis that the blockade of tyrosine kinase-linked receptors signaling protects against chemically induced nephrotoxicity. To test [...] Read more.
The therapeutic use of numerous pharmacological agents may be limited due to their nephrotoxicity and associated kidney injury. The aim of our study is to test the hypothesis that the blockade of tyrosine kinase-linked receptors signaling protects against chemically induced nephrotoxicity. To test our hypothesis, we investigated sunitinib as an inhibitor for tyrosine kinase signaling for both vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptors (PDGFR) against adenine-induced nephrotoxicity. Four groups of adult male Swiss albino mice were investigated: normal group, adenine group, sunitinib group, and the adenine+sunitinib group that received concurrent administration for both adenine and sunitinib. Kidney function and oxidative stress biomarkers were analyzed. Tubular injury and histopathological changes were examined. Renal expression of B-cell lymphoma-2 (Bcl-2), the tumor suppressor p53, transforming growth factor beta-1 (TGF-β1), phospho-extracellular signal-regulated kinase 1/2 (p-ERK1/2), and phospho-signal transducer and activator of transcription (phospho-STAT3) were measured. The results obtained showed significant improvement (p < 0.05) in kidney function and antioxidant biomarkers in the adenine+sunitinib group. Kidney fibrosis and tubular injury scores were significantly (p < 0.05) less in the adenine+sunitinib group and that of p53 expression as well. Furthermore, sunitinib decreased (p < 0.5) renal levels of TGF-β1, p-ERK1/2, and phospho-STAT3 while elevating Bcl-2 expression score. In conclusion, sunitinib diminished adenine-induced nephrotoxicity through interfering with profibrogenic pathways, activating anti-apoptotic mechanisms, and possessing potential antioxidant capabilities. Full article
(This article belongs to the Section Pharmacology)
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Editorial
Introduction to “Immunotherapies for Multiple Myeloma”
Pharmaceuticals 2020, 13(11), 396; https://doi.org/10.3390/ph13110396 - 17 Nov 2020
Viewed by 600
Abstract
Multiple myeloma (MM) is the second most common hematological cancer after diffuse large B-cell lymphoma, accounting for about 10% of all blood cancers [...] Full article
Article
Solubility, Solution Thermodynamics, and Preferential Solvation of Amygdalin in Ethanol + Water Solvent Mixtures
Pharmaceuticals 2020, 13(11), 395; https://doi.org/10.3390/ph13110395 - 16 Nov 2020
Cited by 2 | Viewed by 982
Abstract
The equilibrium solubility of amygdalin in [ethanol (1) + water (2)] mixtures at 293.15 K to 328.15 K was reported. The thermodynamic properties (standard enthalpy ΔsolnH°, standard entropy ΔsolnS°, and standard Gibbs energy of solution ΔsolnG°) were [...] Read more.
The equilibrium solubility of amygdalin in [ethanol (1) + water (2)] mixtures at 293.15 K to 328.15 K was reported. The thermodynamic properties (standard enthalpy ΔsolnH°, standard entropy ΔsolnS°, and standard Gibbs energy of solution ΔsolnG°) were computed using the generated solubility data via van’t Hoff and Gibbs equations. The dissolution process of amygdalin is endothermic and the driving mechanism in all mixtures is entropy. Maximal solubility was achieved in 0.4 mole fraction of ethanol at 328.15 K and the minimal one in neat ethanol at 293.15 K. Van’t Hoff, Jouyban–Acree–van’t Hoff, and Buchowski–Ksiazczak models were used to simulate the obtained solubility data. The calculated solubilities deviate reasonably from experimental data. Preferential solvation parameters of amygdalin in mixture solvents were analyzed using the inverse Kirkwood–Buff integrals (IKBI) method. Amygdalin is preferentially solvated by water in ethanol-rich mixtures, whereas in water-rich mixtures, there is no clear evidence that determines which of water or ethanol solvents would be most likely to solvate the molecule. Full article
(This article belongs to the Section Pharmaceutical Technology)
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Review
Treatment of Alzheimer’s Disease and Blood–Brain Barrier Drug Delivery
Pharmaceuticals 2020, 13(11), 394; https://doi.org/10.3390/ph13110394 - 16 Nov 2020
Cited by 9 | Viewed by 1469
Abstract
Despite the enormity of the societal and health burdens caused by Alzheimer’s disease (AD), there have been no FDA approvals for new therapeutics for AD since 2003. This profound lack of progress in treatment of AD is due to dual problems, both related [...] Read more.
Despite the enormity of the societal and health burdens caused by Alzheimer’s disease (AD), there have been no FDA approvals for new therapeutics for AD since 2003. This profound lack of progress in treatment of AD is due to dual problems, both related to the blood–brain barrier (BBB). First, 98% of small molecule drugs do not cross the BBB, and ~100% of biologic drugs do not cross the BBB, so BBB drug delivery technology is needed in AD drug development. Second, the pharmaceutical industry has not developed BBB drug delivery technology, which would enable industry to invent new therapeutics for AD that actually penetrate into brain parenchyma from blood. In 2020, less than 1% of all AD drug development projects use a BBB drug delivery technology. The pathogenesis of AD involves chronic neuro-inflammation, the progressive deposition of insoluble amyloid-beta or tau aggregates, and neural degeneration. New drugs that both attack these multiple sites in AD, and that have been coupled with BBB drug delivery technology, can lead to new and effective treatments of this serious disorder. Full article
(This article belongs to the Special Issue Treatment of Alzheimer Disease)
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Article
Potent Quinoline-Containing Combretastatin A-4 Analogues: Design, Synthesis, Antiproliferative, and Anti-Tubulin Activity
Pharmaceuticals 2020, 13(11), 393; https://doi.org/10.3390/ph13110393 - 15 Nov 2020
Cited by 1 | Viewed by 890
Abstract
A novel series of quinoline derivatives of combretastatin A-4 incorporating rigid hydrazone and a cyclic oxadiazole linkers were synthesized and have demonstrated potent tubulin polymerization inhibitory properties. Many of these novel derivatives have shown significant antiproliferative activities in the submicromolar range. The most [...] Read more.
A novel series of quinoline derivatives of combretastatin A-4 incorporating rigid hydrazone and a cyclic oxadiazole linkers were synthesized and have demonstrated potent tubulin polymerization inhibitory properties. Many of these novel derivatives have shown significant antiproliferative activities in the submicromolar range. The most potent compound, 19h, demonstrated superior IC50 values ranging from 0.02 to 0.04 µM against four cancer cell lines while maintaining low cytotoxicity in MCF-10A non-cancer cells, thereby suggesting 19h’s selectivity towards proliferating cancer cells. In addition to tubulin polymerization inhibition, 19h caused cell cycle arrest in MCF-7 cells at the G2/M phase and induced apoptosis. Collectively, these findings indicate that 19h holds potential for further investigation as a potent chemotherapeutic agent targeting tubulin. Full article
(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2020)
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Review
Assembly of Peptidoglycan Fragments—A Synthetic Challenge
Pharmaceuticals 2020, 13(11), 392; https://doi.org/10.3390/ph13110392 - 15 Nov 2020
Viewed by 751
Abstract
Peptidoglycan (PGN) is a major constituent of most bacterial cell walls that is recognized as a primary target of the innate immune system. The availability of pure PGN molecules has become key to different biological studies. This review aims to (1) provide an [...] Read more.
Peptidoglycan (PGN) is a major constituent of most bacterial cell walls that is recognized as a primary target of the innate immune system. The availability of pure PGN molecules has become key to different biological studies. This review aims to (1) provide an overview of PGN biosynthesis, focusing on the main biosynthetic intermediates; (2) focus on the challenges for chemical synthesis posed by the unique and complex structure of PGN; and (3) cover the synthetic routes of PGN fragments developed to date. The key difficulties in the synthesis of PGN molecules mainly involve stereoselective glycosylation involving NAG derivatives. The complex synthesis of the carbohydrate backbone commonly involves multistep sequences of chemical reactions to install the lactyl moiety at the O-3 position of NAG derivatives and to control enantioselective glycosylation. Recent advances are presented and synthetic routes are described according to the main strategy used: (i) based on the availability of starting materials such as glucosamine derivatives; (ii) based on a particular orthogonal synthesis; and (iii) based on the use of other natural biopolymers as raw materials. Full article
(This article belongs to the Special Issue Glycomimetics and Glycoconjugates in Drug Discovery)
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Article
Novel 1-Amidino-4-Phenylpiperazines as Potent Agonists at Human TAAR1 Receptor: Rational Design, Synthesis, Biological Evaluation and Molecular Docking Studies
Pharmaceuticals 2020, 13(11), 391; https://doi.org/10.3390/ph13110391 - 14 Nov 2020
Cited by 2 | Viewed by 892
Abstract
Targeting trace amine-associated receptor 1 (TAAR1) receptor continues to offer an intriguing opportunity to develop innovative therapies in different pharmacological settings. Pursuing our endeavors in the search for effective and safe human TAAR1 (hTAAR1) ligands, we synthesized a new series of [...] Read more.
Targeting trace amine-associated receptor 1 (TAAR1) receptor continues to offer an intriguing opportunity to develop innovative therapies in different pharmacological settings. Pursuing our endeavors in the search for effective and safe human TAAR1 (hTAAR1) ligands, we synthesized a new series of 1-amidino-4-phenylpiperazine derivatives (116) based on the application of a combined pharmacophore model/scaffold simplification strategy for an in-house series of biguanide-based TAAR1 agonists. Most of the novel compounds proved to be more effective than their prototypes, showing nanomolar EC50 values in functional activity at hTAAR1 and low general cytotoxicity (CC50 > 80 µM) when tested on the Vero-76 cell line. In this new series, the main determinant for TAAR1 agonism ability appears to result from the appropriate combination between the steric size and position of the substituents on the phenyl ring rather than from their different electronic nature, since both electron-withdrawing and electron donor groups are permitted. In particular, the ortho-substitution seems to impose a more appropriate spatial geometry to the molecule that entails an enhanced TAAR1 potency profile, as experienced, in the following order, by compounds 15 (2,3-diCl, EC50 = 20 nM), 2 (2-CH3, EC50 = 30 nM), 6 (2-OCH3, EC50 = 93 nM) and 3 (2-Cl, EC50 = 160 nM). Apart from the interest in them as valuable leads for the development of promising hTAAR1 agonists, these simple small molecules have further allowed us to identify the minimal structural requirements for producing an efficient hTAAR1 targeting ability. Full article
(This article belongs to the Section Medicinal Chemistry)
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Article
Synthesis of New 1, 3, 4-Oxadiazole-Incorporated 1, 2, 3-Triazole Moieties as Potential Anticancer Agents Targeting Thymidylate Synthase and Their Docking Studies
Pharmaceuticals 2020, 13(11), 390; https://doi.org/10.3390/ph13110390 - 14 Nov 2020
Cited by 8 | Viewed by 893
Abstract
Thymidylate synthase (TS) has emerged as a hot spot in cancer treatment, as it is directly involved in DNA synthesis. In the present article, nine hybrids containing 1,2,3-triazole and 1,3,4-oxadiazole moieties (614) were synthesized and evaluated for anticancer and [...] Read more.
Thymidylate synthase (TS) has emerged as a hot spot in cancer treatment, as it is directly involved in DNA synthesis. In the present article, nine hybrids containing 1,2,3-triazole and 1,3,4-oxadiazole moieties (614) were synthesized and evaluated for anticancer and in vitro thymidylate synthase activities. According to in silico pharmacokinetic studies, the synthesized hybrids exhibited good drug likeness properties and bioavailability. The cytotoxicity results indicated that compounds 12 and 13 exhibited remarkable inhibition on the tested Michigan Cancer Foundation (MCF-7) and Human colorectal Carcinoma (HCT-116) cell lines. Compound 12 showed four-fold inhibition to a standard drug, 5-fluoruracil, and comparable inhibition to tamoxifen, whereas compound 13 exerted five-fold activity of tamoxifen and 24-fold activity of 5-fluorouracil for MCF-7 cells. Compounds 12 and 13 inhibited thymidylate synthase enzyme, with an half maximal inhibitory concentration, IC50 of 2.52 µM and 4.38 µM, while a standard drug, pemetrexed, showed IC50 = 6.75 µM. The molecular docking data of compounds 12 and 13 were found to be in support of biological activities data. In conclusion, hybrids (12 and 13) may inhibit thymidylate synthase enzyme, which could play a significant role as a chemotherapeutic agent. Full article
(This article belongs to the Special Issue Anticancer Drugs 2021)
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Review
The Landscape of Novel Therapeutics and Challenges in Glioblastoma Multiforme: Contemporary State and Future Directions
Pharmaceuticals 2020, 13(11), 389; https://doi.org/10.3390/ph13110389 - 14 Nov 2020
Cited by 5 | Viewed by 1852
Abstract
Background: Glioblastoma multiforme is a malignant intracranial neoplasm that constitutes a therapeutic challenge because of the associated high morbidity and mortality given the lack of effective approved medication and aggressive nature of the tumor. However, there has been extensive research recently to address [...] Read more.
Background: Glioblastoma multiforme is a malignant intracranial neoplasm that constitutes a therapeutic challenge because of the associated high morbidity and mortality given the lack of effective approved medication and aggressive nature of the tumor. However, there has been extensive research recently to address the reasons implicated in the resistant nature of the tumor to pharmaceutical compounds, which have resulted in several clinical trials investigating promising treatment approaches. Methods: We reviewed literature published since 2010 from PUBMED and several annual meeting abstracts through 15 September 2020. Selected articles included those relevant to topics of glioblastoma tumor biology, original basic research, clinical trials, seminal reviews, and meta-analyses. We provide a discussion based on the collected evidence regarding the challenging factors encountered during treatment, and we highlighted the relevant trials of novel therapies including immunotherapy and targeted medication. Results: Selected literature revealed four main factors implicated in the low efficacy encountered with investigational treatments which included: (1) blood-brain barrier; (2) immunosuppressive microenvironment; (3) genetic heterogeneity; (4) external factors related to previous systemic treatment that can modulate tumor microenvironment. Investigational therapies discussed in this review were classified as immunotherapy and targeted therapy. Immunotherapy included: (1) immune checkpoint inhibitors; (2) adoptive cell transfer therapy; (3) therapeutic vaccines; (4) oncolytic virus therapy. Targeted therapy included tyrosine kinase inhibitors and other receptor inhibitors. Finally, we provide our perspective on future directions in treatment of glioblastoma. Conclusion: Despite the limited success in development of effective therapeutics in glioblastoma, many treatment approaches hold potential promise including immunotherapy and novel combinational drugs. Addressing the molecular landscape and resistant immunosuppressive nature of glioblastoma are imperative in further development of effective treatments. Full article
(This article belongs to the Special Issue Malignant Glioma: Novel Therapeutic Strategies)
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Review
Allosteric Modulators of G Protein-Coupled Dopamine and Serotonin Receptors: A New Class of Atypical Antipsychotics
Pharmaceuticals 2020, 13(11), 388; https://doi.org/10.3390/ph13110388 - 14 Nov 2020
Cited by 2 | Viewed by 799
Abstract
Schizophrenia was first described by Emil Krapelin in the 19th century as one of the major mental illnesses causing disability worldwide. Since the introduction of chlorpromazine in 1952, strategies aimed at modifying the activity of dopamine receptors have played a major role for [...] Read more.
Schizophrenia was first described by Emil Krapelin in the 19th century as one of the major mental illnesses causing disability worldwide. Since the introduction of chlorpromazine in 1952, strategies aimed at modifying the activity of dopamine receptors have played a major role for the treatment of schizophrenia. The introduction of atypical antipsychotics with clozapine broadened the range of potential targets for the treatment of this psychiatric disease, as they also modify the activity of the serotoninergic receptors. Interestingly, all marketed drugs for schizophrenia bind to the orthosteric binding pocket of the receptor as competitive antagonists or partial agonists. In recent years, a strong effort to develop allosteric modulators as potential therapeutic agents for schizophrenia was made, mainly for the several advantages in their use. In particular, the allosteric binding sites are topographically distinct from the orthosteric pockets, and thus drugs targeting these sites have a higher degree of receptor subunit specificity. Moreover, “pure” allosteric modulators maintain the temporal and spatial fidelity of native orthosteric ligand. Furthermore, allosteric modulators have a “ceiling effect”, and their modulatory effect is saturated above certain concentrations. In this review, we summarize the progresses made in the identification of allosteric drugs for dopamine and serotonin receptors, which could lead to a new generation of atypical antipsychotics with a better profile, especially in terms of reduced side effects. Full article
(This article belongs to the Special Issue Molecular and Cellular Targets of Old and New Atypical Antipsychotics)
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