Pharmaceuticals

15 pages, 831 KiB

Open AccessReview

by Nicole Lounsbury

Pharmaceuticals 2020, 13(2), 33; https://doi.org/10.3390/ph13020033 - 21 Feb 2020

Cited by 28 | Viewed by 6462

CXC chemokine receptor 7 (CXCR7) is a G-protein-coupled receptor that signals through the β-arrestin pathway. Its ligands include interferon-inducible T cell α chemoattractant (CXCL11) and stromal cell-derived factor-1 (CXCL12). It interacts with CXCR4, and the two are associated with various cancers, as well [...] Read more.

CXC chemokine receptor 7 (CXCR7) is a G-protein-coupled receptor that signals through the β-arrestin pathway. Its ligands include interferon-inducible T cell α chemoattractant (CXCL11) and stromal cell-derived factor-1 (CXCL12). It interacts with CXCR4, and the two are associated with various cancers, as well as other disease states such as coronary artery disease, stroke, inflammation and human immunodeficiency virus (HIV). Antibodies and small interfering RNA (siRNA) have shown the utility of antagonists of CXCR7 in these disease states. Although some small molecules were initially reported as antagonists due to their displayed activity, many function as agonists while still producing the desired pharmacologic effects. A potential reason for this contradiction is that effects may be due to elevated extracellular CXCL12 levels. Full article

(This article belongs to the Section Medicinal Chemistry)

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15 pages, 1043 KiB

Open AccessArticle

Grаdiеnt HPLC Mеthоd fоr Simultаnеоus Dеtеrminаtiоn оf Еight Sаrtаn аnd Stаtin Drugs in Thеir Purе аnd Dоsаgе Fоrms

by Mоhsеn M. Zаrеh, Mоnir Z. Sааd, Wаfаа S. Hаssаn, Mоstаfа Е. Еlhеnnаwу, Moustafa K. Soltan and Mаhmоud M. Sеbаiу

Pharmaceuticals 2020, 13(2), 32; https://doi.org/10.3390/ph13020032 - 20 Feb 2020

Cited by 9 | Viewed by 4411

Abstract

А grаdiеnt HPLC mеthоd was dеvеlоpеd аnd vаlidаtеd fоr rаpid simultаnеоus sеpаrаtiоn аnd dеtеrminаtiоn оf the following eight drugs оf sаrtаn аnd stаtin clаssеs in thеir purе аnd dоsаgе fоrms within 15 minutes: irbеsаrtаn (IRB), lоsаrtаn (LОS), vаlsаrtаn (VАL), оlmеsаrtаn (ОLM), rоsuvаstаtin (RОS), [...] Read more.

А grаdiеnt HPLC mеthоd was dеvеlоpеd аnd vаlidаtеd fоr rаpid simultаnеоus sеpаrаtiоn аnd dеtеrminаtiоn оf the following eight drugs оf sаrtаn аnd stаtin clаssеs in thеir purе аnd dоsаgе fоrms within 15 minutes: irbеsаrtаn (IRB), lоsаrtаn (LОS), vаlsаrtаn (VАL), оlmеsаrtаn (ОLM), rоsuvаstаtin (RОS), аtоrvаstаtin (АTR), lоvаstаtin (LОV), аnd simvаstаtin (SIM). Sеpаrаtiоn wаs cаrriеd оut оn а Kinеtеx C₁₈ 100А cоlumn (2.60 m, 4.60 mm × 100 mm) using а grаdiаnt binаrу mоbilе phаsе оf 0.05M pоtаssium dihуdrоgеn phоsphаtе buffеr (pH 3.50 аdjustеd bу оrthо-phоsphоric аcid) аnd аcеtоnitrilе аt rооm tеmpеrаturе. Thе flоw rаtе wаs 1.00 mL/min аnd mаximum аbsоrptiоn wаs mеаsurеd using a DАD dеtеctоr аt 280 nm. Thе rеtеntiоn timеs оf IRB, LОS, RОS, VАL, АTR, LОV, ОLM, аnd SIM wеrе rеcоrdеd tо bе 4.72, 5.32, 6.06, 7.19, 7.96, 9.30, 11.91, аnd 14.66 minutеs, rеspеctivеlу. Limits оf dеtеctiоn wеrе rеpоrtеd tо bе 2.01, 1.32, 1.10, 0.76, 0.21, 1.50, 0.38, аnd 0.55 mM fоr thе sаmе sеquеncе оf drugs, rеspеctivеlу, shоwing а high dеgrее оf mеthоd sеnsitivitу. Thе mеthоd wаs thеn vаlidаtеd аccоrding tо the intеrnаtiоnаl cоnfеrеncе оf hаrmоnizаtiоn (ICH) guidеlinеs fоr thе dеtеrminаtiоn оf thе drugs in thеir dоsаgе fоrms with highlу prеcisе rеcоvеriеs. Аlsо, a stаtisticаl cоmpаrisоn with rеfеrеncе mеthоds wаs pеrfоrmеd shоwing nо significаnt diffеrеncеs bеtwееn thе prоpоsеd mеthоd аnd rеpоrtеd оnеs in tеrms оf prеcisiоn аnd аccurаcу. Full article

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18 pages, 703 KiB

Open AccessFeature PaperReview

Cell Secretome: Basic Insights and Therapeutic Opportunities for CNS Disorders

by Andreia G. Pinho, Jorge R. Cibrão, Nuno A. Silva, Susana Monteiro and António J. Salgado

Pharmaceuticals 2020, 13(2), 31; https://doi.org/10.3390/ph13020031 - 20 Feb 2020

Cited by 45 | Viewed by 5945

Abstract

Transplantation of stem cells, in particular mesenchymal stem cells (MSCs), stands as a promising therapy for trauma, stroke or neurodegenerative conditions such as spinal cord or traumatic brain injuries (SCI or TBI), ischemic stroke (IS), or Parkinson’s disease (PD). Over the last few [...] Read more.

Transplantation of stem cells, in particular mesenchymal stem cells (MSCs), stands as a promising therapy for trauma, stroke or neurodegenerative conditions such as spinal cord or traumatic brain injuries (SCI or TBI), ischemic stroke (IS), or Parkinson’s disease (PD). Over the last few years, cell transplantation-based approaches have started to focus on the use of cell byproducts, with a strong emphasis on cell secretome. Having this in mind, the present review discusses the current state of the art of secretome-based therapy applications in different central nervous system (CNS) pathologies. For this purpose, the following topics are discussed: (1) What are the main cell secretome sources, composition, and associated collection techniques; (2) Possible differences of the therapeutic potential of the protein and vesicular fraction of the secretome; and (3) Impact of the cell secretome on CNS-related problems such as SCI, TBI, IS, and PD. With this, we aim to clarify some of the main questions that currently exist in the field of secretome-based therapies and consequently gain new knowledge that may help in the clinical application of secretome in CNS disorders. Full article

(This article belongs to the Special Issue Therapeutics Agents for Neural Repair)

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15 pages, 2140 KiB

Open AccessArticle

Binding Constants of Substituted Benzoic Acids with Bovine Serum Albumin

by Diliara Khaibrakhmanova, Alena Nikiforova and Igor Sedov

Pharmaceuticals 2020, 13(2), 30; https://doi.org/10.3390/ph13020030 - 20 Feb 2020

Cited by 10 | Viewed by 3191

Abstract

Experimental data on the affinity of various substances to albumin are essential for the development of empirical models to predict plasma binding of drug candidates. Binding of 24 substituted benzoic acid anions to bovine serum albumin was studied using spectrofluorimetric titration. The equilibrium [...] Read more.

Experimental data on the affinity of various substances to albumin are essential for the development of empirical models to predict plasma binding of drug candidates. Binding of 24 substituted benzoic acid anions to bovine serum albumin was studied using spectrofluorimetric titration. The equilibrium constants of binding at 298 K were determined according to 1:1 complex formation model. The relationships between the ligand structure and albumin affinity are analyzed. The binding constant values for m- and p-monosubstituted acids show a good correlation with the Hammett constants of substituents. Two- and three-parameter quantitative structure–activity relationship (QSAR) models with theoretical molecular descriptors are able to satisfactorily describe the obtained values for the whole set of acids. It is shown that the electron-density distribution in the aromatic ring exerts crucial influence on the albumin affinity. Full article

(This article belongs to the Section Medicinal Chemistry)

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12 pages, 3568 KiB

Open AccessFeature PaperArticle

Metabolic Stability of New Mito-Protective Short-Chain Naphthoquinones

by Zikai Feng, Jason A. Smith, Nuri Gueven and Joselito P. Quirino

Pharmaceuticals 2020, 13(2), 29; https://doi.org/10.3390/ph13020029 - 12 Feb 2020

Cited by 5 | Viewed by 2509

Abstract

Short-chain quinones (SCQs) have been identified as potential drug candidates against mitochondrial dysfunction, which is largely dependent on their reversible redox characteristics of the active quinone core. We recently synthesized a SCQ library of > 148 naphthoquinone derivatives and identified 16 compounds with [...] Read more.

Short-chain quinones (SCQs) have been identified as potential drug candidates against mitochondrial dysfunction, which is largely dependent on their reversible redox characteristics of the active quinone core. We recently synthesized a SCQ library of > 148 naphthoquinone derivatives and identified 16 compounds with enhanced cytoprotection compared to the clinically used benzoquinone idebenone. One of the major drawbacks of idebenone is its high metabolic conversion in the liver, which significantly restricts its therapeutic activity. Therefore, this study assessed the metabolic stability of the 16 identified naphthoquinone derivatives 1–16 using hepatocarcinoma cells in combination with an optimized reverse-phase liquid chromatography (RP-LC) method. Most of the derivatives showed significantly better stability than idebenone over 6 hours (p < 0.001). By extending the side-chain of SCQs, increased stability for some compounds was observed. Metabolic conversion from the derivative 3 to 5 and reduced idebenone metabolism in the presence of 5 were also observed. These results highlight the therapeutic potential of naphthoquinone-based SCQs and provide essential insights for future drug design, prodrug therapy and polytherapy, respectively. Full article

(This article belongs to the Section Pharmacology)

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11 pages, 254 KiB

Open AccessReview

Therapeutic Plasmapheresis with Albumin Replacement in Alzheimer’s Disease and Chronic Progressive Multiple Sclerosis: A Review

by Rut Navarro-Martínez and Omar Cauli

Pharmaceuticals 2020, 13(2), 28; https://doi.org/10.3390/ph13020028 - 12 Feb 2020

Cited by 7 | Viewed by 3221

Abstract

Background: Reducing the burden of beta-amyloid accumulation and toxic autoimmunity-related proteins, one of the recognized pathophysiological markers of chronic and common neurological disorders such as Alzheimer’s disease (AD) and multiple sclerosis (MS), may be a valid alternative therapy to reduce their accumulation in [...] Read more.

Background: Reducing the burden of beta-amyloid accumulation and toxic autoimmunity-related proteins, one of the recognized pathophysiological markers of chronic and common neurological disorders such as Alzheimer’s disease (AD) and multiple sclerosis (MS), may be a valid alternative therapy to reduce their accumulation in the brain and thus reduce the progression of these disorders. The objective of this review was to evaluate the efficacy of plasmapheresis (PP) in AD and chronic progressive MS patients (in terms of improving clinical symptoms) and to analyze its safety and protocols. Methods: Articles related to this topic and published without time limitations in the Medline, and Cochrane databases were reviewed. Results: In AD patients, PP reduced amyloid beta (Aβ) levels in the brain, accompanied by a tendency towards cognitive stabilization, and improved language and verbal fluency. In regards to structural and functional brain changes, PP reduced brain volume and favored the stabilization, or absence, of the progression of perfusion. In chronic progressive form of MS patients, PP improved neurological deficits in 20–70% of patients with a chronic progressive form of MS, and restored interferon (IFN) responsiveness, which was not accompanied by any image change in brain plaques. Conclusions: Therapeutic plasmapheresis with albumin replacement is a promising strategy for reducing Aβ mediated toxicity and slowing the progression of the disorder. Some patients with chronic progressive forms of MS show improvement in neurological deficits. The features of AD and MS patients who benefit most from this approach need further research. Full article

(This article belongs to the Special Issue Therapeutics Agents for Neural Repair)

9 pages, 3007 KiB

Open AccessTechnical Note

A Fast and Simple Method for the Determination of TBA in ¹⁸F-Labeled Radiopharmaceuticals

by Nils Erik Halvorsen and Ole Heine Kvernenes

Pharmaceuticals 2020, 13(2), 27; https://doi.org/10.3390/ph13020027 - 11 Feb 2020

Cited by 4 | Viewed by 2807

Abstract

A simple color spot test for determining the presence of residual tetrabutylammonium (TBA) in various ¹⁸F-radiopharmaceuticals is described. The test can be performed in less than five minutes. Iodoplatinate-saturated TLC plates are initially spotted with the ¹⁸F-radiopharmaceutical to be tested and [...] Read more.

A simple color spot test for determining the presence of residual tetrabutylammonium (TBA) in various ¹⁸F-radiopharmaceuticals is described. The test can be performed in less than five minutes. Iodoplatinate-saturated TLC plates are initially spotted with the ¹⁸F-radiopharmaceutical to be tested and TBA, then with deionized water or hydrogen peroxide (H₂O₂) solution, depending on if an antioxidant stabilizer is part of the pharmaceutical matrix. A distinct brown spot is visible at TBA concentrations of 50 µg/mL and up. Full article

(This article belongs to the Section Radiopharmaceutical Sciences)

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14 pages, 2831 KiB

Open AccessArticle

Cyclin-Dependent Kinase and Antioxidant Gene Expression in Cancers with Poor Therapeutic Response

by George S. Scaria, Betsy T. Kren and Mark A. Klein

Pharmaceuticals 2020, 13(2), 26; https://doi.org/10.3390/ph13020026 - 05 Feb 2020

Cited by 1 | Viewed by 2581

Abstract

Pancreatic cancer, hepatocellular carcinoma (HCC), and mesothelioma are treatment-refractory cancers, and patients afflicted with these cancers generally have a very poor prognosis. The genomics of these tumors were analyzed as part of The Cancer Genome Atlas (TCGA) project. However, these analyses are an [...] Read more.

Pancreatic cancer, hepatocellular carcinoma (HCC), and mesothelioma are treatment-refractory cancers, and patients afflicted with these cancers generally have a very poor prognosis. The genomics of these tumors were analyzed as part of The Cancer Genome Atlas (TCGA) project. However, these analyses are an overview and may miss pathway interactions that could be exploited for therapeutic targeting. In this study, the TCGA Pan-Cancer datasets were queried via cBioPortal for correlations among mRNA expression of key genes in the cell cycle and mitochondrial (mt) antioxidant defense pathways. Here we describe these correlations. The results support further evaluation to develop combination treatment strategies that target these two critical pathways in pancreatic cancer, hepatocellular carcinoma, and mesothelioma. Full article

(This article belongs to the Special Issue Protein Kinases and Cancer)

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20 pages, 1722 KiB

Open AccessArticle

Synthesis and Bioactivity of Phthalimide Analogs as Potential Drugs to Treat Schistosomiasis, a Neglected Disease of Poverty

by Snigdha Singh, Nelly El-Sakkary, Danielle E. Skinner, Prem Prakash Sharma, Sabine Ottilie, Yevgeniya Antonova-Koch, Prashant Kumar, Elizabeth Winzeler, Poonam, Conor R. Caffrey and Brijesh Rathi

Pharmaceuticals 2020, 13(2), 25; https://doi.org/10.3390/ph13020025 - 03 Feb 2020

Cited by 9 | Viewed by 3385

Abstract

The neglected tropical disease, schistosomiasis, is caused by trematode blood flukes of the Schistosoma genus and infects approximately 200 million people worldwide. With just one partially effective drug available for disease treatment, new drugs are urgently needed. Herein, a series of 47 phthalimide [...] Read more.

The neglected tropical disease, schistosomiasis, is caused by trematode blood flukes of the Schistosoma genus and infects approximately 200 million people worldwide. With just one partially effective drug available for disease treatment, new drugs are urgently needed. Herein, a series of 47 phthalimide (Pht) analogues possessing high-value bioactive scaffolds (i.e., benzimidazole and 1,2,3,-triazoles) was synthesized by click-chemistry. Compounds were evaluated for anti-schistosomal activity in culture against somules (post-infective larvae) and adults of Schistosoma mansoni, their predicted ADME (absorption, distribution, metabolism, and excretion) properties, and toxicity vs. HepG2 cells. The majority showed favorable parameters for surface area, lipophilicity, bioavailability and Lipinski score. Thirteen compounds were active at 10 µM against both somules and adults (6d, 6f, 6i–6l, 6n–6p, 6s, 6r’, 6t’ and 6w). Against somules, the majority caused degeneracy and/or death after 72 h; whereas against adult parasites, five compounds (6l, 6d, 6f, 6r’ and 6s) elicited degeneracy, tegumental (surface) damage and/or death. Strongest potency against both developmental stages was recorded for compounds possessing n-butyl or isobutyl as a linker, and a pentafluorophenyl group on triazole. Apart from five compounds for which anti-parasite activity tracked with toxicity to HepG2 cells, there was apparently no toxicity to HepG2 cells (EC₅₀ values ≥50 µM). The data overall suggest that phthaloyl-triazole compounds are favorable synthons for additional studies as anti-schistosomals. Full article

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20 pages, 4396 KiB

Open AccessArticle

Hormetic-Like Effects of L-Homocysteine on Synaptic Structure, Function, and Aβ Aggregation

by Carla Montecinos-Oliva, Macarena S. Arrázola, Claudia Jara, Cheril Tapia-Rojas and Nibaldo C. Inestrosa

Pharmaceuticals 2020, 13(2), 24; https://doi.org/10.3390/ph13020024 - 02 Feb 2020

Cited by 11 | Viewed by 3117

Abstract

Alzheimer’s Disease (AD) is the primary cause of dementia among the elderly population. Elevated plasma levels of homocysteine (HCy), an amino acid derived from methionine metabolism, are considered a risk factor and biomarker of AD and other types of dementia. An increase in [...] Read more.

Alzheimer’s Disease (AD) is the primary cause of dementia among the elderly population. Elevated plasma levels of homocysteine (HCy), an amino acid derived from methionine metabolism, are considered a risk factor and biomarker of AD and other types of dementia. An increase in HCy is mostly a consequence of high methionine and/or low vitamin B intake in the diet. Here, we studied the effects of physiological and pathophysiological HCy concentrations on oxidative stress, synaptic protein levels, and synaptic activity in mice hippocampal slices. We also studied the in vitro effects of HCy on the aggregation kinetics of Aβ₄₀. We found that physiological cerebrospinal concentrations of HCy (0.5 µM) induce an increase in synaptic proteins, whereas higher doses of HCy (30–100 µM) decrease their levels, thereby increasing oxidative stress and causing excitatory transmission hyperactivity, which are all considered to be neurotoxic effects. We also observed that normal cerebrospinal concentrations of HCy slow the aggregation kinetic of Aβ₄₀, whereas high concentrations accelerate its aggregation. Finally, we studied the effects of HCy and HCy + Aβ₄₂ over long-term potentiation. Altogether, by studying an ample range of effects under different HCy concentrations, we report, for the first time, that HCy can exert beneficial or toxic effects over neurons, evidencing a hormetic-like effect. Therefore, we further encourage the use of HCy as a biomarker and modifiable risk factor with therapeutic use against AD and other types of dementia. Full article

(This article belongs to the Special Issue Therapeutics Agents for Neural Repair)

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35 pages, 6666 KiB

Open AccessReview

Ultrasound for Drug Synthesis: A Green Approach

by Micheline Draye, Gregory Chatel and Romain Duwald

Pharmaceuticals 2020, 13(2), 23; https://doi.org/10.3390/ph13020023 - 31 Jan 2020

Cited by 47 | Viewed by 5870

Abstract

This last century, the development of new medicinal molecules represents a real breakthrough in terms of humans and animal life expectancy and quality of life. However, this success is tainted by negative environmental consequences. Indeed, the synthesis of drug candidates requires the use [...] Read more.

This last century, the development of new medicinal molecules represents a real breakthrough in terms of humans and animal life expectancy and quality of life. However, this success is tainted by negative environmental consequences. Indeed, the synthesis of drug candidates requires the use of many chemicals, solvents, and processes that are very hazardous, toxic, energy consuming, expensive, and generates a large amount of waste. Many large pharmaceutical companies have thus moved to using green chemistry practices for drug discovery, development, and manufacturing. One of them is the use of energy-efficient activation techniques, such as ultrasound. This review summarizes the latest most representative works published on the use of ultrasound for sustainable bioactive molecules synthesis. Full article

(This article belongs to the Special Issue New Tools for Medicinal Chemists)

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38 pages, 2090 KiB

Open AccessReview

Radiolabelled Peptides for Positron Emission Tomography and Endoradiotherapy in Oncology

by Christine Rangger and Roland Haubner

Pharmaceuticals 2020, 13(2), 22; https://doi.org/10.3390/ph13020022 - 30 Jan 2020

Cited by 27 | Viewed by 5440

Abstract

This review deals with the development of peptide-based radiopharmaceuticals for the use with positron emission tomography and peptide receptor radiotherapy. It discusses the pros and cons of this class of radiopharmaceuticals as well as the different labelling strategies, and summarises approaches to optimise [...] Read more.

This review deals with the development of peptide-based radiopharmaceuticals for the use with positron emission tomography and peptide receptor radiotherapy. It discusses the pros and cons of this class of radiopharmaceuticals as well as the different labelling strategies, and summarises approaches to optimise metabolic stability. Additionally, it presents different target structures and addresses corresponding tracers, which are already used in clinical routine or are being investigated in clinical trials. Full article

(This article belongs to the Special Issue The Future Direction of Radiopharmaceutical Development for Cancer Theranostics)

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14 pages, 1323 KiB

Open AccessArticle

Development and Validation of Liquid Chromatography-Tandem Mass Spectrometry Method for Simple Analysis of Sumatriptan and its Application in Bioequivalence Study

by Wisut Wichitnithad, Siriwan Nantaphol, Petploy Vicheantawatchai, Thanyaporn Kiatkumjorn, Wachirasak Wangkangwan and Pornchai Rojsitthisak

Pharmaceuticals 2020, 13(2), 21; https://doi.org/10.3390/ph13020021 - 24 Jan 2020

Cited by 10 | Viewed by 3529

Abstract

This work demonstrated a sensitive, selective, and simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantitation of sumatriptan in human plasma samples. Terazosin was used as an internal standard to minimize the variability during sample processing and detection. Sample cleanup prior to chromatographic [...] Read more.

This work demonstrated a sensitive, selective, and simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantitation of sumatriptan in human plasma samples. Terazosin was used as an internal standard to minimize the variability during sample processing and detection. Sample cleanup prior to chromatographic analysis was accomplished by liquid-liquid extraction (LLE) with tert-butyl methyl ether (t-BME). The separation was performed on a reversed-phase Symmetry^® C18 column (150 × 4.6 mm i.d., 5 µm) under a gradient mode, using a 0.2% formic acid aqueous solution and acetonitrile at a flow rate of 0.5 mL/min. Sumatriptan (m/z 296.26→251.05) and terazosin (m/z 388.10→290.25) were quantified using a triple quadrupole mass spectrometer, operating in the multiple reaction monitoring (MRM) under the positive ion mode. The method was fully validated following US-FDA and EMA guidelines. The LC-MS/MS assay had a calibration range of 0.5–50.0 ng/mL. The assay was precise and accurate with a between-run precision of <9.51%, and between-run accuracy between −7.27 to 8.30%. The developed method was subsequently applied in the determination of plasma concentration-time profile of a sumatriptan 50-mg tablet following oral administration in healthy volunteers. Full article

(This article belongs to the Section Pharmaceutical Technology)

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22 pages, 6763 KiB

Open AccessArticle

Structure–Activity Relationships (SARs) of α-Ketothioamides as Inhibitors of Phosphoglycerate Dehydrogenase (PHGDH)

by Quentin Spillier, Séverine Ravez, Judith Unterlass, Cyril Corbet, Charline Degavre, Olivier Feron and Raphaël Frédérick

Pharmaceuticals 2020, 13(2), 20; https://doi.org/10.3390/ph13020020 - 22 Jan 2020

Cited by 14 | Viewed by 4736

Abstract

For many years now, targeting deregulation within cancer cells’ metabolism has appeared as a promising strategy for the development of more specific and efficient cancer treatments. Recently, numerous reports highlighted the crucial role of the serine synthetic pathway, and particularly of the phosphoglycerate [...] Read more.

For many years now, targeting deregulation within cancer cells’ metabolism has appeared as a promising strategy for the development of more specific and efficient cancer treatments. Recently, numerous reports highlighted the crucial role of the serine synthetic pathway, and particularly of the phosphoglycerate dehydrogenase (PHGDH), the first enzyme of the pathway, to sustain cancer progression. Yet, because of very weak potencies usually in cell-based settings, the inhibitors reported so far failed to lay ground on the potential of this approach. In this paper, we report a structure–activity relationship study of a series of α-ketothioamides that we have recently identified. Interestingly, this study led to a deeper understanding of the structure–activity relationship (SAR) in this series and to the identification of new PHGDH inhibitors. The activity of the more potent compounds was confirmed by cellular thermal shift assays and in cell-based experiments. We hope that this research will eventually provide a new entry point, based on this promising chemical scaffold, for the development of therapeutic agents targeting PHGDH. Full article

(This article belongs to the Special Issue Recent Contributions in Medicinal Chemistry Within European GP2A Network)

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15 pages, 2942 KiB

Open AccessArticle

Peptide-Based Soft Hydrogels Modified with Gadolinium Complexes as MRI Contrast Agents

by Enrico Gallo, Carlo Diaferia, Enza Di Gregorio, Giancarlo Morelli, Eliana Gianolio and Antonella Accardo

Pharmaceuticals 2020, 13(2), 19; https://doi.org/10.3390/ph13020019 - 21 Jan 2020

Cited by 29 | Viewed by 4161

Abstract

Poly-aromatic peptide sequences are able to self-assemble into a variety of supramolecular aggregates such as fibers, hydrogels, and tree-like multi-branched nanostructures. Due to their biocompatible nature, these peptide nanostructures have been proposed for several applications in biology and nanomedicine (tissue engineering, drug delivery, [...] Read more.

Poly-aromatic peptide sequences are able to self-assemble into a variety of supramolecular aggregates such as fibers, hydrogels, and tree-like multi-branched nanostructures. Due to their biocompatible nature, these peptide nanostructures have been proposed for several applications in biology and nanomedicine (tissue engineering, drug delivery, bioimaging, and fabrication of biosensors). Here we report the synthesis, the structural characterization and the relaxometric behavior of two novel supramolecular diagnostic agents for magnetic resonance imaging (MRI) technique. These diagnostic agents are obtained for self-assembly of DTPA(Gd)-PEG8-(FY)3 or DOTA(Gd)-PEG8-(FY)3 peptide conjugates, in which the Gd-complexes are linked at the N-terminus of the PEG8-(FY)3 polymer peptide. This latter was previously found able to form self-supporting and stable soft hydrogels at a concentration of 1.0% wt. Analogously, also DTPA(Gd)-PEG8-(FY)3 and DOTA(Gd)-PEG8-(FY)3 exhibit the trend to gelificate at the same range of concentration. Moreover, the structural characterization points out that peptide (FY)3 moiety keeps its capability to arrange into β-sheet structures with an antiparallel orientation of the β-strands. The high relaxivity value of these nanostructures (~12 mM⁻¹·s⁻¹ at 20 MHz) and the very low in vitro cytotoxicity suggest their potential application as supramolecular diagnostic agents for MRI. Full article

(This article belongs to the Special Issue Metal-Based Drugs: Updates and Perspectives)

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Pharmaceuticals, Volume 13, Issue 2 (February 2020) – 15 articles

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