New Issue | Current Topics in Medicinal Chemistry; Volume 19 Issue 31

 

Current Topics in Medicinal Chemistry is a forum for the review of areas of keen and topical interest to medicinal chemists and others in the allied disciplines. Each issue is solely devoted to a specific topic, containing six to nine reviews, which provide the reader a comprehensive survey of that area. A Guest Editor who is an expert in the topic under review, will assemble each issue. The scope of Current Topics in Medicinal Chemistry will cover all areas of medicinal chemistry, including current developments in rational drug design, synthetic chemistry, bioorganic chemistry, high-throughput screening, combinatorial chemistry, compound diversity measurements, drug absorption, drug distribution, metabolism, new and emerging drug targets, natural products, pharmacogenomics, and structure-activity relationships. Medicinal chemistry is a rapidly maturing discipline. The study of how structure and function are related is absolutely essential to understanding the molecular basis of life. Current Topics in Medicinal Chemistry aims to contribute to the growth of scientific knowledge and insight, and facilitate the discovery and development of new therapeutic agents to treat debilitating human disorders. The journal is essential for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important advances.

 

Articles from the journal: Current Topics in Medicinal Chemistry; Volume 19 Issue 31

• Salivary mir-27b Expression in Oral Lichen Planus Patients: A Series of Cases and a Narrative Review of Literature
• The Cooperative Effect between Polybasic Region (PBR) and Polysialyltransferase Domain (PSTD) within Tumor-Target Polysialyltranseferase ST8Sia II
• Mechanism and Development of Modern General Anesthetics
• Medicinal Value and Potential Therapeutic Mechanisms of Gynostemma pentaphyllum (Thunb.) Makino and Its Derivatives: An Overview
• Marine Actinomycetes-derived Natural Products
• Progress in the Mechanism and Clinical Application of Cilostazol

 

 

 

For details on the articles, please visit this link: http://www.eurekaselect.com/node/615/current-topics-in-medicinal-chemistry/issue/19/2599/31/9575

Editors Choice Article | In vitro Identification of Spinosin Metabolites in Human Liver Microsomes Using a Simple and Sensitive UHPLC-Q-TOF-MS/MS Method

Journal Name: Current Pharmaceutical Analysis

Author(s): Qiaoyue Zhang, Xia Zhang, Yanyan Liu, Changchen Wan, Yupeng Sun, Lantong Zhang*.

 

 

 

 

Graphical Abstract:

 

Abstract:

Background: Spinosin is one of the major bioactive constituents among the total flavonoids in semen ziziphi spinosae, which has sedation and hypnosis actions.

Methods: A simple and rapid high-resolution ultra-high-performance liquid chromatography coupled with a quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF/MS) method was developed and validated for predicting the structures of its spinosin metabolic products. This paper presents the first research focused on the metabolites of spinosin in human liver microsomes.

Results: Based on the analytical strategy, 8 spinosin metabolites were detected in human liver microsome incubation samples, and the metabolic pathways required to generate these metabolites were proposed. However, no phase II metabolites were found. The cytochrome P450 enzyme is the main metabolic enzyme involved in drug metabolism, accounting for approximately 75% of the total number of different metabolic reactions.

Conclusion: The in vitro metabolism of spinosin was proposed. These results allow us to learn about spinosin metabolism, leading to a better understanding of drug biotransformation and providing a basis for clinical applications. Moreover, this study laid the foundation for developing new pharmaceutical drugs. To read out more, please visit: http://www.eurekaselect.com/165902/article

New Issue | Current Topics in Medicinal Chemistry; Volume 19 Issue 25

 

 

Current Topics in Medicinal Chemistry is a forum for the review of areas of keen and topical interest to medicinal chemists and others in the allied disciplines. Each issue is solely devoted to a specific topic, containing six to nine reviews, which provide the reader a comprehensive survey of that area. A Guest Editor who is an expert in the topic under review, will assemble each issue. The scope of Current Topics in Medicinal Chemistry will cover all areas of medicinal chemistry, including current developments in rational drug design, synthetic chemistry, bioorganic chemistry, high-throughput screening, combinatorial chemistry, compound diversity measurements, drug absorption, drug distribution, metabolism, new and emerging drug targets, natural products, pharmacogenomics, and structure-activity relationships. Medicinal chemistry is a rapidly maturing discipline. The study of how structure and function are related is absolutely essential to understanding the molecular basis of life. Current Topics in Medicinal Chemistry aims to contribute to the growth of scientific knowledge and insight, and facilitate the discovery and development of new therapeutic agents to treat debilitating human disorders. The journal is essential for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important advances.

 

Articles from the journal: Current Topics in Medicinal Chemistry; Volume 19 Issue 25

• A Possible Modulation Mechanism of Intramolecular and Intermolecular Interactions for NCAM Polysialylation and Cell Migration
• Impacts of Pseudo Amino Acid Components and 5-steps Rule to Proteomics and Proteome Analysis
• Identifying Cancer Targets Based on Machine Learning Methods via Chou’s 5-steps Rule and General Pseudo Components
• A Study for Therapeutic Treatment against Parkinson’s Disease via Chou’s 5-steps Rule
• Recent Advances in Ginsenosides as Potential Therapeutics Against Breast Cancer
• Biological Production of (S)-acetoin: A State-of-the-Art Review
• Cyclodextrin Inclusion of Medicinal Compounds for Enhancement of their Physicochemical and Biopharmaceutical Properties

For details on the articles, please visit this link: http://www.eurekaselect.com/node/615/current-topics-in-medicinal-chemistry/issue/19/2599/25/9462

New Issue | Current Topics in Medicinal Chemistry; Volume: 19, Issue: 6

 

Current Topics in Medicinal Chemistry is a forum for the review of areas of keen and topical interest to medicinal chemists and others in the allied disciplines. Each issue is solely devoted to a specific topic, containing six to nine reviews, which provide the reader a comprehensive survey of that area. A Guest Editor who is an expert in the topic under review, will assemble each issue. The scope of Current Topics in Medicinal Chemistry will cover all areas of medicinal chemistry, including current developments in rational drug design, synthetic chemistry, bioorganic chemistry, high-throughput screening, combinatorial chemistry, compound diversity measurements, drug absorption, drug distribution, metabolism, new and emerging drug targets, natural products, pharmacogenomics, and structure-activity relationships. Medicinal chemistry is a rapidly maturing discipline. The study of how structure and function are related is absolutely essential to understanding the molecular basis of life. Current Topics in Medicinal Chemistry aims to contribute to the growth of scientific knowledge and insight, and facilitate the discovery and development of new therapeutic agents to treat debilitating human disorders. The journal is essential for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important advances.

 

 

Articles from the journal: Current Topics in Medicinal Chemistry; Volume: 19, Issue: 6

• How Cancer Cells Resist Chemotherapy: Design and Development of Drugs Targeting Protein-Protein Interactions
• Algorithmic and Stochastic Representations of Gene Regulatory Networks and Protein-Protein Interactions
• Quantum Molecular Dynamics, Topological, Group Theoretical and Graph Theoretical Studies of Protein-Protein Interactions
• Protein/ Hormone Based Nanoparticles as Carriers for Drugs Targeting Protein-Protein Interactions
• Influence of Amino Acid Mutations and Small Molecules on Targeted Inhibition of Proteins Involved in Cancer
• Targeting Kinase Interaction Networks: A New Paradigm in PPI Based Design of Kinase Inhibitors

 

For details on the articles, please visit this link: http://www.eurekaselect.com/node/615/current-topics-in-medicinal-chemistry/issue/19/2599/6/9078

 

 

 

PRESS RELEASE – LC-MS/MS Identification and characterization of biodegradation products of Nitroproston

This article by Dr. Natalia Vladimirovna Mesonzhnik et al. is published in Drug Metabolism Letters, Volume 12, 2018

Nitroproston (11(S),15(S)-dihydroxy-9-keto-5Z,13E-prostadienoic acid 1?,3?-dinitroglycerol ester) is a novel prostaglandin-based compound with potential application in obstructive respiratory diseases such as asthma and obstructive bronchitis. Its pharmacological activity is provided by combined multi-target action on prostanoid EP4 receptors and soluble guanylylcyclase. Nitroproston is bearing a prostaglandin E2 (PGE2) moiety modified by an additional NO-donating fragment of glycerol-1,3-dinitrate (1,3-GDN) via ester bond and can be consider as nitrated derivative of glycerol ester of PGE2 ? the natural COX-2 metabolite of endogenous cannabinoid-like molecule 2-arachidonoyl glycerol. The presence of NO-donating fragment extremely changes pharmacological properties of PGE2. Nitroproston is more than 20-fold as active as prostaglandin E2 in the relaxation of respiratory muscles. Due to this enhanced myorelaxant activity Nitroproston is well tolerated by asthmatic subjects and is the first-in-class pharmaceutical candidate for therapy of asthma attacks utilized both prostanoid and NO receptors.

Despite the fact that Nitroproston has been extensively studied using various pharmacological models, its biological stability is still unknown. Thereby, the main aim of the present study was to evaluate Nitroproston stability in vitro, as well as to identify and characterize its biodegradation products. The principal in vitro biodegradation products of Nitroproston were identified using liquid chromatography/ion trap – time-of-flight mass-spectrometry (LC-HRMS/MS). The postulated structure of metabolites was confirmed using authentic reference standards. Rat, rabbit and human plasma and human whole blood samples were used for comparative in vitro degradation study. Nitroproston and its biodegradation products in biological samples were measured by target liquid chromatography/triple-stage quadrupole mass spectrometry (LC-MS/MS).

LC-HRMS/MS of spiked rat plasma samples clearly indicated the presence of two main metabolites of Nitroproston – 1,3-GDN and PGE2, the later can undergo dehydration to cyclopentenone prostaglandins. The applied LC-HRMS/MS screening method did not reveal the presence of biodegradation products of Nitroproston with one nitro-group or PGE2 glycerol ester. We assume that nitrate esters are more resistant to enzymatic hydrolysis in rat plasma than carboxyl ester moieties.

Target LC-MS/MS quantitative analysis was used to quantify the amount of Nitroproston and its major biodegradation products in rodent’s plasma. The degradation was higher in rat plasma where only 5 % of parent Nitroproston was identified at the first moment of incubation. Similar pattern was observed for rabbit plasma where half-life (T1/2) of Nitroproston was about 2.0 minutes. Additionally, whole human blood and plasma samples were taken to perform stability and blood cell distribution study. Nitroproston biodegradation rate for human plasma was the slowest (T1/2 = 2.1 h) among tested species, but occurred more rapidly in whole blood (T1/2 = 14.8 min). Nitroproston was distributed between human RBCs and plasma with partition ratio of 0.82. These data suggest that metabolism of drug candidate in human whole blood was mainly associated with an enzymes located in RBC fraction. The observed interspecies variability highlights the need of suitable animal model selection for Nitroproston follow-up PK/PD studies. Our findings do not exclude that Nitroproston may be relatively stable in human after inhalation and may exert its therapeutic actions either as a whole drug molecule or as a prostaglandin E2 and nitric oxide prodrugs thanks to its active metabolites.

Nitroproston is being developed as a drug candidate for relief of bronchial asthma. The key principle of the action of Nitroproston is not only the effect on two targets having similar pharmacological activity with respect to bronchial smooth muscle, but also the synchronization of the pharmacological activity when the prostaglandin E2 is the driver of the donor part releasing the NO in the activity sites. Due to this, a powerful synergy of pharmacological activity is achieved and the dose of PGE2 drops sharply, which brings us back to the possibility of starting new and more successful attempts to use the of NO donating PGE2 derivatives for relief the bronchial asthma.

For more information about the research, please visit: http://www.eurekaselect.com/160373/article

OPEN ACCESS ARTICLE – Moving to the Rhythm with Clock (Circadian) Genes, Autophagy, mTOR, and SIRT1 in Degenerative Disease and Cancer – Current Neurovascular Research

Journal: Current Neurovascular Research

Author(s):  Kenneth Maiese

Abstract:

Background: The mammalian circadian clock and its associated clock genes are increasingly been recognized as critical components for a number of physiological and disease processes that extend beyond hormone release, thermal regulation, and sleep-wake cycles. New evidence suggests that clinical behavior disruptions that involve prolonged shift work and even space travel may negatively impact circadian rhythm and lead to multi-system disease.

Methods: In light of the significant role circadian rhythm can hold over the body’s normal physiology as well as disease processes, we examined and discussed the impact circadian rhythm and clock genes hold over lifespan, neurodegenerative disorders, and tumorigenesis.

Results: In experimental models, lifespan is significantly reduced with the introduction of arrhythmic mutants and leads to an increase in oxidative stress exposure. Interestingly, patients with Alzheimer’s disease and Parkinson’s disease may suffer disease onset or progression as a result of alterations in the DNA methylation of clock genes as well as prolonged pharmacological treatment for these disorders that may lead to impairment of circadian rhythm function. Tumorigenesis also can occur with the loss of a maintained circadian rhythm and lead to an increased risk for nasopharyngeal carcinoma, breast cancer, and metastatic colorectal cancer. Interestingly, the circadian clock system relies upon the regulation of the critical pathways of autophagy, the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), and silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) as well as proliferative mechanisms that involve the wingless pathway of Wnt/β-catenin pathway to foster cell survival during injury and block tumor cell growth.

Conclusion: Future targeting of the pathways of autophagy, mTOR, SIRT1, and Wnt that control mammalian circadian rhythm may hold the key for the development of novel and effective therapies against aging- related disorders, neurodegenerative disease, and tumorigenesis.

Read more here: http://www.eurekaselect.com/154252

Testimonial by Roberto Mandrioli!

Contributed Article: “New-Generation, Non-SSRI Antidepressants: Therapeutic Drug Monitoring and Pharmacological Interactions”

Most Accessed Article – Warming Up to New Possibilities with the Capsaicin Receptor TRPV1: mTOR, AMPK, and Erythropoietin – Current Neurovascular Research

Journal: Current Neurovascular Research

Author(s): Kenneth Maiese.

Abstract:

Background: Transient receptor potential (TRP) channels are a superfamily of ion channels termed after the trp gene in Drosophila that are diverse in structure and control a wide range of biological functions including cell development and growth, thermal regulation, and vascular physiology. Of significant interest is the transient receptor potential cation channel subfamily V member 1 (TRPV1) receptor, also known as the capsaicin receptor and the vanilloid receptor 1, that is a non-selective cation channel sensitive to a host of external stimuli including capsaicin and camphor, venoms, acid/basic pH changes, and temperature.

Methods: Given the multiple modalities that TRPV1 receptors impact in the body, we examined and discussed the role of these receptors in vasomotor control, metabolic disorders, cellular injury, oxidative stress, apoptosis, autophagy, and neurodegenerative disorders and their overlap with other signal transduction pathways that impact trophic factors.

Results: Surprisingly, TRPV1 receptors do not rely entirely upon calcium signaling to affect cellular biology, but also have a close relationship with the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), and protein kinase B (Akt) that have roles in pain sensitivity, stem cell development, cellular survival, and cellular metabolism. These pathways with TRPV1 converge in the signaling of growth factors with recent work highlighting a relationship with erythropoietin (EPO). Angiogenesis and endothelial tube formation controlled by EPO requires, in part, the activation of TRPV1 receptors in conjunction with Akt and AMPK pathways.

Conclusion: TRPV1 receptors could prove to become vital to target disorders of vascular origin and neurodegeneration. Broader and currently unrealized implementations for both EPO and TRPV1 receptors can be envisioned for for the development of novel therapeutic strategies in multiple systems of the body.

 

To access the article, please visit: http://www.eurekaselect.com/150838

Article by Disease – “FoxO1 Inhibitors: The Future Medicine for Metabolic Disorders?”

Article by Disease on “Metabolism”

Abstract:

FoxO1, one of the most widely expressed sub-families of the winged helix forkhead factors, is biologically ‘omni-functional’ owing to its far-flung roles in metabolism, cell cycle, tissue differentiation and development and oxidative stress response. The knowledge of involvement of FoxO1 in metabolic disorders has long been there, but the potential target remained underutilized due to unavailability of specific and potent inhibitors. The review provides an insight into the role of FoxO1 in orchestrating metabolic diseases’ pathogenesis (including diabetes, its secondary complications and obesity) and compiles the literature on FoxO1 inhibitors. The emergence of various natural molecules and synthesized small molecules like AS1842856 as FoxO1 inhibitors urges us to think further and decide the future course of drug development for the management of metabolic disorders.

Read more: http://benthamscience.com/journals/current-diabetes-reviews/volume/12/issue/3/page/223/

Most Accessed Article – “Essential Roles of Intracellular Calcium Release Channels in Muscle, Brain, Metabolism, and Aging”

Abstract: Calcium (Ca²⁺) release from intracellular stores controls numerous cellular processes, including cardiac and skeletal muscle contraction, synaptic transmission and metabolism. The ryanodine receptors (RyRs: RyR1, RyR2, RyR3) and inositol 1,4,5-trisphosphate receptors (IP3Rs: IP3R1, IP3R2, IP3R3) are the major Ca²⁺ release channels (CRCs) on the endo/sarcoplasmic reticulum (ER/SR). RyRs and IP3Rs comprise macromolecular signaling complexes that include modulatory proteins which regulate channel activity in response to extracellular signals resulting in intracellular Ca²⁺ release. Here we focus on the roles of CRCs in heart, skeletal muscle, brain, metabolism, and aging.

Find out more: http://benthamscience.com/journals/current-molecular-pharmacology/volume/8/issue/2/page/206/