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Journal of the American Chemical Society Oct 2023Reactions capable of transposing the oxidation levels of adjacent carbon atoms enable rapid and fundamental alteration of a molecule's reactivity. Herein, we report the...
Reactions capable of transposing the oxidation levels of adjacent carbon atoms enable rapid and fundamental alteration of a molecule's reactivity. Herein, we report the 1,2-transposition of the carbon atom oxidation level in cyclic and acyclic tertiary amides, resulting in the one-pot synthesis of 1,2- and 1,3-oxygenated tertiary amines. This oxidation level transfer was facilitated by the careful orchestration of an iridium-catalyzed reduction with the functionalization of transiently formed enamine intermediates. A novel 1,2-carbonyl transposition is described, and the breadth of this redox transposition strategy has been further explored by the development of aminoalcohol and enaminone syntheses. The diverse β-functionalized amine products were shown to be multifaceted and valuable synthetic intermediates, accessing challenging biologically relevant motifs.
PubMed: 37756523
DOI: 10.1021/jacs.3c08466 -
Pharmacology Research & Perspectives Dec 2019Paul Ehrlich's concept of the magic bullet, by which a induces pharmacological effects by interacting with a has been a strong driving force in pharmacology for a... (Review)
Review
Paul Ehrlich's concept of the magic bullet, by which a induces pharmacological effects by interacting with a has been a strong driving force in pharmacology for a century. It is continually thwarted, though, by the fact that the treated organism is highly dynamic and the target molecule(s) is (are) never static. In this article, we address some of the factors that modify and cause the mobility and plasticity of drug targets and their interactions with ligands and discuss how these can lead to unexpected (lack of) effects of drugs. These factors include genetic, epigenetic, and phenotypic variability, cellular plasticity, chronobiological rhythms, time, age and disease resolution, sex, drug metabolism, and distribution. We emphasize four existing approaches that can be taken, either singly or in combination, to try to minimize effects of pharmacological plasticity. These are firstly, to enhance specificity using target conditions close to those in diseases, secondly, by simultaneously or thirdly, sequentially aiming at multiple targets, and fourthly, in synchronization with concurrent dietary, psychological, training, and biorhythm-synchronizing procedures to optimize drug therapy.
Topics: Epigenesis, Genetic; Gene Expression Regulation; Humans; Ligands; Molecular Targeted Therapy; Pharmacology, Clinical
PubMed: 31768257
DOI: 10.1002/prp2.532 -
Frontiers in Plant Science 2022The liaison between Nitric oxide (NO) and phytohormones regulates a myriad of physiological processes at the cellular level. The interaction between NO and phytohormones... (Review)
Review
The liaison between Nitric oxide (NO) and phytohormones regulates a myriad of physiological processes at the cellular level. The interaction between NO and phytohormones is mainly influenced by NO-mediated post-translational modifications (PTMs) under basal as well as induced conditions. Protein S-nitrosylation is the most prominent and widely studied PTM among others. It is the selective but reversible redox-based covalent addition of a NO moiety to the sulfhydryl group of cysteine (Cys) molecule(s) on a target protein to form S-nitrosothiols. This process may involve either direct S-nitrosylation or indirect S-nitrosylation followed by transfer of NO group from one thiol to another (transnitrosylation). During S-nitrosylation, NO can directly target Cys residue (s) of key genes involved in hormone signaling thereby regulating their function. The phytohormones regulated by NO in this manner includes abscisic acid, auxin, gibberellic acid, cytokinin, ethylene, salicylic acid, jasmonic acid, brassinosteroid, and strigolactone during various metabolic and physiological conditions and environmental stress responses. S-nitrosylation of key proteins involved in the phytohormonal network occurs during their synthesis, degradation, or signaling roles depending upon the response required to maintain cellular homeostasis. This review presents the interaction between NO and phytohormones and the role of the canonical NO-mediated post-translational modification particularly, S-nitrosylation of key proteins involved in the phytohormonal networks under biotic and abiotic stresses.
PubMed: 35401598
DOI: 10.3389/fpls.2022.865542 -
Cancer Diagnosis & Prognosis 2023DNA mismatch repair system (MMR) is considered a leading genetic mechanism in stabilizing DNA structure and maintaining its function. DNA MMR is a highly conserved... (Review)
Review
DNA mismatch repair system (MMR) is considered a leading genetic mechanism in stabilizing DNA structure and maintaining its function. DNA MMR is a highly conserved system in bacteria, prokaryotic, and eukaryotic cells, and provides the highest protection to DNA by repairing micro-structural alterations. DNA MMR proteins are involved in the detection and repair of intra-nucleotide base-to-base errors inside the complementary DNA strand recognizing the recently synthesized strand from the parental template. During DNA replication, a spectrum of errors including base insertion, deletion, and miss-incorporation negatively affect the molecule's structure and its functional stability. A broad spectrum of genomic alterations such as promoter hyper methylation, mutation, and loss of heterozygosity (LOH) in MMR genes including predominantly hMLH1, hMSH2, hMSH3, hMSH6, hPMS1, and hPMS2 lead to their loss of base-to-base error repairing procedure. Microsatellite instability (MSI) refers to the DNA MMR gene alterations that are observed in a variety of malignancies of different histological origins. In the current review, we present the role of DNA MMR deficiency in breast adenocarcinoma, a leading cancer-based cause of death in females worldwide.
PubMed: 36875308
DOI: 10.21873/cdp.10197 -
Biomedicine & Pharmacotherapy =... Sep 2023Plant bioactive molecules could play key preventive and therapeutic roles in chronological aging and the pathogenesis of many chronic diseases, often accompanied by... (Review)
Review
Plant bioactive molecules could play key preventive and therapeutic roles in chronological aging and the pathogenesis of many chronic diseases, often accompanied by increased oxidative stress and low-grade inflammation. Dietary antioxidants, including genkwanin, could decrease oxidative stress and the expression of pro-inflammatory cytokines or pathways. The present study is the first comprehensive review of genkwanin, a methoxyflavone found in several plant species. Indeed, natural sources, and pharmacokinetics of genkwanin, the biological properties were discussed and highlighted in detail. This review analyzed and considered all original studies related to identification, isolation, quantification, investigation of the biological and pharmacological properties of genkwanin. We consulted all published papers in peer-reviewed journals in the English language from the inception of each database to 12 May 2023. Different phytochemical demonstrated that genkwanin is a non-glycosylated flavone found and isolated from several medicinal plants such as Genkwa Flos, Rosmarinus officinalis, Salvia officinalis, and Leonurus sibiricus. In vitro and in vivo biological and pharmacological investigations showed that Genkwanin exhibits remarkable antioxidant and anti-inflammatory activities, genkwanin, via activation of glucokinase, has shown antihyperglycemic activity with a potential role against metabolic syndrome and diabetes. Additionally, it revealed cardioprotective and neuroprotective properties, thus reducing the risk of cardiovascular diseases and assisting against neurodegenerative diseases. Furthermore, genkwanin showed other biological properties like antitumor capability, antibacterial, antiviral, and dermato-protective effects. The involved mechanisms include sub-cellular, cellular and molecular actions at different levels such as inducing apoptosis and inhibiting the growth and proliferation of cancer cells. Despite the findings from preclinical studies that have demonstrated the effects of genkwanin and its diverse mechanisms of action, additional research is required to comprehensively explore its therapeutic potential. Primarily, extensive studies should be carried out to enhance our understanding of the molecule's pharmacodynamic actions and pharmacokinetic pathways. Moreover, toxicological and clinical investigations should be undertaken to assess the safety and clinical efficacy of genkwanin. These forthcoming studies are of utmost importance in fully unlocking the potential of this molecule in the realm of therapeutic applications.
Topics: Flavones; Anti-Inflammatory Agents; Cytokines; Plant Extracts; Antioxidants
PubMed: 37481929
DOI: 10.1016/j.biopha.2023.115159 -
Journal of Molecular Recognition : JMR Dec 2019This review describes selected basics of water in biomolecular recognition. We focus on a qualitative understanding of the most important physical aspects, how these... (Review)
Review
This review describes selected basics of water in biomolecular recognition. We focus on a qualitative understanding of the most important physical aspects, how these change in magnitude between bulk water and protein environment, and how the roles that water plays for proteins arise from them. These roles include mechanical support, thermal coupling, dielectric screening, mass and charge transport, and the competition with a ligand for the occupation of a binding site. The presence or absence of water has ramifications that range from the thermodynamic binding signature of a single ligand up to cellular survival. The large inhomogeneity in water density, polarity and mobility around a solute is hard to assess in experiment. This is a source of many difficulties in the solvation of protein models and computational studies that attempt to elucidate or predict ligand recognition. The influence of water in a protein binding site on the experimental enthalpic and entropic signature of ligand binding is still a point of much debate. The strong water-water interaction in enthalpic terms is counteracted by a water molecule's high mobility in entropic terms. The complete arrest of a water molecule's mobility sets a limit on the entropic contribution of a water displacement process, while the solvent environment sets limits on ligand reactivity.
Topics: Binding Sites; Hydrogen Bonding; Ligands; Proteins; Water
PubMed: 31456282
DOI: 10.1002/jmr.2810 -
Pharmaceuticals (Basel, Switzerland) Aug 2021Ubiquitination represents a post-translational modification (PTM) essential for the maintenance of cellular homeostasis. Ubiquitination is involved in the regulation of... (Review)
Review
Ubiquitination represents a post-translational modification (PTM) essential for the maintenance of cellular homeostasis. Ubiquitination is involved in the regulation of protein function, localization and turnover through the attachment of a ubiquitin molecule(s) to a target protein. Ubiquitination can be reversed through the action of deubiquitinating enzymes (DUBs). The DUB enzymes have the ability to remove the mono- or poly-ubiquitination signals and are involved in the maturation, recycling, editing and rearrangement of ubiquitin(s). Ubiquitin-specific proteases (USPs) are the biggest family of DUBs, responsible for numerous cellular functions through interactions with different cellular targets. Over the past few years, several studies have focused on the role of USPs in carcinogenesis, which has led to an increasing development of therapies based on USP inhibitors. In this review, we intend to describe different cellular functions, such as the cell cycle, DNA damage repair, chromatin remodeling and several signaling pathways, in which USPs are involved in the development or progression of cancer. In addition, we describe existing therapies that target the inhibition of USPs.
PubMed: 34577547
DOI: 10.3390/ph14090848 -
Frontiers in Pharmacology 2016Traditional medicine has a history extending back to thousands of years, and during the intervening time, man has identified the healing properties of a very broad range... (Review)
Review
Traditional medicine has a history extending back to thousands of years, and during the intervening time, man has identified the healing properties of a very broad range of plants. Globally, the use of herbal therapies to treat and manage cardiovascular disease (CVD) is on the rise. This is the second part of our comprehensive review where we discuss the mechanisms of plants and herbs used for the treatment and management of high blood pressure. Similar to the first part, PubMed and ScienceDirect databases were utilized, and the following keywords and phrases were used as inclusion criteria: hypertension, high blood pressure, herbal medicine, complementary and alternative medicine, endothelial cells, nitric oxide (NO), vascular smooth muscle cell (VSMC) proliferation, hydrogen sulfide, nuclear factor kappa-B (NF-κB), oxidative stress, and epigenetics/epigenomics. Each of the aforementioned keywords was co-joined with plant or herb in question, and where possible with its constituent molecule(s). This part deals in particular with plants that are used, albeit less frequently, for the treatment and management of hypertension. We then discuss the interplay between herbs/prescription drugs and herbs/epigenetics in the context of this disease. The review then concludes with a recommendation for more rigorous, well-developed clinical trials to concretely determine the beneficial impact of herbs and plants on hypertension and a disease-free living.
PubMed: 27014064
DOI: 10.3389/fphar.2016.00050 -
Journal of Genetics Jul 2018Tauopathies represent a group of neurodegenerative disorder which are characterized by the presence of tau positive specialized argyrophilic and insoluble intraneuronal... (Review)
Review
Tauopathies represent a group of neurodegenerative disorder which are characterized by the presence of tau positive specialized argyrophilic and insoluble intraneuronal and glial fibrillar lesions known as neurofibrillary tangles (NFTs). Tau is a neuron specific microtubule binding protein which is required for the integrity and functioning of neuronal cells, and hyperphosphorylation of tau and its subsequent aggregation and paired helical filaments (PHFs) and NFTs has emerged as one of the major pathogenic mechanisms of tauopathies in human and mammalian model systems. Modeling of human tauopathies in results in manifestation of associated phenotypes, and a recent study has demonstrated that similar to human and mammalian models, accumulation of insoluble tau aggregates in the form of typical neurotoxic NFTs triggers the pathogenesis of tauopathies in fly models. In view of the availability of remarkable genetic tools, tau models could be extremely useful for in-depth analysis of the role of NFTs in neurodegeneration and tau aetiology, and also for the screening of novel gene(s) and molecule(s) which suppress the toxicity of tau aggregates.
Topics: Animals; Disease Models, Animal; Drosophila melanogaster; Humans; Neurofibrillary Tangles; Neurons; Tauopathies; tau Proteins
PubMed: 30027909
DOI: No ID Found