ABSTRACT
Protein kinase CK2 sustains cancer growth, especially in hematological malignancies. Its inhibitor SRPIN803, based on a 6-methylene-5-imino-1,3,4-thiadiazolopyrimidin-7-one scaffold, showed notable specificity. Our synthesis of the initially proposed SRPIN803 resulted in its constitutional isomer SRPIN803-revised, where the 2-cyano-2-propenamide group does not cyclise and fuse to the thiadiazole ring. Its crystallographic structure in complex with CK2α identifies the structural determinants of the reported specificity. SRPIN803-revised explores the CK2 open hinge conformation, extremely rare among kinases, also interacting with side chains from this region. Its optimization lead to the more potent compound 4, which inhibits endocellular CK2, significantly affects viability of tumour cells and shows remarkable selectivity on a panel of 320 kinases.
Subject(s)
Casein Kinase II/antagonists & inhibitors , Casein Kinase II/chemistry , Drug Design , Protein Kinase Inhibitors/pharmacology , Casein Kinase II/metabolism , Humans , Jurkat Cells , Molecular Docking Simulation , Protein Conformation , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/metabolism , Pyrimidinones/chemistry , Pyrimidinones/metabolism , Pyrimidinones/pharmacology , Structure-Activity Relationship , Thiadiazoles/chemistry , Thiadiazoles/metabolism , Thiadiazoles/pharmacologyABSTRACT
This article discloses a new horizon for the application of peroxides in medical chemistry. Stable cyclic peroxides are demonstrated to have cytotoxic activity against cancer cells; in addition a mechanism of cytotoxic action is proposed. Synthetic bridged 1,2,4,5-tetraoxanes and ozonides were effective against HepG2 cancer cells and some ozonides selectively targeted liver cancer cells (the selectivity indexes for compounds 11 b and 12 a are 8 and 5, respectively). In some cases, tetraoxanes and ozonides were more selective than paclitaxel, artemisinin, and artesunic acid. Annexin V flow-cytometry analysis revealed that the active ozonides 22 a and 23 a induced cell death of HepG2 by apoptosis. Further study showed that compounds 22 a and 23 a exhibited a strong inhibitory effect on P-glycoprotein (P-gp/ABCB5)-overexpressing HepG2 cancer cells. ABCB5 is a key player in the multidrug-resistant phenotype of liver cancer. Peroxides failed to demonstrate a direct correlation between oxidative potential and their biological activity. To our knowledge this is the first time that peroxide diastereoisomers have been found to show stereospecific antimalarial action against the chloroquine-sensitive 3D7 strain of Plasmodium falciparum. Stereoisomeric ozonide 12 b is 11 times more active than stereoisomeric ozonide 12 a (IC50 =5.81 vs 65.18â µm). Current findings mean that ozonides merit further investigation as potential therapeutic agents for drug-resistant hepatocellular carcinoma.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B/antagonists & inhibitors , Antimalarials/pharmacology , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Peroxides/pharmacology , Plasmodium falciparum/drug effects , ATP Binding Cassette Transporter, Subfamily B/metabolism , Antimalarials/chemical synthesis , Antimalarials/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Parasitic Sensitivity Tests , Peroxides/chemical synthesis , Peroxides/chemistry , Plasmodium falciparum/growth & development , Structure-Activity RelationshipABSTRACT
BACE-1 is considered to be one of the targets for prevention and treatment of Alzheimer's disease (AD). We here report a novel class of semi-synthetic derivatives of prenylated isoflavones, obtained from the derivatization of natural flavonoids from Maclura pomifera. In vitro anti-AD effect of the synthesized compounds were evaluated via human recombinant BACE-1 inhibition assay. Compound 7, 8 and 13 were found to be the most active candidates which demonstrates good correlation between the computational docking and pharmacokinetic predictions. Moreover, cytotoxic studies demonstrated that the compounds are not toxic against normal and cancer cell lines. Among these three compounds, compound 7 enhance the activity of P-glycoprotein (P-gp) on A549 cancer cells and increases the activity of P-gp ATPase with a possible role on the efflux of amyloid-ß across the blood- brain barrier. In conclusion, the present findings may pave the way for the discovery of a novel class of compounds to prevent and/or treat AD.
Subject(s)
Alzheimer Disease/drug therapy , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Isoflavones/pharmacology , Neuroprotective Agents/pharmacology , Alzheimer Disease/metabolism , Amyloid Precursor Protein Secretases/metabolism , Aspartic Acid Endopeptidases/metabolism , Cell Line , Cell Survival/drug effects , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Isoflavones/chemical synthesis , Isoflavones/chemistry , Molecular Docking Simulation , Molecular Structure , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry , Recombinant Proteins/metabolism , Structure-Activity RelationshipABSTRACT
BACKGROUND: The possibilities of treatment for oncological diseases are growing enormously in the last decades. Unfortunately, these developments have led to the onset of resistances with regards to the new treatments. This is particularly true if we face with the therapeutic field of Tyrosine Kinase Inhibitors (TKIs). This review gives an overview of possible TKI resistances that can occur during the treatment of an oncologic diesease and available strategies that can be adopted, taking cues from a successful example such as CML. METHODS: We performed a literature search for peer-reviewed articles using different databases, such as PubMed and Scopus, and exploiting different keywords and different logical operators. RESULTS: 68 papers were included in the review. Twenty-four papers give an overview of the causes of TKIs resistances in the wide oncologic field. The remaining papers deal CML, deeply analysing the TKIs Resistances present in this pathology and the strategies adopted to overcome them. CONCLUSION: The aim of this review is to furnish an overview and a methodological guideline for the approach and the overcoming of TKIs Resistances.
Subject(s)
Drug Resistance, Neoplasm , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Protein Kinase Inhibitors/therapeutic use , Allosteric Regulation , Carboxylic Ester Hydrolases/antagonists & inhibitors , Carboxylic Ester Hydrolases/metabolism , Dasatinib/therapeutic use , Fusion Proteins, bcr-abl/antagonists & inhibitors , Fusion Proteins, bcr-abl/genetics , Fusion Proteins, bcr-abl/metabolism , Humans , Imatinib Mesylate/therapeutic use , Imidazoles/therapeutic use , Pyridazines/therapeutic useABSTRACT
The introduction of tyrosine kinase inhibitors (TKIs) in the clinical management of oncological patients spread the light on the use of selective, rationally designed small molecules for the treatment of cancer. First-generation TKIs bared high response against these malignancies, although the unavoidable shadow of resistance limits their long-term efficacy. Non-small-cell lung cancer (NSCLC) accounts for 85% of lung cancer cases, and it is the first cause of cancer deaths worldwide for men and women. Traditional chemotherapy is marginally effective against this form, and erlotinib and gefitinib were introduced as first-line treatments based on the observation that the epidermal growth factor receptor (EGFR), a receptor tyrosine kinase (RTK), is mutated in several cases and, thus, represents a druggable target. EGFR-mutant and anaplastic lymphoma kinase (ALK)-positive patients are more responsive to these treatments, even if secondary mutations causing resistance soon emerged. The efforts of medicinal chemists are currently oriented toward the development of new generations of TKIs overcoming these obstacles. We here overview the novel strategies from the point of view of the medicinal chemist: the rational structure-based drug design that led to the development of irreversible and non-ATP-competitive inhibitors. Such improvements parallel the novel therapeutic strategies adopted in the clinic, which are also discussed.
Subject(s)
Antineoplastic Agents/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , Drug Resistance, Neoplasm/drug effects , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Antineoplastic Agents/chemistry , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/genetics , ErbB Receptors/metabolism , Humans , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Protein Kinase Inhibitors/chemistryABSTRACT
Parkinson's disease (PD) is a neurodegenerative disorder bearing motor and nonmotor symptoms. The treatment today is symptomatical rather than preventive or curative and this leaves the field open for the search of both novel molecular targets and drug candidates. Interference with α-synuclein fibrillation, monoamine oxidase (MAO) inhibition, modulation of adenosine receptors and the inhibition of specific phosphodiesterase (PDE) isoforms are some of the currently pursued strategies. We synthesised and studied some semi-synthetic berberine derivatives using a set of in silico tools. We evaluated their drug-likeness and tested the compounds against a set of target proteins involved in the onset or progression of PD, with a particular attention to MAO-B. Preliminary in vitro assay on MAO-B confirmed our in silico predictions.
Subject(s)
Antiparkinson Agents/chemistry , Antiparkinson Agents/pharmacology , Berberine/chemistry , Monoamine Oxidase Inhibitors/pharmacology , Berberine/pharmacology , Computer Simulation , Drug Evaluation, Preclinical/methods , Humans , Magnetic Resonance Spectroscopy , Molecular Docking Simulation , Molecular Targeted Therapy , Monoamine Oxidase/chemistry , Monoamine Oxidase/metabolism , Parkinson Disease/drug therapyABSTRACT
Among the diseases affecting the central nervous system (CNS), neurodegenerations attract the interest of both the clinician and the medicinal chemist. The increasing average age of population, the growing number of patients, and the lack of long-term effective remedies push ahead the quest for novel tools against this class of pathologies. We present a review on the state of the art of the molecules (or combination of molecules) of natural origin that are currently under study against two well-defined pathologies: Parkinson's disease (PD) and Huntington's disease (HD). Nowadays, very few tools are available for preventing or counteracting the progression of such diseases. Two major parameters were considered for the preparation of this review: particular attention was reserved to these research works presenting well-defined molecular mechanisms for the studied compounds, and where available, papers reporting in vivo data were preferred. A literature search for peer-reviewed articles using PubMed, Scopus, and Reaxys databases was performed, exploiting different keywords and logical operators: 91 papers were considered (preferentially published after 2015). The review presents a brief overview on the etiology of the studied neurodegenerations and the current treatments, followed by a detailed discussion of the natural and semisynthetic compounds dividing them in different paragraphs considering their several mechanisms of action.
Subject(s)
Anti-Dyskinesia Agents/chemistry , Biological Products/chemistry , Huntington Disease/drug therapy , Parkinson Disease/drug therapy , Animals , Anti-Dyskinesia Agents/chemical synthesis , Anti-Dyskinesia Agents/economics , Anti-Dyskinesia Agents/therapeutic use , Antioxidants/pharmacology , Antioxidants/therapeutic use , Antiparkinson Agents/chemical synthesis , Antiparkinson Agents/chemistry , Antiparkinson Agents/economics , Antiparkinson Agents/therapeutic use , Autophagy/drug effects , Biological Products/economics , Biological Products/therapeutic use , Dementia/drug therapy , Dementia/economics , Dementia/epidemiology , Dopamine/metabolism , Drug Discovery , Drug Evaluation, Preclinical , Humans , Huntington Disease/economics , Huntington Disease/epidemiology , Huntington Disease/physiopathology , Microglia/drug effects , Mitochondria/drug effects , Molecular Targeted Therapy , Monoamine Oxidase Inhibitors/therapeutic use , Oxidative Stress/drug effects , Parkinson Disease/economics , Parkinson Disease/epidemiology , Parkinson Disease/physiopathology , Plant Preparations/pharmacology , Plant Preparations/therapeutic use , Protein Aggregation, Pathological/drug therapy , Signal Transduction/drug effects , alpha-Synuclein/antagonists & inhibitorsABSTRACT
BACKGROUND: Dementias and all related neurodegenerative diseases of the Central Nervous System (CNS) are a current issue arousing a great deal of interest in the international scientific community. This is due to the increasing number of patients suffering from these diseases. These pathologies represent a serious problem, not only concerning the quality of life of the patient, but in addition, the enormous economic efforts that society has to do for their treatment. There are currently a few strategies that are available in order to prevent the progression or to mitigate symptoms of the aforementioned diseases. This consideration is particularly true if we consider the specific pathology of Alzheimer's Disease (AD). METHODS: We performed a literature search for peer-reviewed articles using different databases, such as PubMed or Scopus, and exploiting different keywords and different logical operators. RESULTS: Ninety-eight papers were included in the review. Four papers give an overview of the background of the dementias all over the world. The remaining papers are focused on new possibilities of treatment with natural and semi-synthetic compounds for AD. CONCLUSION: The aim of this review is to give an overview of new and promising natural products and semi-synthetic compounds which could represent a source of "lead compounds" for the development of new potential drugs that could be a valid therapeutic strategy for the treatment of this pathology.
