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Science (New York, N.Y.) Nov 2020New antifungal drugs are urgently needed to address the emergence and transcontinental spread of fungal infectious diseases, such as pandrug-resistant Leveraging the...
New antifungal drugs are urgently needed to address the emergence and transcontinental spread of fungal infectious diseases, such as pandrug-resistant Leveraging the microbiomes of marine animals and cutting-edge metabolomics and genomic tools, we identified encouraging lead antifungal molecules with in vivo efficacy. The most promising lead, turbinmicin, displays potent in vitro and mouse-model efficacy toward multiple-drug-resistant fungal pathogens, exhibits a wide safety index, and functions through a fungal-specific mode of action, targeting Sec14 of the vesicular trafficking pathway. The efficacy, safety, and mode of action distinct from other antifungal drugs make turbinmicin a highly promising antifungal drug lead to help address devastating global fungal pathogens such as
Topics: Animals; Antifungal Agents; Benzopyrans; Candida; Candidiasis, Invasive; Disease Models, Animal; Drug Resistance, Multiple, Fungal; Fungal Proteins; Isoquinolines; Mice; Microbiota; Micromonospora; Phospholipid Transfer Proteins; Urochordata
PubMed: 33214279
DOI: 10.1126/science.abd6919 -
Molecules (Basel, Switzerland) Sep 20184-Arylcoumarins (4-aryl-2-1-benzopyran-2-one), also known as neoflavones, comprise a minor subclass of naturally occurring flavonoids. Because of their broad-spectrum... (Review)
Review
4-Arylcoumarins (4-aryl-2-1-benzopyran-2-one), also known as neoflavones, comprise a minor subclass of naturally occurring flavonoids. Because of their broad-spectrum biological activities, arylcoumarins have been attracting the attention of the organic and medicinal chemistry communities, and are considered as an important privileged scaffold. Since the development of Pechmann condensation, a classical acid-catalyzed condensation between phenol and β-keto-carboxylic acid, several versatile and efficient synthetic approaches for 4-arylcoumarins have been reported. This review summarizes recent advances in the synthesis of the 4-arylcoumarin scaffold by classifying them based on the final bond-formation type. In particular, synthetic methods executed under mild and highly efficient conditions, such as solvent-free reactions and transition metal catalysis, are highlighted.
Topics: Catalysis; Coumarins; Flavonoids; Humans; Molecular Structure; Phenol; Solvents
PubMed: 30241375
DOI: 10.3390/molecules23102417 -
Molecules (Basel, Switzerland) Apr 2014Natural dibenzo-α-pyrones are an important group of metabolites derived from fungi, mycobionts, plants and animal feces. They exhibit a variety of biological activities... (Review)
Review
Natural dibenzo-α-pyrones are an important group of metabolites derived from fungi, mycobionts, plants and animal feces. They exhibit a variety of biological activities such as toxicity on human and animals, phytotoxicity as well as cytotoxic, antioxidant, antiallergic, antimicrobial, antinematodal, and acetylcholinesterase inhibitory properties. Dibenzo-α-pyrones are biosynthesized via the polyketide pathway in microorganisms or metabolized from plant-derived ellagitannins and ellagic acid by intestinal bacteria. At least 53 dibenzo-α-pyrones have been reported in the past few decades. This mini-review aims to briefly summarize the occurrence, biosynthesis, biotransformation, as well as their biological activities and functions. Some considerations related to synthesis, production and applications of dibenzo-α-pyrones are also discussed.
Topics: Animals; Anti-Allergic Agents; Anti-Infective Agents; Antioxidants; Bacteria; Benzopyrans; Biological Products; Biotransformation; Feces; Fungi; Humans; Plants; Pyrones; Structure-Activity Relationship
PubMed: 24759070
DOI: 10.3390/molecules19045088 -
Journal of Medicinal Chemistry Apr 2019σ and/or σ receptors play a crucial role in pathological conditions such as pain, neurodegenerative disorders, and cancer. A set of spirocyclic cyclohexanes with...
σ and/or σ receptors play a crucial role in pathological conditions such as pain, neurodegenerative disorders, and cancer. A set of spirocyclic cyclohexanes with diverse O-heterocycles and amino moieties (general structure III) was prepared and pharmacologically evaluated. In structure-activity relationships studies, the σ receptor affinity and σ:σ selectivity were correlated with the stereochemistry, the kind and substitution pattern of the O-heterocycle, and the substituents at the exocyclic amino moiety. cis-configured 2-benzopyran cis-11b bearing a methoxy group and a tertiary cyclohexylmethylamino moiety showed the highest σ affinity ( K = 1.9 nM) of this series of compounds. In a Ca influx assay, cis-11b behaved as a σ antagonist. cis-11b reveals high selectivity over σ and opioid receptors. The interactions of the novel σ ligands were analyzed on the molecular level using the recently reported X-ray crystal structure of the σ receptor protein. The protonated amino moiety forms a persistent salt bridge with E172. The spiro[benzopyran-1,1'-cyclohexane] scaffold and the cyclohexylmethyl moiety occupy two hydrophobic pockets. Exchange of the N-cyclohexylmethyl moiety by a benzyl group led unexpectedly to potent and selective μ-opioid receptor ligands.
Topics: Benzopyrans; Binding Sites; Crystallography, X-Ray; Humans; Hydrophobic and Hydrophilic Interactions; Ligands; Molecular Dynamics Simulation; Protein Structure, Tertiary; Receptors, Opioid, mu; Receptors, sigma; Spiro Compounds; Structure-Activity Relationship; Sigma-1 Receptor
PubMed: 30939014
DOI: 10.1021/acs.jmedchem.9b00449 -
ChemMedChem Jan 2021Metabotropic glutamate receptors (mGlu) are class C G protein-coupled receptors of eight subtypes that are omnipresently expressed in the central nervous system. mGlus... (Review)
Review
Metabotropic glutamate receptors (mGlu) are class C G protein-coupled receptors of eight subtypes that are omnipresently expressed in the central nervous system. mGlus have relevance in several psychiatric and neurological disorders, therefore they raise considerable interest as drug targets. Allosteric modulators of mGlus offer advantages over orthosteric ligands owing to their increased potential to achieve subtype selectivity, and this has prompted discovery programs that have produced a large number of reported allosteric mGlu ligands. However, the optimization of allosteric ligands into drug candidates has proved to be challenging owing to induced-fit effects, flat or steep structure-activity relationships and unexpected changes in theirpharmacology. Subtle structural changes identified as molecular switches might modulate the functional activity of allosteric ligands. Here we review these switches discovered in the metabotropic glutamate receptor family..
Topics: Allosteric Regulation; Allosteric Site; Benzopyrans; Drug Discovery; Humans; Ligands; Molecular Dynamics Simulation; Pyrimidines; Receptors, Metabotropic Glutamate; Structure-Activity Relationship
PubMed: 32686363
DOI: 10.1002/cmdc.202000444 -
Current Medicinal Chemistry 2013Ormeloxifene is a non-steroidal Selective Estrogen Receptor Modulator (SERM) that is used as an oral contraceptive. Recent studies have shown its potent anti-cancer... (Review)
Review
Ormeloxifene is a non-steroidal Selective Estrogen Receptor Modulator (SERM) that is used as an oral contraceptive. Recent studies have shown its potent anti-cancer activities in breast, head and neck, and chronic myeloid leukemia cells. Several in vivo and clinical studies have reported that ormeloxifene possesses an excellent therapeutic index and has been well-tolerated, without any haematological, biochemical or histopathological toxicity, even with chronic administration. A reasonably long period of time and an enormous financial commitment are required to develop a lead compound into a clinically approved anti-cancer drug. For these reasons and to circumvent these obstacles, ormeloxifene is a promising candidate on a fast track for the development or repurposing established drugs as anti-cancer agents for cancer treatment. The current review summarizes recent findings on ormeloxifene as an anti-cancer agent and future prospects of this clinically safe pharmacophore.
Topics: Antineoplastic Agents; Apoptosis; Benzopyrans; Cell Cycle Checkpoints; Clinical Trials as Topic; Humans; Neoplasms; Selective Estrogen Receptor Modulators
PubMed: 23895678
DOI: 10.2174/09298673113209990197 -
Cancer Chemotherapy and Pharmacology Feb 2017Recurrent, chemo-resistant ovarian cancer is thought to be due to a subgroup of slow-growing, drug-resistant cancer cells with stem-like properties and a high capacity... (Review)
Review
PURPOSE
Recurrent, chemo-resistant ovarian cancer is thought to be due to a subgroup of slow-growing, drug-resistant cancer cells with stem-like properties and a high capacity for tumour repair. Cantrixil targets this sub-population of cells and is being developed as an intraperitoneal therapy to be used as first-line therapy in combination with carboplatin for epithelial ovarian cancer. The studies presented here justify further development.
METHODS
A GLP dog CV study using a 4 × 4 Latin Square Crossover study was conducted using telemetric ECG recordings from dogs post IP administration to assess for cardiac abnormalities. Mutagenic potential was assessed using the bacterial reverse mutation assay. Clastogenicity was assessed by determining micronuclei formation in the bone marrow of SPF Arc(S) Swiss mice dosed at clinical concentrations. TRX-E-002-1 toxicology was evaluated in GLP-compliant MTD and 28-day repeat-dose studies in rats and dogs.
RESULTS
In vitro TRX-E-002-1 has potent cytotoxic activity against human cancer cells including CD44+/MyD88+ ovarian cancer stem cells. TRX-E-002-1 increased phosphorylated c-Jun levels in these cancer cells resulting in caspase-mediated apoptosis. In vivo, Cantrixil was active in a model of disseminated ovarian cancer as a monotherapy and in combination with Cisplatin. Cantrixil was active as maintenance therapy in a model of drug-resistant, recurrent ovarian cancer and in an orthotopic model of pancreatic cancer.
CONCLUSIONS
In animals, this clinical formulation and route of administration of Cantrixil demonstrated acceptable activity, safety pharmacology, genotoxicity and toxicology profile and constituted a successful Investigational New Drug application to the US Food and Drug Administration.
Topics: Animals; Antineoplastic Agents; Benzopyrans; Cell Line, Tumor; Cross-Over Studies; Dogs; Drug Interactions; Flavonoids; Humans; Mice; Rats; Species Specificity
PubMed: 28013349
DOI: 10.1007/s00280-016-3224-2 -
Molecules (Basel, Switzerland) May 2023The biological significance of benzopyran-4-ones as cytotoxic agents against multi-drug resistant cancer cell lines and isoxazoles as anti-inflammatory agents in...
The biological significance of benzopyran-4-ones as cytotoxic agents against multi-drug resistant cancer cell lines and isoxazoles as anti-inflammatory agents in cellular assays prompted us to design and synthesize their hybrid compounds and explore their antiproliferative activity against a panel of six cancer cell lines and two normal cell lines. Compounds - displayed significant antiproliferative activities against all the cancer cell lines tested, and IC values were in the range of 5.2-22.2 μM against MDA-MB-231 cancer cells, while they were minimally cytotoxic to the HEK-293 and LLC-PK1 normal cell lines. The IC values of - against normal HEK-293 cells were in the range of 102.4-293.2 μM. Compound was screened for kinase inhibitory activity, proteolytic human serum stability, and apoptotic activity. The compound was found inactive towards different kinases, while it completely degraded after 2 h of incubation with human serum. At 5 μM concentration, it induced apoptosis in MDA-MB-231 by 50.8%. Overall, these findings suggest that new benzopyran-4-one-isoxazole hybrid compounds, particularly -, are selective anticancer agents, potentially safe for human cells, and could be synthesized at low cost. Additionally, Compound exhibits potential anticancer activity mediated via inhibition of cancer cell proliferation and induction of apoptosis.
Topics: Humans; Drug Resistance, Multiple; HEK293 Cells; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Benzopyrans; Antineoplastic Agents; Cell Proliferation; Structure-Activity Relationship; Molecular Structure; Dose-Response Relationship, Drug
PubMed: 37241960
DOI: 10.3390/molecules28104220 -
Molecules (Basel, Switzerland) Oct 2023Traditional medicinal plants have been used for decades in folk medicines in the treatment and management of several ailments and diseases including diabetes, pain,... (Review)
Review
Traditional medicinal plants have been used for decades in folk medicines in the treatment and management of several ailments and diseases including diabetes, pain, ulcers, cancers, and wounds, among others. This study focused on the phytochemical and antidiabetic activity of the commonly used antidiabetic medicinal species in Kenya. Phytochemical profiling of these species revealed flavonoids and terpenoids as the major chemical classes reported which have been linked with strong biological activities against the aforementioned diseases, among others. However, out of the selected twenty-two species, many of the natural product isolation studies have focused on only a few species, as highlighted in the study. All of the examined crude extracts from thirteen antidiabetic species demonstrated strong antidiabetic activities by inhibiting α-glucosidase and α-amylase among other mechanisms, while nine are yet to be evaluated for their antidiabetic activities. Isolated compounds S-Methylcysteine sulfoxide, quercetin, alliuocide G, 2-(3,4-Dihydroxybenzoyl)-2,4,6-trihydroxy-3 (2)-benzofuranone, Luteolin-7--D-glucopyranoside, quercetin, 1,3,11-Trihydroxy-9-(3,5,7-trihydroxy-4-1-benzopyran-7-on-2-yl)-5-(3,4-dihydroxy-phenyl)-5,6,11-hexahydro-5,6,11-trioxanaphthacene-12-one and [1,3,11-Trihydroxy-9-(3,5,7-trihydroxy-4-1-benzopyran-7-on-2-yl)-5-(3,4-dihydroxy-phenyl)-5,6,11-hexahydro-5,6,11-trioxanaphthacene-12-one]-4'--D-gluco-pyranoside from have been found to exhibit significant antidiabetic activities. With the huge number of adults living with diabetes in Kenya and the available treatment methods being expensive yet not so effective, this study highlights alternative remedies by documenting the commonly used antidiabetic medicinal plants. Further, the study supports the antidiabetic use of these plants with the existing pharmacological profiles and highlights research study gaps. Therefore, it is urgent to conduct natural products isolation work on the selected antidiabetic species commonly used in Kenya and evaluate their antidiabetic activities, both in vitro and in vivo, to validate their antidiabetic use and come up with new antidiabetic drugs.
Topics: Plants, Medicinal; Hypoglycemic Agents; Quercetin; Kenya; Plant Extracts; Diabetes Mellitus; Benzopyrans; Phytochemicals
PubMed: 37894680
DOI: 10.3390/molecules28207202 -
TheScientificWorldJournal 2012Because cancers are caused by deregulation of hundreds of genes, an ideal anticancer agent should target multiple gene products or signaling pathways simultaneously.... (Review)
Review
Because cancers are caused by deregulation of hundreds of genes, an ideal anticancer agent should target multiple gene products or signaling pathways simultaneously. Recently, extensive research has addressed the chemotherapeutic potential of plant-derived compounds. Among the ever-increasing list of naturally occurring anticancer agents, Rottlerin appears to have great potentiality for being used in chemotherapy because it affects several cell machineries involved in survival, apoptosis, autophagy, and invasion. The underlying mechanisms that have been described are diverse, and the final, cell-specific, Rottlerin outcome appears to result from a combination of signaling pathways at multiple levels. This paper seeks to summarize the multifocal signal modulatory properties of Rottlerin, which merit to be further exploited for successful prevention and treatment of cancer.
Topics: Acetophenones; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Apoptosis; Autophagy; Benzopyrans; Drug Therapy, Combination; Humans; Neoplasms
PubMed: 22272173
DOI: 10.1100/2012/350826