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Molecules (Basel, Switzerland) Mar 2021A novel series of arylidene amino imidazole-2-thiones were synthesized, identified using IR, H-NMR, and C-NMR spectral data. Cytotoxic effect of the prepared compounds...
A novel series of arylidene amino imidazole-2-thiones were synthesized, identified using IR, H-NMR, and C-NMR spectral data. Cytotoxic effect of the prepared compounds was carried out utilizing three cancer cell lines; MCF-7 breast cancer, HepG2 liver cancer, and HCT-116 colon cancer cell lines. Imidazole derivative was the most potent of all against three cell lines. DNA flow cytometric analysis showed that, imidazoles and exhibit pre-G1 apoptosis and cell cycle arrest at G2/M phase. The results of the VEGFR-2 and B-Raf kinase inhibition assay revealed that compounds and displayed good inhibitory activity compared with reference drug erlotinib.
Topics: Antineoplastic Agents; Apoptosis; Cell Survival; Drug Screening Assays, Antitumor; Erlotinib Hydrochloride; G2 Phase Cell Cycle Checkpoints; HCT116 Cells; Hep G2 Cells; Humans; Imidazoles; In Vitro Techniques; MCF-7 Cells; Molecular Docking Simulation; Proto-Oncogene Proteins B-raf; Structure-Activity Relationship; Thiones; Vascular Endothelial Growth Factor Receptor-2
PubMed: 33803877
DOI: 10.3390/molecules26061706 -
ChemMedChem Jun 2021Insulin-degrading enzyme (IDE) is a human mononuclear Zn -dependent metalloenzyme that is widely regarded as the primary peptidase responsible for insulin degradation....
Insulin-degrading enzyme (IDE) is a human mononuclear Zn -dependent metalloenzyme that is widely regarded as the primary peptidase responsible for insulin degradation. Despite its name, IDE is also critically involved in the hydrolysis of several other disparate peptide hormones, including glucagon, amylin, and the amyloid β-protein. As such, the study of IDE inhibition is highly relevant to deciphering the role of IDE in conditions such as type-2 diabetes mellitus and Alzheimer disease. There have been few reported IDE inhibitors, and of these, inhibitors that directly target the active-site Zn ion have yet to be fully explored. In an effort to discover new, zinc-targeting inhibitors of IDE, a library of ∼350 metal-binding pharmacophores was screened against IDE, resulting in the identification of 1-hydroxypyridine-2-thione (1,2-HOPTO) as an effective Zn -binding scaffold. Screening a focused library of HOPTO compounds identified 3-sulfonamide derivatives of 1,2-HOPTO as inhibitors of IDE (K values of ∼50 μM). Further structure-activity relationship studies yielded several thiophene-sulfonamide HOPTO derivatives with good, broad-spectrum activity against IDE that have the potential to be useful pharmacological tools for future studies of IDE.
Topics: Enzyme Inhibitors; Humans; Insulysin; Models, Molecular; Molecular Structure; Pyridines; Thiones
PubMed: 33686743
DOI: 10.1002/cmdc.202100111 -
Neurochemical Research Apr 2012Tricyclodecan-9-yl-xanthogenate (D609) is known for its antiviral and antitumor properties. D609 actions are widely attributed to inhibiting phosphatidylcholine... (Review)
Review
Tricyclodecan-9-yl-xanthogenate (D609) is known for its antiviral and antitumor properties. D609 actions are widely attributed to inhibiting phosphatidylcholine (PC)-specific phospholipase C (PC-PLC). D609 also inhibits sphingomyelin synthase (SMS). PC-PLC and/or SMS inhibition will affect lipid second messengers 1,2-diacylglycerol (DAG) and/or ceramide. Evidence indicates either PC-PLC and/or SMS inhibition affected the cell cycle and arrested proliferation, and stimulated differentiation in various in vitro and in vivo studies. Xanthogenate compounds are also potent antioxidants and D609 reduced Aß-induced toxicity, attributed to its antioxidant properties. Zn²⁺ is necessary for PC-PLC enzymatic activity; inhibition by D609 might be attributed to its Zn²⁺ chelation. D609 has also been proposed to inhibit acidic sphingomyelinase or down-regulate hypoxia inducible factor-1α; however these are down-stream events related to PC-PLC inhibition. Characterization of the mammalian PC-PLC is limited to inhibition of enzymatic activity (frequently measured using Amplex red assay with bacterial PC-PLC as a standard). The mammalian PC-PLC has not been cloned; sequenced and structural information is unavailable. D609 showed promise in cancer studies, reduced atherosclerotic plaques (inhibition of PC-PLC) and cerebral infarction after stroke (PC-PLC or SMS). D609 actions as an antagonist to pro-inflammatory cytokines have been attributed to PC-PLC. The purpose of this review is to comprehensively evaluate the literature and summarize the findings and relevance to cell cycle and CNS pathologies.
Topics: Animals; Antioxidants; Bridged-Ring Compounds; Cell Cycle; Central Nervous System Diseases; Humans; Norbornanes; Sphingomyelin Phosphodiesterase; Thiocarbamates; Thiones; Type C Phospholipases
PubMed: 22101393
DOI: 10.1007/s11064-011-0659-z -
Natural Product Reports Mar 2020Covering: 1990 to 2019 Many medicinally-relevant compounds are derived from non-ribosomal peptide synthetase (NRPS) products. Type I NRPSs are organized into large... (Review)
Review
Covering: 1990 to 2019 Many medicinally-relevant compounds are derived from non-ribosomal peptide synthetase (NRPS) products. Type I NRPSs are organized into large modular complexes, while type II NRPS systems contain standalone or minimal domains that often encompass specialized tailoring enzymes that produce bioactive metabolites. Protein-protein interactions and communication between the type II biosynthetic machinery and various downstream pathways are critical for efficient metabolite production. Importantly, the architecture of type II NRPS proteins makes them ideal targets for combinatorial biosynthesis and metabolic engineering. Future investigations exploring the molecular basis or protein-protein recognition in type II NRPS pathways will guide these engineering efforts. In this review, we consolidate the broad range of NRPS systems containing type II proteins and focus on structural investigations, enzymatic mechanisms, and protein-protein interactions important to unraveling pathways that produce unique metabolites, including dehydrogenated prolines, substituted benzoic acids, substituted amino acids, and cyclopropanes.
Topics: Amino Acids; Benzoic Acid; Cyclopropanes; Hydroxylation; Lactams; Macrolides; Netropsin; Peptide Synthases; Proline; Protein Interaction Maps; Pyrroles; Thiazoles; Thiones
PubMed: 31593192
DOI: 10.1039/c9np00047j -
Toxicology and Applied Pharmacology Jul 2014Mammalian flavin-containing monooxygenase (FMO) is active towards many drugs with a heteroatom having the properties of a soft nucleophile. Thiocarbamides and thiones...
Mammalian flavin-containing monooxygenase (FMO) is active towards many drugs with a heteroatom having the properties of a soft nucleophile. Thiocarbamides and thiones are S-oxygenated to the sulfenic acid which can either react with glutathione and initiate a redox-cycle or be oxygenated a second time to the unstable sulfinic acid. In this study, we utilized LC-MS/MS to demonstrate that the oxygenation by hFMO of the thioureas under test terminated at the sulfenic acid. With thiones, hFMO catalyzed the second reaction and the sulfinic acid rapidly lost sulfite to form the corresponding imidazole. Thioureas are often pulmonary toxicants in mammals and, as previously reported by our laboratory, are excellent substrates for hFMO2. This isoform is expressed at high levels in the lung of most mammals, including non-human primates. Genotyping to date indicates that individuals of African (up to 49%) or Hispanic (2-7%) ancestry have at least one allele for functional hFMO2 in lung, but not Caucasians nor Asians. In this study the major metabolite formed by hFMO2 with thioureas from Allergan, Inc. was the sulfenic acid that reacted with glutathione. The majority of thiones were poor substrates for hFMO3, the major form in adult human liver. However, hFMO1, the major isoform expressed in infant and neonatal liver and adult kidney and intestine, readily S-oxygenated thiones under test, with Kms ranging from 7 to 160 μM and turnover numbers of 30-40 min(-1). The product formed was identified by LC-MS/MS as the imidazole. The activities of the mouse and human FMO1 and FMO3 orthologs were in good agreement with the exception of some thiones for which activity was much greater with hFMO1 than mFMO1.
Topics: Animals; Cell Line; Humans; Insecta; Mice; Oxidation-Reduction; Oxygenases; Thiones; Thiourea
PubMed: 24727368
DOI: 10.1016/j.taap.2014.04.002 -
Advanced Drug Delivery Reviews Aug 2015RAFT- mediated polymerization, providing control over polymer length and architecture as well as facilitating post polymerization modification of end groups, has been... (Review)
Review
RAFT- mediated polymerization, providing control over polymer length and architecture as well as facilitating post polymerization modification of end groups, has been applied to virtually every facet of biomedical materials research. RAFT polymers have seen particularly extensive use in drug delivery research. Facile generation of functional and telechelic polymers permits straightforward conjugation to many therapeutic compounds while synthesis of amphiphilic block copolymers via RAFT allows for the generation of self-assembled structures capable of carrying therapeutic payloads. With the large and growing body of literature employing RAFT polymers as drug delivery aids and vehicles, concern over the potential toxicity of RAFT derived polymers has been raised. While literature exploring this complication is relatively limited, the emerging consensus may be summed up in three parts: toxicity of polymers generated with dithiobenzoate RAFT agents is observed at high concentrations but not with polymers generated with trithiocarbonate RAFT agents; even for polymers generated with dithiobenzoate RAFT agents, most reported applications call for concentrations well below the toxicity threshold; and RAFT end-groups may be easily removed via any of a variety of techniques that leave the polymer with no intrinsic toxicity attributable to the mechanism of polymerization. The low toxicity of RAFT-derived polymers and the ability to remove end groups via straightforward and scalable processes make RAFT technology a valuable tool for practically any application in which a polymer of defined molecular weight and architecture is desired.
Topics: Animals; Biocompatible Materials; Drug Delivery Systems; Humans; Molecular Weight; Polymerization; Polymers; Thiones
PubMed: 26050529
DOI: 10.1016/j.addr.2015.05.016 -
Inorganic Chemistry Sep 2022The complex [TEA][Tp*Mo(O)(SBMOPP)] () [TEA = tetraethylammonium, Tp* = tris(3,5-dimethylpyrazolyl)hydroborate, and BMOPP = 6-(3-butynyl-2-methyl-2-ol)-2-pivaloyl...
The complex [TEA][Tp*Mo(O)(SBMOPP)] () [TEA = tetraethylammonium, Tp* = tris(3,5-dimethylpyrazolyl)hydroborate, and BMOPP = 6-(3-butynyl-2-methyl-2-ol)-2-pivaloyl pterin] is a structural analogue of the molybdenum cofactor common to all pyranopterin molybdenum enzymes because it possesses a pyranopterin-ene-1,2-dithiolate ligand (SBMOPP) that exists primarily in the ring-closed pyrano structure as a resonance hybrid of ene-dithiolate and thione-thiolate forms. Compound , the protonated [Tp*Mo(O)(SBMOPP-H)] () and one-electron-oxidized [Tp*Mo(O)(SBMOPP)] [] species have been studied using a combination of electrochemistry, electronic absorption, and electron paramagnetic resonance (EPR) spectroscopy. Additional insight into the nature of these molecules has been derived from electronic structure computations. Differences in dithiolene C-S bond lengths correlate with relative contributions from both ene-dithiolate and thione-thiolate resonance structures. Upon protonation of to form , large spectroscopic changes are observed with transitions assigned as Mo(xy) → pyranopterin metal-to-ligand charge transfer and dithiolene → pyranopterin intraligand charge transfer, respectively, and this underscores a dramatic change in electronic structure between and . The changes in electronic structure that occur upon protonation of are also reflected in a large >300 mV increase in the Mo(V/IV) redox potential for , resulting from the greater thione-thiolate resonance contribution and decreased charge donation that stabilize the Mo(IV) state in with respect to one-electron oxidation. EPR spin Hamiltonian parameters for one-electron-oxidized and uncyclized [Tp*Mo(O)(SBDMPP)] [] [BDMPP = 6-(3-butynyl-2,2-dimethyl)-2-pivaloyl pterin] are very similar to each other and to those of [Tp*MoO(bdt)] (bdt = 1,2-ene-dithiolate). This indicates that the dithiolate form of the ligand dominates at the Mo(V) level, consistent with the demand for greater S → Mo charge donation and a corresponding increase in Mo-S covalency as the oxidation state of the metal is increased. Protonation of represents a simple reaction that models how the transfer of a proton from neighboring acidic amino acid residues to the Mo cofactor at a nitrogen atom within the pyranopterin dithiolene (PDT) ligand in pyranopterin molybdenum enzymes can impact the electronic structure of the Mo-PDT unit. This work also illustrates how pyran ring-chain tautomerization drives changes in resonance contributions to the dithiolene chelate and may adjust the reduction potential of the Mo ion.
Topics: Electron Spin Resonance Spectroscopy; Ligands; Molybdenum; Pterins; Thiones
PubMed: 36000991
DOI: 10.1021/acs.inorgchem.2c01234 -
Preventive Medicine Sep 1993Oltipraz (4-methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione) is an antischistosomal drug presently under evaluation as a possible chemoprotective agent in humans. To date,... (Review)
Review
Oltipraz (4-methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione) is an antischistosomal drug presently under evaluation as a possible chemoprotective agent in humans. To date, oltipraz has proved effective as an inhibitor of carcinogenesis in experimental models for breast, bladder, liver, forestomach, colon, tracheal, lung, and skin cancer. Studies on the mechanisms of action of oltipraz indicate that it affects the metabolism and disposition of chemical carcinogens, principally through the induction of electrophile detoxication enzymes. While this feature is common to many different classes of both natural and synthetic experimental chemoprotectors (i.e., phenolic antioxidants, isothiocyanates, flavonoids, indoles, cinnamates, coumarins, terpenes, and others), oltipraz may offer the earliest and easiest prospect for examining the role of enzyme induction as a protective strategy in humans. Unlike the situation with many of the anutrients, substantial preclinical research has already been conducted with oltipraz to establish its safety and efficacy in animals. Hopefully, Phase I investigations will demonstrate a high tolerance for oltipraz in the chemoprotective dose range of the drug. A major concern for the success of any trial is selecting participants who are likely to adhere to the intervention as well as to all aspects of the protocol. Factors influencing participation and adherence in a trial include the design of the trial, the nature of the disease under study as well as the nature of the intervention, in particular the toxicities of the intervention (J. A. Tangrea, M. E. Adrianza, and W. E. Helsel, Cancer Epi Biomarkers Prev 1992; 1:325-330). Chemoprotection trials with oltipraz have an excellent prospect for success. Individuals with known carcinogenic exposures are likely to be interested in participation in trials designed to reduce the risks of the exposures. Moreover, the availability of intermediate markers reflecting the modulation of the biologically effective dose of environmental carcinogens as study end points will enable efficient trials to be designed.
Topics: Animals; Anticarcinogenic Agents; Clinical Trials as Topic; Drug Screening Assays, Antitumor; Female; Humans; Male; Neoplasms; Neoplasms, Experimental; Pyrazines; Thiones; Thiophenes
PubMed: 8234218
DOI: 10.1006/pmed.1993.1072 -
The American Journal of Pathology Feb 2021Inflammation and oxidative stress accompany aging. This study investigated the interplay between oxidative stress and inflammation in the lacrimal gland. C57BL/6 mice...
Inflammation and oxidative stress accompany aging. This study investigated the interplay between oxidative stress and inflammation in the lacrimal gland. C57BL/6 mice were used at 2 to 3, 12, and 24 months of age. Nuclear factor erythroid derived-2-related factor 2 (Nrf2) and corresponding wild-type mice were used at 2 to 3 and 12 to 13 months of age. A separate group of 15.5 to 17 months of age C57BL/6 mice received a diet containing an Nrf2 inducer (Oltipraz) for 8 weeks. Aged C57BL/6 lacrimal glands showed significantly greater lymphocytic infiltration, higher levels of MHC II, IFN-γ, IL-1β, TNF-α, and cathepsin S (Ctss) mRNA transcripts, and greater nitrotyrosine and 4-hydroxynonenal protein. Young Nrf2 mice showed an increase in IL-1β, IFN-γ, MHC II, and Ctss mRNA transcripts compared with young wild-type mice and greater age-related changes at 12 to 13 months of age. Oltipraz diet significantly decreased nitrotyrosine and 4-hydroxynonenal and decreased the expression of IL-1β and TNF-α mRNA transcripts, while decreasing the frequency of CD45CD4 cells in lacrimal glands and significantly increasing conjunctival goblet cell density compared with a standard diet. The findings provide novel insight into the development of chronic, low-grade inflammation and oxidative stress in age-related dry eye. New therapies targeting oxidative stress pathways will be valuable in treating age-related dry eye.
Topics: Aging; Animals; Dry Eye Syndromes; Female; Inflammation; Lacrimal Apparatus; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; Oxidative Stress; Pyrazines; Thiones; Thiophenes
PubMed: 33159886
DOI: 10.1016/j.ajpath.2020.10.013 -
Chemical & Pharmaceutical Bulletin 2022An efficient synthetic method for novel 4,4-disubstituted 3,4-dihydropyrimidin-2(1H)-ones 5 and -thiones 6 was developed. The cyclocondensation reaction of...
Synthesis of 4,4-Disubstituted 3,4-Dihydropyrimidin-2(1H)-ones and -thiones, the Corresponding Products of Biginelli Reaction Using Ketone, and Their Antiproliferative Effect on HL-60 Cells.
An efficient synthetic method for novel 4,4-disubstituted 3,4-dihydropyrimidin-2(1H)-ones 5 and -thiones 6 was developed. The cyclocondensation reaction of O-methylisourea hemisulfate salt 11 with 8 gives a tautomeric mixture of dihydropyrimidines 12 and 13 following acidic hydrolysis of the cyclized products to produce 5 in high yields. Thionation reaction of 5 at the 2-position smoothly proceeds to give 2-thioxo derivatives 6. These compounds 5 and 6, corresponding to the products of a Biginelli-type reaction using urea or thiourea, a ketone and a 1,3-dicarbonyl compound, have long been inaccessible and hitherto unavailable for medicinal chemistry. These methods are invaluable for the synthesis of 5 and 6, which have been inaccessible by conventional methods. Therefore, the synthetic methods established in this study will expand the molecular diversity of their related derivatives. These compounds were also assessed for their antiproliferative effect on a human promyelocytic leukemia cell line, HL-60. Treatment of 10 µM 6b and 6d showed high inhibitory activity similarly to 1 µM all-trans retinoic acid (ATRA), indicating that the 2-thioxo group and length of two alkyl substituents at the 4-position are strongly related to activity.
Topics: Antineoplastic Agents; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; HL-60 Cells; Humans; Ketones; Molecular Structure; Pyrimidinones; Structure-Activity Relationship; Thiones
PubMed: 35110431
DOI: 10.1248/cpb.c21-00794