- A novel H2S releasing-monastrol hybrid (MADTOH) inhibits L-type calcium channels
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A new alleged monastrol-H2S releasing hybrid, named MADTOH, was designed based on the structure of monastrol (M) and 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (ADTOH) and synthesized in 7.8% overall yield. MADTOH was shown to be an H2S donor under physiological conditions. In addition, the hybrid causes a decrease in global calcium transient in cardiomyocytes similar to nifedipine (NIFE), taken as a positive control. Whole-cell voltage-clamp showed that MADTOH decreases L-type Ca2+ current in isolated ventricular cardiomyocytes.
- Braga, Taniris Cafiero,De Jesus, Itamar Couto Guedes,Soares, Kathleen Viveiros,Guatimosim, Silvia,Da Silva Neto, Leonardo,Da-Silva, Cristiane Jovelina,Modolo, Luzia Valentina,Menezes Filho, José Evaldo Rodrigues,Rhana, Paula,Cruz, Jader Santos,De Fátima, ?ngelo
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p. 671 - 678
(2021/01/25)
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- Gallic acid hydrogen sulfide derivative and preparation method and medical application thereof
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The invention discloses a gallic acid hydrogen sulfide derivative and a preparation method and medical application thereof. The general formula of the gallic acid hydrogen sulfide derivative is A-Y-X,and A is gallic acid; Y is -C (O) O-, -C (O) NH-, -C (O) OC (O)-, -C (O) NHCH2 C (O)- or is absent, and when Y is absent, the compound is A-X; X is a moiety capable of releasing hydrogen sulfide alone or in combination with A. Compared with gallic acid and existing classic non-steroidal anti-inflammatory drugs, the gallic acid hydrogen sulfide derivative has the advantages that the anti-inflammatory activity is equivalent or enhanced, the side effects of gastrointestinal tracts and cardiovascular diseases are weakened, and the gallic acid hydrogen sulfide derivative has high anti-tumor activity and good cardiovascular and neuroprotective effects.
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Paragraph 0063-0066
(2021/03/31)
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- Synthesis of Dithiolethiones and Identification of Potential Neuroprotective Agents via Activation of Nrf2-Driven Antioxidant Enzymes
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Oxidative stress is implicated in the pathogenesis of a wide variety of neurodegenerative disorders, and accordingly, dietary supplement of exogenous antioxidants or/and upregulation of the endogenous antioxidant defense system are promising for therapeutic intervention or chemoprevention of neurodegenerative diseases. Nrf2, a master regulator of the cellular antioxidant machinery, cardinally participates in the transcription of cytoprotective genes against oxidative/electrophilic stresses. Herein, we report the synthesis of 59 structurally diverse dithiolethiones and evaluation of their neuroprotection against 6-hydroxydopamine-or H2O2-induced oxidative damages in PC12 cells, a neuron-like rat pheochromocytoma cell line. Initial screening identified compounds 10 and 11 having low cytotoxicity but conferring remarkable protection on PC12 cells from oxidative-mediated damages. Further studies demonstrated that both compounds upregulated a battery of antioxidant genes as well as corresponding genes' products. Significantly, silence of Nrf2 expression abolishes cytoprotection of 10 and 11, indicating targeting Nrf2 activation is pivotal for their cellular functions. Taken together, the two lead compounds discovered here with potent neuroprotective functions against oxidative stress via Nrf2 activation merit further development as therapeutic or chemopreventive candidates for neurodegenerative disorders.
- Bai, Feifei,Fang, Jianguo,Song, Zi-Long,Zhang, Baoxin
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p. 2214 - 2231
(2020/03/06)
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- Method for synthesizing 1,2-disulfide-3-thioketone derivative by using copper to catalyze
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The invention relates to a method for synthesizing 1,2-disulfide-3-thioketone derivative by copper-catalyzed propargylamine sulfur cyclization, and the method comprises the following steps: N, N-dimethyl-3-phenyl propyl-2-alkynyl-1-amine is taken as a substrate, cuprous chloride, cuprous bromide or cuprous iodide is added into the substrate to serve as a catalyst, potassium phosphate, sodium bicarbonate or sodium acetate is taken as an alkali, elemental sulfur is taken as a sulfur source, stirring reaction is performed in a solvent for 12 hours at the temperature of 100-120 DEG C. The elemental sulfur is used as the sulfur source, and the method has the advantages of simple and easily available raw materials, simple reaction operation, relatively mild conditions, wide substrate universality, relatively high yield and good functional group compatibility.
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Paragraph 0020
(2019/06/12)
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- Copper-Catalyzed Tandem Sulfuration/Annulation of Propargylamines with Sulfur via C-N Bond Cleavage
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Copper-catalyzed aerobic oxidative sulfuration and annulation of propargylamines with elemental sulfur is described. The tandem reaction involves C-N bond cleavage and the formation of multiple C-S bonds, affording 1,2-dithiole-3-thiones in good to excellent yields with good functional group tolerance.
- Xu, Hong-Hui,Zhang, Xiao-Hong,Zhang, Xing-Guo
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p. 7894 - 7900
(2019/06/27)
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- 1,2-dithio-3-thioketone derivative synthesized by cyclizing of fluorine-sulfur removal of trifluoropropyne via copper catalyzing
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The invention discloses a 1,2-dithio-3-thioketone derivative synthesized by cyclizing of fluorine-sulfur removal of trifluoropropyne via copper catalyzing. The 1,2-dithio-3-thioketone derivative is prepared by the following steps of using a 2-chloro-3,3,3-trifluoro-1 propene compound as a primer; adding cuprous bromide as a catalyst into the primer, using cesium carbonate as alkaline, using tetramethylethylenediamine as a ligand, using elemental sulfur as a sulfur source, and stirring to react for 12 hours in a N,N-dimethyl formamide solvent at the temperature of 120 DEG C; after reaction is finished, filtering a reaction liquid, extracting a filtrate twice by a saturated sodium chloride solution, reversely extracting once, separating to obtain an organic phase, and drying with anhydrous sodium sulfate; filtering again, and removing the solvent out of the filtrate by a rotary evaporator, so as to obtain the remaining matter; performing column chromatography separating on the remainingmatter by a silicon gel column, spraying by an elution solution, and collecting an effluent solution containing the target product; combining the effluent solution, concentrating under the vacuum condition, and removing the solvent, so as to obtain the target product. The 1,2-dithio-3-thioketone derivative has the advantages that the raw materials are simple and are easy to obtain, the preparationtechnology is novel and simple, the pollution is little, the energy consumption is low, and the yield rate is high.
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Paragraph 0030
(2018/11/03)
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- Copper-Catalyzed Defluorinative Thioannulation of Trifluoropropynes for the Synthesis of 1,2-Dithiole-3-thiones
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A simple and practical strategy for the preparation of 1,2-dithiole-3-thiones via copper-catalyzed defluorinative thioannulation of trifluoropropynes has been developed using elemental sulfur as the sole sulfur source. This reaction displays a wide substrate scope and high functional group tolerance to afford the corresponding S-heterocycles in moderate to good yields and features efficient construction of multiple C?S bonds through C?F bond cleavage of CF3 groups. (Figure presented.).
- Wei, Feng,Shen, Xiao-Qin,Zhang, Xiao-Hong,Zhang, Xing-Guo
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p. 3911 - 3915
(2018/09/21)
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- Convenient method for the synthesis of 5-(4-methoxyphenyl)-3H-1,2-dithiole-3-thione (ADT-OMe) and 5-(4-hydroxyphenyl)-3H-1,2-dithiol-3-thione (ADT-OH) using microwave irradiation
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A convenient method is described for the rapid synthesis of 5-(4-methoxyphenyl)-3H-1,2-dithiole-3-thione (ADT-OMe) from anethole and elemental sulfur using microwave irradiation. Various reaction conditions were applied to reduce the reaction time from several hours to 10?min, resulting in an improvement in yield and overcoming the undesired by-product formation associated with conventional methods. 5-(4-Hydroxyphenyl)-3H-1,2-dithiol-3-thione (ADT-OH) was obtained by the deprotection of ADT-OMe using pyridine hydrochloride under microwave irradiation.
- Pournara, Dimitra,Heropoulos, Georgios A.,Koufaki, Maria
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supporting information
p. 2378 - 2380
(2017/05/29)
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- Switching Selectivity of α-Enolic Dithioesters: One Pot Access to Functionalized 1,2- and 1,3-Dithioles
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An operationally simple cascade protocol has been developed for the construction of 1,2- and 1,3-dithiole derivatives from α-enolic dithioesters. 1,2-Dithioles are achieved by the reaction of dithioesters with elemental sulfur in the presence of InCl3 under solvent-free conditions. 1,3-Dithioles have been constructed via DABCO mediated self-coupling of dithioesters in open air enabling the formation of two new C-S bonds and one ring in a single operation in contiguous fashion. The reactions proceeded smoothly affording the desired sulfur-rich heterocycles in good to excellent yields, exhibiting gram-scale ability and broad functional group tolerance utilizing easy to handle cheap and easily available reagents. The probable mechanisms for the formation of 1,2- and 1,3-dithioles from α-enolic dithioesters have been suggested.
- Koley, Suvajit,Chanda, Tanmoy,Samai, Subhasis,Singh, Maya Shankar
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p. 11594 - 11602
(2016/12/09)
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- Synthesis of Amino-ADT Provides Access to Hydrolytically Stable Amide-Coupled Hydrogen Sulfide Releasing Drug Targets
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As additional physiological functions of hydrogen sulfide (H2S) are discovered, developing practical methods for exogenous H2S delivery is important. In particular, nonsteroidal anti-inflammatory drugs (NSAIDs) functionalized with H2S-releasing anethole dithiolethione (ADT-OH) through ester bonds are being investigated for their combined anti-inflammatory and antioxidant potential. The chemical robustness of the connection between drug and H2S-delivery components, however, is a key and controllable linkage in these compounds. Because esters are susceptible to hydrolysis, particularly under acidic conditions such as stomach acid in oral drug delivery applications, we report here a simple synthesis of amino-ADT (ADT-NH2) and provide conditions for successful ADT-NH2 derivatization with the drugs naproxen and valproic acid. Using UV-vis spectroscopy and HPLC analysis, we demonstrate that amide-functionalized ADT derivatives are significantly more resistant to hydrolysis than ester-functionalized ADT derivatives.
- Hammers, Matthew D.,Singh, Loveprit,Montoya, Leticia A.,Moghaddam, Alan D.,Pluth, Michael D.
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supporting information
p. 1349 - 1353
(2016/06/01)
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- Synthesis and Pharmacological Evaluation of Novel Adenine-Hydrogen Sulfide Slow Release Hybrids Designed as Multitarget Cardioprotective Agents
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This work deals with the design, synthesis, and evaluation of the cardioprotective properties of a number of novel hybrid compounds combining the adenine nucleus with a suitable H2S slow-releasing moiety, coupled via a stable ether bond. The H2S release rate of the hybrids and their ability to increase cGMP were estimated in vitro. The most promising derivatives 4 and 11, both containing 4-hydroxythiobenzamide moiety as H2S donor, were selected for further in vivo evaluation. Their ability to release H2S in vivo was recorded using a new fully validated UPLC-DAD method. Both compounds reduced significantly the infarct size when administered at the end of sustained ischemia. Mechanistic studies showed that they conferred enhanced cardioprotection compared to adenine or 4-hydroxythiobenzamide. They activate the PKG/PLN pathway in the ischemic myocardium, suggesting that the combination of both pharmacophores results in synergistic cardioprotective activity through the combination of both molecular pathways that trigger cardioprotection.
- Lougiakis, Nikolaos,Papapetropoulos, Andreas,Gikas, Evangelos,Toumpas, Spyridon,Efentakis, Panagiotis,Wedmann, Rudolf,Zoga, Anastasia,Zhou, Zhongmin,Iliodromitis, Efstathios K.,Skaltsounis, Alexios-Leandros,Filipovic, Milos R.,Pouli, Nicole,Marakos, Panagiotis,Andreadou, Ioanna
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p. 1776 - 1790
(2016/03/22)
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- 3H-1,2-DITHIOCYCLOPENTENE-3-THIOKETONE COMPOUNDS AND APPLICATION THEREOF
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The present invention relates to the field of medicaments, and in particular relates to 3H-1,2-dithiocyclopentene-3-thione compounds and application thereof. 3H-1,2-dithiocyclopentene-3-thione compounds disclosed by the invention have new structures shown in formula I or formula II. Proved by experiments, 3H-1,2-dithiocyclopentene-3-thione compounds can directly protect neurons in a cellular model, and can significantly restrain excessive inflammatory responses of brain inflammatory cells; and by using 3H-1,2-dithiocyclopentene-3-thione, focal ischemic cerebral infarct volumes of mice can be remarkably reduced in an animal model. Therefore, the invention provides the application of 3H-1,2-dithiocyclopentene-3-thione compounds and pharmaceutically acceptable salts thereof in the preparation of medicaments for preventing or treating cerebral apoplexy diseases.
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Paragraph 0029; 0036
(2015/07/15)
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- 3-H-[1,2]Dithiole as a new anti-trypanosoma cruzi chemotype: Biological and mechanism of action studies
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The current pharmacological Chagas disease treatments, using Nifurtimox or Benznidazole, show limited therapeutic results and are associated with potential side effects, like mutagenicity. Using random screening we have identified new chemotypes that were able to inhibit relevant targets of the Trypanosoma cruzi. We found 3H-[1,2]dithioles with the ability to inhibit Trypanosoma cruzi triosephosphate isomerase (TcTIM). Herein, we studied the structural modifications of this chemotype to analyze the influence of volume, lipophilicity and electronic properties in the anti-T. cruzi activity. Their selectivity to parasites vs. mammalian cells was also examined. To get insights into a possible mechanism of action, the inhibition of the enzymatic activity of TcTIM and cruzipain, using the isolated enzymes, and the inhibition of membrane sterol biosynthesis and excreted metabolites, using the whole parasite, were achieved. We found that this structural framework is interesting for the generation of innovative drugs for the treatment of Chagas disease.
- Couto, Marcos,Sánchez, Carina,Dávila, Belén,Machín, Valentina,Varela, Javier,álvarez, Guzmán,Cabrera, Mauricio,Celano, Laura,Aguirre-López, Beatriz,Cabrera, Nallely,De Gómez-Puyou, Marieta Tuena,Gómez-Puyou, Armando,Pérez-Montfort, Ruy,Cerecetto, Hugo,González, Mercedes
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p. 14595 - 14610
(2015/09/21)
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- PROSTAGLANDIN PHARMACEUTICAL COMPOSITIONS
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The present invention relates to new prostaglandin derivatives having improved pharmacological activity and enhanced tolerability. They can be employed for the treatment of glaucoma and ocular hypertension.
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Page/Page column 4
(2010/07/08)
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- NEW ANTICANCER COMPOUNDS
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The present invention relates to new polysulf urated compounds containing 2 or more sulphur atoms belonging to the class of organic thiosulf onates, or dithiole-thione derivatives cyclic or linear, or trithiocarbonates for the use alone or in combination with other anticancer treatments for the treatment and/or prevention of cancer and inflammatory diseases.
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Page/Page column 17-18
(2009/06/27)
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- NEW AGENTS FOR THE TREATMENT OF THE LOW URINARY TRACT DYSFUNCTIONS
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The present invention relates to novel compounds that are derivatives of 5 -phosphodiesterase inhibitors that comprise in their formula a polysulfurated group and that are useful for treating dysfunctions of low urinary tract such as incontinence, benign prostatic hyperplasia and erectile dysfunction.
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Page/Page column 20
(2009/04/25)
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- 5-Fluorouracil derivatives and their use for the treatment of cancer
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The present invention relates to 5-fluoropyrimidine compounds of formula I that are useful for preventing, treating or reducing tumoral diseases and pathological conditions involving various cancer forms.
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Page/Page column 6
(2008/12/06)
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- PROSTAGLANDIN PHARMACEUTICAL COMPOSITIONS
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The present invention relates to new prostaglandin derivatives having improved pharmacological activity and enhanced tolerability. They can be employed for the treatment of glaucoma and ocular hypertension.
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Page/Page column 17-18
(2009/01/20)
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- Cardiovascular agents
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The present invention relates to novel compounds that are derivatives of angiotensin receptor blocker (ARB) that comprise in their formula a polysulfurated group and that are useful for treating cardio-vascular diseases, such as hypertension, ischemic heart disease, atherosclerosis, metabolic syndrome, etc. also in combination with other cardiovascular agents.
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Page/Page column 9
(2008/12/04)
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- COMPOUNDS FOR TREATING METABOLIC SYNDROME
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Compounds of general formula (I), wherein R’, R, x and z have the meaning reported in the specification, are useful for treating inflammatory diseases including metabolic syndrome, diabetes, obesity, dyslipidemia, and insulin resistance.
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Page/Page column 16-19
(2008/06/13)
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- SULINDAC DERIVATIVES FOR TREATMENT OF CANCER
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The present invention relates to novel non steroidal anti-inflammatory compounds (NSAIDs) derivatives of sulindac, for the treatment/prevention, alone or in combination, of cancer.
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Page/Page column 13-14
(2008/06/13)
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- NEW ANTI-INFLAMMATORY COMPOUNDS
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The present invention relates to novel non steroidal anti-inflammatory compounds (NSAIDs) that release hydrogen sulfide (H2S). The present invention also provides methods for treating, preventing and/or reducing inflammation-associated diseases by releasing H2S in the cardiovascular, connective tissue, pulmonary, gastrointestinal, respiratory, urogenital, nervous, or cutaneous systems as well as infective diseases employing said compounds.
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Page/Page column 8-10
(2008/06/13)
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- New nuclear transcription factors regulators
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The present invention relates to novel compounds that are nuclear transcription factors (NTF) regulators. The present invention also provides methods for treating, preventing and/or reducing inflammation-associated diseases by regulating NTF in the cardiovascular, connective tissue, pulmonary, gastrointestinal, respiratory, urogenital, nervous, or cutaneous systems as well as tumoral and infective diseases employing said compounds. The present invention is based on the discovery that it is possible to link regulators of NTF to a pharmacologically active compound helpful for treating disorders in the cardiovascular, connective tissue, pulmonary, gastrointestinal, respiratory, urogenital, nervous, or cutaneous systems or tumoral and infective diseases. The resulting compounds have good bioavailability, increased activity and/or safety.
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Page/Page column 5
(2008/06/13)
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- Dianions of 3-oxodithioic acids: Preparation and conversion to 3H-1,2-dithiole-3-thiones
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Reaction of ketones with CS2 and 2 equivalents of KH in THF-N,N'-dimethylpropyleneurea solution produces the dianions of 3-oxodithioic acids. These dianions are converted in good yield to 3H-1,2-dithiole-3-thiones by the sequential action of hexamethyldisilathiane and an oxidizing agent such as hexachloroethane. (C) 2000 Elsevier Science Ltd.
- Curphey,Libby
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p. 6977 - 6980
(2007/10/03)
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