- Arene Osmium Complexes with Ethacrynic Acid-Modified Ligands: Synthesis, Characterization, and Evaluation of Intracellular Glutathione S-Transferase Inhibition and Antiproliferative Activity
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Four arene osmium complexes were prepared containing derivatives of ethacrynic acid, a potent inhibitor of glutathione S-transferases, either by direct coordination or via N- or P-donor ligands. The complexes were characterized by spectroscopic and analytical methods and, for Os(η6-p-cymene)(acetylacetonato)(2-(2,3-dichloro-4-(2-ethylenebutanoyl)phenoxy)acetato) and Os(η6-p-cymene)Cl2(2-(2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)acetoxy)ethyl nicotinato), by single-crystal X-ray diffraction. The cytotoxicity of the complexes toward human ovarian cancer cells and nontumorous human embryonic kidney cells was investigated, and two of the complexes, for which ruthenium analogues are known, helped to delineate the influence of the metal ion. Inhibition studies of intracellular glutathione S-transferases (GSTs, detoxification enzymes implicated in drug resistance) indicate that the observed cytotoxicity of the complexes involves GST inhibition, as well as other targets following dissociation of the ethacrynic acid group from the osmium(II) ion.
- Agonigi, Gabriele,Riedel, Tina,Gay, M. Pilar,Biancalana, Lorenzo,O?ate, Enrique,Dyson, Paul J.,Pampaloni, Guido,Pǎunescu, Emilia,Esteruelas, Miguel A.,Marchetti, Fabio
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- Development of an Efficient Dual-Action GST-Inhibiting Anticancer Platinum(IV) Prodrug
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The cytotoxicity of cisplatin (cDDP) is enhanced when co-administered with ethacrynic acid (EA), a glutathione S-transferase (GST) inhibitor. A PtIV–EA conjugate containing a cDDP core and two axial ethacrynate ligands (compound 1) was shown to be an excellent inhibitor of GST, but did not readily release a PtII species to exert a synergistic cytotoxic effect. In this study, a redesigned PtIV construct composed of a cDDP core with one axial ethacrynate ligand and one axial hydroxido ligand (compound 2) was prepared and shown to overcome the limitations of compound 1. The EA ligand in 2 is readily released in vitro together with a cytotoxic PtII species derived from cisplatin, working together to inhibit cell proliferation in cDDP-resistant human ovarian cancer cells. The in vitro activity translates well in vivo with 2, showing effective (~80 %) inhibition of tumor growth in a human ovarian carcinoma A2780 tumor model, while showing considerably lower toxicity than cisplatin, thus validating the new design strategy.
- Lee, Keefe Guang Zhi,Babak, Maria V.,Weiss, Andrea,Dyson, Paul J.,Nowak-Sliwinska, Patrycja,Montagner, Diego,Ang, Wee Han
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p. 1210 - 1217
(2018/06/04)
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- Process for the Preparation of Ethacrynic Acid
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The invention provides an improved process for preparing Ethacrynic acid of formula I, including the steps of: (a) reacting 4-butyryl-2,3-dichloro-phenoxy acetic acid of formula II with dimethylamine or its salt to obtain [2,3-dichloro-4-[2-dimethylaminomethyl butyryl phenoxy acetic acid of formula III or its salt; (b) hydrolysing [2,3-dichloro-4-[2-dimethylaminomethyl butyryl phenoxy acetic acid hydrochloride of formula III obtained in step a) with t-butyl amine to obtain t-butyl amine salt of Ethacrynic acid; (c) acidifying the t-butyl amine salt of Ethacrynic acid formed in step b) to obtain Ethacrynic acid of formula I; and(d) optionally purifying the obtained Ethacrynic acid with a solvent mixture of alkyl acetate and hydrocarbon solvent. The invention also provides crystalline t-butylamine salt of Ethacrynic acid and process thereof. Also provide compound Ethacrynic acid having a purity of greater than or equal to 99% and a composition including the compound.
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Paragraph 0080
(2018/05/03)
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- Synthesis and spectroscopic/DFT structural characterization of coordination compounds of Nb(V) and Ti(IV) with bioactive carboxylic acids
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The reactions are reported of NbX5 (X = Cl, Br), TiCl4 and Ti(OiPr)4 with a selection of carboxylic acids exhibiting a known biological role, in a chlorinated solvent. The reactions of NbX5 with acetylsalicylic acid (aspirin) proceeded with selective deacetylation of the organic reactant and formation of the salicylate complexes NbX4(C7H5O3) (1a, X = Cl; 1b, X = Br) in 60–65% yields. NbCl5 reacted with diclofenac and ethacrynic acid (EA-CO2H) to give NbCl3[κ3O,O,N-O2CCH2(C6H4)NC6H3Cl2], 2 (80% yield), and NbCl4(O2C-EA), 3 (72% yield), respectively. Ti(OiPr)4 reacted with ethacrynic acid giving Ti(OiPr)2(O2C-EA)2, 4, in 74% yield, as a mixture of two isomers. All the products were characterized by means of analytical and spectroscopic methods, moreover DFT studies were carried out to give insight into structural features.
- De Palo, Alice,Biancalana, Lorenzo,Bortoluzzi, Marco,Alessandra Martini, Maria,Marchetti, Fabio,Pampaloni, Guido
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p. 208 - 214
(2017/12/26)
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- Environmental-protection preparation method for high yielding of 1,2,4-oxadiazole compounds containing alpha,beta-unsaturated ketones
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The invention provides an environmental-protection preparation method for high yielding of 1,2,4-oxadiazole compounds containing alpha,beta-unsaturated ketones; with 2,3-dichlorophenol as a raw material, an intermediate 5 is obtained through methylation and protection of phenolic hydroxyl groups, Friedel-Crafts acylation, methyl protecting group removal, nucleophilic substitution, ester hydrolysis, aldol condensation and dehydration reaction and then undergoes cyclization reaction with substituted amine oxime to obtain the target products 6r, 6s and 6u. The method has the advantages of mild reaction conditions, has no use of first-class reagents and other reagents harmful on the environment and operating personnel, fewer by-products, stable and controllable reactions, simple postprocessing, high yield and purity, and easy industrialized production.
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- Ethacrynic acid as a lead structure for the development of potent urease inhibitors
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Ethacrynic acid and a series of its analogues were synthesized and subsequently evaluated for their inhibitory effect on jack bean urease. Ethacrynic acid showed, even at low concentrations, very potent inhibitory activity against the enzyme. For ethacrynic acid, the inhibition potential increased with increasing preincubation time of ethacrynic acid and enzyme, whereas for some other compounds a higher preincubation time lead to a significant reduction of their activity. We could demonstrate that the α,β-unsaturated carbonyl unit of our compounds is mandatory to inhibit the enzyme, possibly due to its ability to bind to cysteine residues in the active site of the jack bean urease.
- Janser, Ingo,Vortolomei, Caitlyn M.,Meka, Ranjith K.,Walsh, Courtney A.,Janser, Romy F.J.
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p. 660 - 664
(2013/08/15)
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- Synthesis and Evaluation of Non-peptidic Cysteine Protease Inhibitors of P. falciparum Derived from Etacrynic Acid
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A series of etacrynic acid derivatives was synthesized and screened for their in vitro activity against Plasmodium falciparum, as well as their activity against recombinantly expressed falcipain-2 and -3. The two most active compounds of the series displayed IC50 values of 9.0 and 18.8 μM against Plasmodia.
- Dude, Marie-Adrienne,Kaeppler, Ulrich,Herb, Monika,Schiller, Markus,Schulz, Franziska,Vedder, Birgit,Heppner, Saskia,Pradel, Gabriele,Gut, Jiri,Rosenthal, Philip J.,Schirmeister, Tanja,Leippe, Matthias,Gelhaus, Christoph
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scheme or table
p. 19 - 35
(2009/09/08)
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- Process for preparation of alpha-aryloxy acetic acids and their salts
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A process for producing aryloxy acetic acids and salts thereof which comprises reacting an alcohol of the formula R-OH wherein R is aryl or substituted aryl with a base in an aprotic organic solvent to give an aryloxide followed by removal of the organic solvent and reaction of the aryloxide with a salt of a monohaloacetic acid in a polar aprotic solvent such as DMSO to give the corresponding aryloxyacetate salt which then may be recovered or may optionally be converted to the corresponding acid by contacting the aryloxyacetate salt with an acid.
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- 2,3-dihydrobenzofuran-5-sulfonamide derivatives useful as antihypertensive diuretic agents
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Highly effective diuretic antihypertensives, i.e., 2,3-dihydrobenzofuran-5-sulfonamide derivatives which is classified to loop diuretics with less adverse side-effects and can be administered orally at a daily dosage of 0.5-200 mg or parenterally of 0.01-50 mg.
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