- New enzymatic and chemical approaches to enantiopure etodolac
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(+)- and (-)-etodolac enantiomers were prepared both by classical resolution via crystallisation of diastereoisomeric salts with (+) and (-)-α-methylbenzylamine, and by suitable manipulation of derivatives (-)-3- and (+)-4, obtained by lipase-catalysed kinetic resolution of racemic 3. X-ray diffraction analysis of the 4-bromobenzoate derivative of (+)-3, obtained from enantiopure acetate (+)-4, allowed us to determine the absolute (R) configuration of (-)-etodolac.
- Brenna, Elisabetta,Fuganti, Claudio,Fuganti, Daniela,Grasselli, Piero,Malpezzi, Luciana,Pedrocchi-Fantoni, Giuseppe
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- Design, synthesis and biological evaluation of antitumor platinum(II) agents conjugated with non-steroidal anti-inflammatory drug species
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As one of the key features of tumor, inflammation attracts much attention of many researchers for antitumor study, in which non-steroidal anti-inflammatory drugs (NSAIDs) have been widely investigated in anti-inflammatory treatments in cancers. Herein, we report a series of novel platinum(II) complexes derived from conjugation of several NSAIDs derivatives with two antitumor platinum(II) agents. The antitumor inhibitory effects of the synthesized compounds on a number of cancer cell lines were estimated. By taking the advantage of two bioactive moieties, these compounds exhibited stronger antitumor activity than their parent platinum agents, and some appeared to have capability of overcoming cisplatin resistance. Among them, IA-1 showed the best cytotoxicity and even exhibited stronger antitumor activity than cisplatin. Further research indicated that IA-1 induced significant DNA damage and ROS generation, accompanied by high cellular platinum accumulation, resulting in a much higher apoptosis rate than cisplatin in A2780 cells. Moreover, IA-1 was found to inhibit metastasis and invasion of A2780 cells by suppressing the COX-2/JAK2/STAT3 axis. All these results revealed that introduction of NSAIDs species efficiently sensitized cancer cells to the synthetic compounds, proving that NSAIDs can enhance the activity of the platinum(II) agents via inhibiting inflammation in cancer cells.
- Gou, Shaohua,Wang, Xinyi,Wang, Yuanjiang,Zang, Ju,Zhang, Bin
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- Method for preparing etodolac methyl ester
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The invention provides a method for preparing etodolac methyl ester, and relates to the technical field of organic synthesis. The method provided by the invention comprises the following steps: (1) mixing reaction raw materials, and carrying out cyclization reaction at 20-25 DEG C to obtain a reaction solution, wherein the reaction raw materials comprise 7-ethyltryptophol, methyl 3-oxovalerate, trimethyl halosilane and methanol, and do not comprise concentrated sulfuric acid, and the trimethyl halosilane is trimethyl chlorosilane or trimethyl bromosilane; and (2) cooling the reaction solutionto 10-15 DEG C, and filtering to obtain etodolac methyl ester and a mother solution. The method provided by the invention is high in yield, and concentrated sulfuric acid which has great harm and easily causes product oxidation is not used. Furthermore, the product yield is further improved through continuous application of the mother liquor, almost quantitative products can be obtained, the workload of solvent treatment is reduced, the operation is simple and convenient, and trimethyl halosilane is easy to recycle and reuse.
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Paragraph 0050-0087
(2020/07/13)
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- Novel Etodolac-Based 1,2,4-Triazole Derivatives as Antimicrobial Agents: Synthesis, Biological Evaluation, and Molecular Docking Study
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Abstract: A series of novel 1,2,4-triazole nonsteroidal anti-inflammatory drugs (NSAIDs)derived from etodolac were designed and synthesized. The synthesized compoundswere identified using 1H and13C NMR, IR, and mass spectra and elementalanalyses and evaluated for their in vitro antibacterial activity againstGram-positive microorganisms like Streptococcuspneumoniae and Klebsiellapneumoniae and Gram-negative strains such as Pseudomonas aeruginosa and Enterobacter cloacae with pefloxacin as a reference drug. Somecompounds showed a potent activity at a concentration 50 mg/mL with inhibitionzones of 30 to 36 mm against S. pneumoniae.Etodolac-derived N-isobutyl- and N-ethyl-1,2,4-triazoles containing4-methoxybenzylsulfanyl and 3-nitrobenzylsulfanyl groups were active againstP. aeruginosa with inhibition zones of25–29 mm at a concentration of 50 mg/mL. All compounds showed excellentantioxidant activity with IC50 values ranging from72.39±0.25 μg/mL to 16.39±0.65 μg/mL in comparison with ascorbic acid(IC50 16.81±0.18 μg/mL). Molecular docking studiesrevealed strong hydrogen bonding, π–π, and π–σ interactions of 3-nitro-,4-methoxy-, and 4-methylbenzyl moieties with Ser421, Val120, Tyr124, Phe319,Ala44, and Val120 amino acid residues of the active site of glycogen synthasekinase-3 (GSK-3) protein.
- Shaik,Rao,Venkatarao,Rao, S. V. M. Mohan,Kishore
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p. 2179 - 2187
(2021/02/09)
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- Synthesis, anticancer activity, and molecular modeling of etodolac-thioether derivatives as potent methionine aminopeptidase (type II) inhibitors
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A series of (R,S)-1-{[5-(substituted)sulfanyl-4-substituted-4H-1,2,4-triazole-3-yl]methyl}-1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indoles (5a–v) were designed and synthesized using a five-step synthetic protocol that involves substituted benzyl chlorides and (R,S)-5-[(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-yl)methyl]-4-substituted-2,4-dihydro-3H-1,2,4-triazole-3-thiones in the final step. The synthesized derivatives were evaluated for cytotoxicity and anticancer activity in vitro using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) colorimetric method against VERO, HEPG2 (human hepatocellular liver carcinoma), SKOV3 (ovarian carcinoma), MCF7 (human breast adenocarcinoma), PC3 and DU145 (prostate carcinoma) cells at 10?5 M (10 μM) for 24 h. Compounds 5d and 5h showed the best biological potency against the SKOV3 cancer cell line (IC50 = 7.22 and 5.10 μM, respectively) and did not display cytotoxicity toward VERO cells compared to etodolac. Compounds 5k, 5s, and 5v showed the most potent biological activity against the PC3 cancer cell line (IC50 = 8.18, 3.10, and 4.00 μM, respectively) and did not display cytotoxicity. Moreover, these compounds were evaluated for caspase-3, -9, and -8 protein expression and activation in the apoptosis pathway for 6, 12, and 24 h, which play a key role in the treatment of cancer. In this study, we also investigated the apoptotic mechanism and molecular modeling of compounds 5k and 5v on the methionine aminopeptidase (type II) enzyme active site in order to get insights into the binding mode and energy.
- ?oruh, I??l,?evik, ?zge,Yelek?i, Kemal,Djikic, Teodora,Kü?ükgüzel, ?. Güniz
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- HPLC monitoring of acid catalyzed conversion of 7-ethyltryptophol to methyl ester of etodolac
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Small scale experimental model for the preparation of methyl ester of etodolac, the key intermediate in the synthesis of nonsteroidal drug etodolac, is thoroughly investigated in order to define the key parameters needed for its large scale production. Ox
- Habinovec, Iva,Car, Zeljka,Ribic, Rosana,Galic, Nives,Novak, Predrag,Mestrovic, Ernest,Tomic, Srdanka
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- Anti-cancer and anti-hepatitis C virus NS5B polymerase activity of etodolac 1,2,4-triazoles
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Arachidonic acid is an unsaturated fatty acid liberated from phospholipids of cell membranes. NSAIDs are known as targets of cyclooxygenase enzyme (COX-1, COX-2 and COX-3) in arachidonic acid metabolism. This mechanism of COX-2 in carcinogenesis causes cancer. In addition, COX-2 plays a role in the early stages of hepatocarcinogenesis. Hepatitis C virus (HCV) infection is cause of liver cirrhosis and hepatocellular carcinoma (HCC). The aim of our study was to improve effective agents against HCV. A novel series of new etodolac 1,2,4-triazoles derivatives (4a-h) have been synthesized and investigated for their activity against HCV NS5B polymerase. Compound 4a was found to be the most active with IC50 value of 14.8 M. In accordance with these results, compound 4a was screened for anti-cancer activity on liver cancer cell lines (Huh7, Mahlavu, HepG2, FOCUS). Compound 4a showed anti-cancer activity against Huh7 human hepatoma cell line with IC50 value of 4.29 M. Therefore, compound 4a could be considered as a new anti-cancer and anti-HCV lead compound.
- ?ikla-Süzgün, Pelin,Kaushik-Basu, Neerja,Basu, Amartya,Arora, Payal,Talele, Tanaji T.,Durmaz, Irem,?etin-Atalay, Rengül,Kü?ükgüzel, ?. Güniz
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p. 778 - 785
(2015/09/15)
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- SYNTHESIS OF THIOSEMICARBAZIDES AND TRIAZOLES DERIVED FROM ETODOLAC
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A novel series of new etodolac hydrazide derivatives, 1 -[2-(1,8-diethyI- 1,3,4,9- tetrahydropyrano[3,4-b]indol-1 -yl)acetyl]-4-alkyl/aryl thiosernicarbazides [SGK224-230, SGK313] and 5-[(l,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)methyl]-4- subsrituted-2,4-dihydro-3H-1,2,4-triazole-3-thiones [SGK238-244, SGK315] have been synthesized in this study.
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Page/Page column 3, 4
(2014/01/17)
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- Synthesis, cytotoxicity, and pro-apoptosis activity of etodolac hydrazide derivatives as anticancer agents
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Etodolac hydrazide and a novel series of etodolac hydrazide-hydrazones 3-15 and etodolac 4-thiazolidinones 16-26 were synthesized in this study. The structures of the new compounds were determined by spectral (FT-IR, 1H NMR, 13C NMR, HREI-MS) methods. Some selected compounds were determined at one dose toward the full panel of 60 human cancer cell lines by the National Cancer Institute (NCI, Bethesda, USA). 2-(1,8-Diethyl-1,3,4,9- tetrahydropyrano[3,4-b]indole-1-yl)acetic acid[(4-chlorophenyl)methylene] hydrazide 9 demonstrated the most marked effect on the prostate cancer cell line PC-3, with 58.24% growth inhibition at 10-5 M (10 μM). Using the MTT colorimetric method, compound 9 was evaluated in vitro against the prostate cell line PC-3 and the rat fibroblast cell line L-929, for cell viability and growth inhibition at different doses. Compound 9 exhibited anticancer activity with an IC50 value of 54 μM (22.842 μg/mL) against the PC-3 cells and did not display any cytotoxicity toward the L-929 rat fibroblasts, compared to etodolac. In addition, this compound was evaluated for caspase-3 and Bcl-2 activation in the apoptosis pathway, which plays a key role in the treatment of cancer. Etodolac hydrazide and a novel series of etodolac hydrazide-hydrazones 3-15 and etodolac 4-thiazolidinones 16-26 were synthesized. 2-(1,8-Diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-yl)acetic acid[(4-chlorophenyl)methylene]hydrazide 9 demonstrated the most marked cell viability and growth inhibition effects. It was evaluated for caspase-3 and Bcl-2 activation in the apoptosis pathway. Copyright
- Cikla, Pelin,Oezsavci, Derya,Bingoel-Oezakpinar, Oezlem,Sener, Azize,Cevik, Oezge,Oezbas-Turan, Suna,Akbuga, Juelide,Sahin, Fikrettin,Kuecuekguezel, S. Gueniz
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p. 367 - 379
(2013/07/11)
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- Direct racemization of indole derivatives
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The present invention discloses processes for the racemization of enantiomers of etodolac and other tetra-hydropyrano indole derivatives.
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Page/Page column 9
(2008/06/13)
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- Process for the preparation of 1,8-disubstituted-1,3,4,9-tetrahydropyrano (3,4-B)-indole-1-acetic acid esters
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A process for the preparation of the esters of 1,8-disubstituted-1,3,4,9-tetrahydropyrano (3,4-b)-indole-1-acetic acid is delineated.
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- A scaleable combined resolution and improved dosage form for etodolac with recycle of the off-isomer
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An efficient resolution process using N-methyl glucamine (meglumine) which directly provides (S)-etodolac as the meglumine salt is described. This salt is also a dosage form with improved absorption characteristics. The off-isomer is efficiently racemised via the ester, prepared by mild esterification, followed by hydrolysis affording rac-etodolac suitable for recycling.
- Woods, Martin,Dyer, Ulrich C.,Andrews, John F.,Morfitt, C. Neil,Valentine, Roy,Sanderson, Joanne
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p. 418 - 426
(2013/08/07)
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- Process for the preparation of etodolac
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Process for the preparation of etodolac, comprising the following steps: a) reacting 7-ethyl-tryptophol of formula (II) with methyl 3-oxo-pentanoate of formula (III) thereby obtaining methyl 1,8-diethyl-1,3,4,9-tetrahydropyrano [3,4-bis] indole-1-acetate of formula (IV) in an apolar solvent; b) hydrolyzing the compound of formula (IV) to etodolac (I), wherein step (a) is carried out at a temperatures of between -20 DEG C. and +50 DEG C. in the presence of a concentrated mineral acid, the molar ratio of the inorganic acid to 7-ethyl-tryptophol being comprised between 0.5 and 5.
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