26171-23-3Relevant articles and documents
Design, synthesis, anticancer evaluation, and molecular modelling studies of novel tolmetin derivatives as potential VEGFR-2 inhibitors and apoptosis inducers
Doghish, Ahmed S.,Gedawy, Ehab M.,Hamed, Mohammed I. A.,Hassan, Rasha A.,Kassab, Asmaa E.
, p. 922 - 939 (2021)
Novel tolmetin derivatives 5a–f to 8a–c were designed, synthesised, and evaluated for antiproliferative activity by NCI (USA) against a panel of 60 tumour cell lines. The cytotoxic activity of the most active tolmetin derivatives 5b and 5c was examined against HL-60, HCT-15, and UO-31 tumour cell lines. Compound 5b was found to be the most potent derivative against HL-60, HCT-15, and UO-31 cell lines with IC50 values of 10.32 ± 0.55, 6.62 ± 0.35, and 7.69 ± 0.41 μM, respectively. Molecular modelling studies of derivative 5b towards the VEGFR-2 active site were performed. Compound 5b displayed high inhibitory activity against VEGFR-2 (IC50 = 0.20 μM). It extremely reduced the HUVECs migration potential exhibiting deeply reduced wound healing patterns after 72 h. It induced apoptosis in HCT-15 cells (52.72-fold). This evidence was supported by an increase in the level of apoptotic caspases-3, -8, and -9 by 7.808-, 1.867-, and 7.622-fold, respectively. Compound 5b arrested the cell cycle in the G0/G1 phase. Furthermore, the ADME studies showed that compound 5b possessed promising pharmacokinetic properties.
Synthesis of Tolmetin Hydrazide-Hydrazones and Discovery of a Potent Apoptosis Inducer in Colon Cancer Cells
Kü?ükgüzel, ?. Güniz,Ko?, Derya,?ikla-Süzgün, Pelin,?zsavci, Derya,Bing?l-?zakpinar, ?zlem,Mega-Tiber,Orun, Oya,Erzincan,Sa?-Erdem, Safiye,?ahin, Fikrettin
, p. 730 - 742 (2015)
Tolmetin hydrazide and a novel series of tolmetin hydrazide-hydrazones 4a-l were synthesized in this study. The structures of the new compounds were determined by spectral (FT-IR, 1H NMR) methods. N′-[(2,6-Dichlorophenyl)methylidene]-2-[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]acetohydrazide (4g) was evaluated in vitro using the MTT colorimetric method against the colon cancer cell lines HCT-116 (ATCC, CCL-247) and HT-29 (ATCC, HTB-38) to determine growth inhibition and cell viability at different doses. Compound 4g exhibited anti-cancer activity with an IC50 value of 76 μM against colon cancer line HT-29 (ATCC, HTB-38) and did not display cytotoxicity toward control NIH3T3 mouse embryonic fibroblast cells compared to tolmetin. In addition, this compound was evaluated for caspase-3, caspase-8, caspase-9, and annexin-V activation in the apoptotic pathway, which plays a key role in the treatment of cancer. We demonstrated that the anti-cancer activity of this compound was due to the activation of caspase-8 and caspase-9 involved in the apoptotic pathway. In addition, in this study, we investigated the catalytical effect of COX on the HT-29 cancer line, the apoptotic mechanism, and the moleculer binding of tolmetin and compound 4g on the COX enzyme active site. The tolmetin hydrazone N′-[(2,6-dichlorophenyl)methylidene]-2-[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]acetohydrazide (4g) exhibited anticancer activity with an IC50 value of 76 μM against HT-29 cells and did not display cytotoxicity toward control fibroblast cells, compared to tolmetin. The anti-cancer activity of 4g was shown to be due to the activation of caspase-8 and caspase-9 involved in apoptosis.
Synthetic method of non-steroidal antiinflammatory drug pain killing
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Paragraph 0068; 0079-0080, (2021/04/17)
The invention discloses a synthesis method of non-steroidal anti-inflammatory drug tolmetin. The methodcomprises the following steps: sequentially preparing a sulfuric acid-containing acetonedicarboxylic acid crude product, 2-(2-acetoxy)-1-methyl-1H-pyrrole-3-formic acid and 2-(2-alkyl acetate)-1-methyl-1H-pyrrole-3-formic acid by taking citric acid or citric acid monohydrate as a raw material; and carrying out decarboxylation, acylation, hydrolysis and acidification to obtain tolmetin. The synthetic method provided by the invention overcomes the defect that the existing tolmetin preparation process depends on N-methylpyrrole, and is a low-cost, low-pollution and high-yield synthetic method of non-steroidal anti-inflammatory drug tolmetin.
Selective PdII-Catalyzed Acylation of Pyrrole with Aldehydes. Application to the Synthesis of Celastramycin Analogues and Tolmetin
Santiago, Carlos,Rubio, Ibon,Sotomayor, Nuria,Lete, Esther
, p. 4284 - 4295 (2020/05/25)
The PdII-catalyzed C-2 acylation of pyrrole with aldehydes in the presence of TBHP as oxidant has been studied for the synthesis of di(hetero)aryl ketones. The use of 2-pyrimidine as directing group leads to 2-acylpyrroles in moderate to good yields, although 2,5-diacylpyrroles are obtained as by products. This side-reaction could be avoided using 3-methy-2-pyridine as directing group, obtaining selectively 2-acylpyrroles. The reaction has been extended to a series of aromatic and heteroaromatic aldehydes, obtaining the best results with electron rich aromatic aldehydes. The methodology has been applied in the synthesis of pyrrolomycin alkaloid Celastramycin analogues and for an improved synthesis of Tolmetin, a nonsteroidal anti-inflammatory drug.
Isotope labelling by reduction of nitriles: Application to the synthesis of isotopologues of tolmetin and celecoxib
Ellis-Sawyer, Kate,Bragg, Ryan A.,Bushby, Nick,Elmore, Charles S.,Hickey, Michael J.
, p. 213 - 220 (2017/04/10)
The aryl methyl group is found in many drug-like compounds, but there are limited ways of preparing compounds with an isotope label in this methyl position. The process of cyanation of an aryl halide followed by complete reduction of the nitrile to a methyl group was investigated as a route for preparing stable and radiolabelled isotopologues of drug-like compounds. Using this methodology, carbon-13, deuterium, carbon-14, and tritium labelled isotopologues of the nonsteroidal anti-inflammatory drug tolmetin were produced, as well as carbon-13, deuterium, and carbon-14 labelled isotopologues of another nonsteroidal anti-inflammatory drug, celecoxib. The radiolabelled compounds were produced at high specific activity and the stable isotope labelled compounds with high incorporation making them suitable for use as internal standards in mass spectrometry assays. This approach provides a common synthetic route to multiple isotopologues of compounds using inexpensive and readily available labelled starting materials.
Radical-promoted site-specific cross dehydrogenative coupling of heterocycles with nitriles
Liu, Zhong-Quan,Li, Zejiang
, p. 14278 - 14281 (2016/12/16)
A first free-radical triggered site-specific cross dehydrogenative coupling reaction of heterocycles with simple nitriles is developed. It allows efficient and facile access to various C-2 cyanoalkylated furans, thiophenes, indoles, and pyrroles. The extremely high selectivities in this case indicate that functionalization of an inert C-H bond could be well-controlled by radical initiation.
An Electrophilic Approach to the Palladium-Catalyzed Carbonylative C-H Functionalization of Heterocycles
Tjutrins, Jevgenijs,Arndtsen, Bruce A.
supporting information, p. 12050 - 12054 (2015/10/05)
A palladium-catalyzed approach to intermolecular carbonylative C-H functionalization is described. This transformation is mediated by PtBu3-coordinated palladium catalyst and allows the derivatization of a diverse range of heterocycles, including pyrroles, indoles, imidazoles, benzoxazoles, and furans. Preliminary studies suggest that this reaction may proceed via the catalytic formation of highly electrophilic intermediates. Overall, this provides with an atom-economical and general synthetic route to generate aryl-(hetero)aryl ketones using stable reagents (aryl iodides and CO) and without the typical need to exploit pre-metalated heterocycles in carbonylative coupling chemistry.
Friedel - Crafts acylation of pyrroles and indoles using 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) as a nucleophilic catalyst
Taylor, James E.,Jones, Matthew D.,Williams, Jonathan M. J.,Bull, Steven D.
, p. 5740 - 5743 (2011/03/18)
1,5-Diazabicyclo[4.3.0]non-5-ene (DBN) has been shown to be an effective catalyst for the regioselective Friedel - Crafts C-acylation of pyrroles and indoles in high yields. A detailed mechanistic study implies that DBN is acting as a nucleophilic organocatalyst, with the X-ray crystal structure of a key N-acyl-amidine intermediate having been determined for the first time.
Synthesis and process optimization of amtolmetin: An antiinflammatory agent
Reddy, Lekkala Amarnath,Chakraborty, Saurya,Swapna, Rodda,Bhalerao, Dinesh,Malakondaiah, Golla China,Ravikumar, Mylavarapu,Kumar, Abhijeet,Reddy, Gade Srinivas,Naram, Jyothirmayi,Dwivedi, Namrata,Roy, Arnab,Himabindu, Vurimidi,Babu, Bangaru,Bhattacharya, Apurba,Bandichhor, Rakeshwar
, p. 362 - 368 (2011/03/21)
Efforts toward the synthesis and process optimization of amtolmetin guacil 1 are described. High-yielding electrophilic substitution followed by Wolf-Kishner reduction are the key features in the novel synthesis of tolmetin 2 which is an advanced intermediate of 1.
Solvent free oxidative radical substitution process. Synthesis of pyrrole fused systems
Flórez-López, Edwin,Gomez-Pérez, Liliana B.,Miranda, Luis D.
supporting information; scheme or table, p. 6000 - 6002 (2010/11/21)
A xanthate-based, solvent free, homolytic substitution on selected substituted pyrrole systems is described. Additionally, a practical entry for the rapid construction of pyrrole fused systems using this solventless radical addition followed by a double nucleophilic alkylation sequence, is also reported.
