- Design, synthesis, anticancer evaluation, and molecular modelling studies of novel tolmetin derivatives as potential VEGFR-2 inhibitors and apoptosis inducers
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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.
- Doghish, Ahmed S.,Gedawy, Ehab M.,Hamed, Mohammed I. A.,Hassan, Rasha A.,Kassab, Asmaa E.
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- Synthesis of Tolmetin Hydrazide-Hydrazones and Discovery of a Potent Apoptosis Inducer in Colon Cancer Cells
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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.
- Kü?ükgüzel, ?. Güniz,Ko?, Derya,?ikla-Süzgün, Pelin,?zsavci, Derya,Bing?l-?zakpinar, ?zlem,Mega-Tiber,Orun, Oya,Erzincan,Sa?-Erdem, Safiye,?ahin, Fikrettin
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- Synthetic method of non-steroidal antiinflammatory drug pain killing
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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.
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Paragraph 0041; 0052-0055; 0066-0067; 0094; 0105-0105
(2021/04/17)
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- Selective PdII-Catalyzed Acylation of Pyrrole with Aldehydes. Application to the Synthesis of Celastramycin Analogues and Tolmetin
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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.
- Santiago, Carlos,Rubio, Ibon,Sotomayor, Nuria,Lete, Esther
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p. 4284 - 4295
(2020/05/25)
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- Isotope labelling by reduction of nitriles: Application to the synthesis of isotopologues of tolmetin and celecoxib
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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.
- Ellis-Sawyer, Kate,Bragg, Ryan A.,Bushby, Nick,Elmore, Charles S.,Hickey, Michael J.
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p. 213 - 220
(2017/04/10)
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- Radical-promoted site-specific cross dehydrogenative coupling of heterocycles with nitriles
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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.
- Liu, Zhong-Quan,Li, Zejiang
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p. 14278 - 14281
(2016/12/16)
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- An Electrophilic Approach to the Palladium-Catalyzed Carbonylative C-H Functionalization of Heterocycles
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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.
- Tjutrins, Jevgenijs,Arndtsen, Bruce A.
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supporting information
p. 12050 - 12054
(2015/10/05)
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- Friedel - Crafts acylation of pyrroles and indoles using 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) as a nucleophilic catalyst
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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.
- Taylor, James E.,Jones, Matthew D.,Williams, Jonathan M. J.,Bull, Steven D.
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supporting information; experimental part
p. 5740 - 5743
(2011/03/18)
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- Synthesis and process optimization of amtolmetin: An antiinflammatory agent
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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.
- 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
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experimental part
p. 362 - 368
(2011/03/21)
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- Solvent free oxidative radical substitution process. Synthesis of pyrrole fused systems
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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.
- Flórez-López, Edwin,Gomez-Pérez, Liliana B.,Miranda, Luis D.
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supporting information; scheme or table
p. 6000 - 6002
(2010/11/21)
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- PROCESS FOR PRODUCING 2-[1-METHYL-5-(4-METHYLBENZOYL)- PYRROL-2- YL]ACETIC ACID OR SALT THEREOF
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The present invention relates to novel process for the preparation of tolmetin sodium, by employing easily available starting material and suitable reaction conditions. This invention is further related to novel crystalline forms of tolmetin methyl ester, tolmetin and tolmetin sodium and their process for the preparation.
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Page/Page column 13
(2009/07/17)
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- 2-ARYL-ACETIC ACIDS, THEIR DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
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Selected 2-arylacetic acids, their derivatives and pharmaceutical compositions that contain these compounds are useful in inhibiting chemotactic activation of neutrophils (PMN leukocytes) induced by the interaction of Interleukin-8 (IL-8) with CXCR1 and CXCR2 membrane receptors. The compounds are used for the prevention and treatment of pathologies deriving from said activation. In particular, 2(ortho)-substituted arylacetic acids or their derivatives, such as amides and sulfonamides, lack cyclo-oxygenase inhibition activity and are particularly useful in the treatment of neutrophil-dependent pathologies such as psoriasis, ulcerative colitis, melanoma, chronic obstructive pulmonary disease (COPD), bullous pemphigoid, rheumatoid arthritis, idiopathic fibrosis, glomerulonephritis and in the prevention and treatment of damages caused by ischemia and reperfusion.
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- 1,3,6-trihydro-6-aza-3-oxapentalen-2-one derivatives for the treatment of neoplasia
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1,3,6-Trihydro-6-Aza-3-Oxapentalen-2-One Derivatives for inhibiting neoplastic conditions.
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- Simple synthetic approach to arylacetic NSAIAs via TosMIC procedure
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Preparation of 1-methylpyrrole-2-acetonitrile, 1-methyl-5-(4-methylbenzoyl) pyrrole-2-acetonitrile and 2-(6-methoxy-2-naphthyl)propionitrile by treatment of 1-methylpyrrole-2-carboxaldehyde, 1-methyl-5-(4-methylbenzoyl)pyrrole-2-carboxaldehyde and, respectively, 6-methoxy-2-acetylnaphthalene with tosylmethylisocyanide (TosMIC) is described. This one-step synthetic procedure is very useful to obtain the nitrile precursors of tolmetin and naproxen, two clinically important non-steroidal antiinflammatory agents (NSAIAs).
- Di Santo,Costi,Massa,Artico
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p. 787 - 793
(2007/10/02)
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- Irreversible binding of tolmetin to macromolecules via its glucuronide: Binding to blood constituents, tissue homogenates and subcellular fractions in vitro
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The degradation of tolmetin glucuronide (TG) in biological fluids and tissue homogenates appears to follow first-order kinetics and is quite rapid in plasma. TG degradation was minimized upon the addition of phenylmethylsulphonyl fluoride (PMSF) and 1,4-saccharolactone, suggesting that the majority of the degradation may be enzymatic, rather than chemical hydrolysis. Irreversible binding via TG was detected in all tissue preparations examined. Upon addition of an inhibitor of esterases (PMSF) to human serum albumin (HSA) and plasma, binding was extensive (2.5%) and the extent of binding was both time- and pH-dependent. Similar extents of binding were obtained with most tissue homogenates, except for spleen and intestine which exhibited much lower binding. Incubation of TG with microsomal protein from sheep and rat yielded no significant differences. Incubations of tolmetin (T) and TG with microsomes, as well as tissue homogenates, indicates that irreversible binding occurs only in the presence of TG. Irreversible binding occurred in all of the blood constituents, the highest extent with haemolyzed erythrocytes. The extent of binding was 15 times higher in disrupted versus intact red blood cells, suggesting a correlation between the extent of binding and the overall exposure of TG to the macromolecules to which it may bind irreversibly.
- Ojingwa,Spahn-Langguth,Benet
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p. 495 - 506
(2007/10/03)
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- Non-steroidal antiinflammatory agents. 1. A novel synthesis of 1-methyl-5-p-tolylpyrrole-2-acetic acid (tolmetin)
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A four-step preparation of 1-methyl-5-p-tolylpyrrole-2-acetic acid (Tolmetin) is reported starting from 1-methyl-2-p-tolylpyrrole. Formylation of this compound followed by condensation with methyl(methylthio)methyl sulfoxide furnished 1-(methylsulfinyl)-1-methylthio-2-(1-methyl-5-p-tolyl-2-pyrrolyl)ethylene. Pummerer rearrangement of the latter compound gave ethyl 1-methyl-5-p-tolypyrrole-2-acetate, which was hydrolyzed in alkaline medium to afford Tolmetin.
- Artico,Corelli,Massa,Stefancich
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p. 1493 - 1495
(2007/10/02)
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- Esters and amides containing the 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetyl moiety
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Compounds of the formula STR1 wherein each X, which may be identical or different from the other X, is oxygen or imino; R1 is hydrogen, fluorine, chlorine or bromine; R2 and R3, which may be identical or different from each other, are each hydrogen; unsubstituted or mono-substituted alkyl of 1 to 6 carbon atoms, where the substituent is phenyl or dialkylamino with 1 to 3 carbon atoms in each alkyl moiety; pyridyl; or cycloalkyl of 5 to 7 carbon atoms; R2 and R3, together with each other and the nitrogen atoms to which they are attached, are pyrrolidino, piperidino, hexamethyleneimino, morpholino, N-aryl-piperazino or N-(alkyl of 1 to 3 carbon atoms)-piperazino; A is cycloalkylene of 5 to 7 carbon atoms; unsubstituted or substituted alkylene of 2 to 10 carbon atoms, where the substituents are one to two alkyls of 1 to 3 carbon atoms each, one to two carbalkoxys of 2 to 4 carbon atoms each, one to two phenyls, one to four hydroxyls, one halomethyl, one hydroxymethyl, one alkanoyloxy of 1 to 18 carbon atoms, one alkanoyloxymethyl of 1 to 18 carbon atoms in the alkanoyl moiety or one STR2 where R1, R2 and R3 have the meanings previously defined; or alkylene of 2 to 10 carbon atoms interrupted by oxygen, sulfur, sulfoxide, sulfonyl, phenyl, cyclohexyl, pyridyl, piperazino or unsubstituted or substituted imino, where the substituent on the imino group is alkyl of 1 to 6 carbon atoms, phenyl or phenylalkyl of 1 to 3 carbon atoms in the alkyl moiety; B is the acyl residue of an antiphlogistic carboxylic acid; and their non-toxic, pharmacologically acceptable acid addition salts. The compounds as well as their salts are useful as anti-inflammatories.
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- Process for preparing aromatic acetic acid
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There are disclosed processes for preparing an aromatic acetic acid by the reaction of an aromatic aldehyde with a combination of a trihalomethane and an alkanethiol, and by the reaction of an alcohol derivative (2,2,2-trihalo-1-arylethanol) with an alkanethiol, in the presence of a base in a mixed medium of water and an aprotic polar solvent.
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- Preparation of 5-(arylcyanohydroxymethyl)-1-loweralkylpyrrole-2-acetic acid derivatives
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5-(Arylcyanohydroxymethyl)-1-loweralkylpyrrole-2-acetic acid derivatives are prepared by the protic acid catalyzed reaction of aroylcyanides with 1-loweralkylpyrrole-2-acetic acid derivatives, which is then converted by treatment with alkali metal hydroxides or heat to form 5-aroyl-1-loweralkylpyrrole-2-acetic acid or derivatives thereof.
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- Halo-substituted 1-loweralkyl-5-aroylpyrrole-2-acetic acid compounds
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Halo-substituted 1-loweralkyl-5-aroylpyrrole-2-acetic acid compounds, useful for their anti-inflammatory activity.
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- 5-Chlorocarbonyl
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A process of preparing certain 5-aroyl-pyrrole-2-alkanoic acid derivatives using phosgene and certain 5-unsubstituted pyrroles as starting materials, and certain novel 5-chlorocarbonyl-pyrrole precursors.
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- Aroyl-substituted pyrroles
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The compounds are of the class of 5-aroyl-pyrrole alkanoic acids and corresponding acid derivatives thereof useful as anti-inflammatory agents and as synthetic intermediates.
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