2882-15-7Relevant articles and documents
The self-association of the drug acemetacin and its interactions and stabilization with beta-cyclodextrin in aqueous solution as inferred from NMR spectroscopy and HPLC studies.
Zouvelekis, Dimitris,Yannakopoulou, Konstantina,Mavridis, Irene M,Antoniadou-Vyza, Ekaterini
, p. 1387 - 1395 (2002)
Strongly concentration dependent, (1)H NMR chemical shifts of the non-steroidal anti-inflammatory drug acemetacin sodium salt (sodium [[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetoxy]acetate), were observed in aqueous solution. Self-titration and nOe experiments, point to a self-association model where stacking takes place via the indole portion of the drug. In addition, conformational isomerism (atropisomerism) of the anti to syn form was confirmed. Further increase of the concentration eventually led to stable chemical shifts and nearly simultaneous appearance of microcrystals. In the presence of betaCD, 1:1 inclusion complexation occurred through the p-chlorobenzoyl part of the drug, whereas with excess betaCD the indole part seemed to participate to a minor degree. The anti isomer is suggested to be involved in the inclusion process. In addition, aggregation of acemetacin was also evident, as competing with the conformational and inclusion equilibria. The present case demonstrates that many competitive processes are simultaneously active in a seemingly simple system. The measurements were strongly dependent upon the pH and use of buffered solutions was mandatory. Finally, for the quantitative analysis of acemetacin in the presence of betaCD, a special HPLC method was developed. The stability of the drug, studied by the identification of the degradation products and the pseudo-first order rate of hydrolysis, was found to be unaffected by the presence of betaCD.
1-Phenyl-1H-indole derivatives as a new class of Bcl-2/Mcl-1 dual inhibitors: Design, synthesis, and preliminary biological evaluation
Xu, Guangsen,Liu, Tingting,Zhou, Yi,Yang, Xinying,Fang, Hao
, p. 5548 - 5556 (2017)
Bcl-2 proteins, such as B-cell lymphoma (Bcl-2) protein, myeloid cell leukemia sequence 1 (Mcl-1) protein, has been implicated in the progression and survival of multiple tumor types and become a validated and attractive target for cancer therapy. In this work, a series of 1-phenyl-1H-indole derivatives has been designed and synthesized. The preliminary biological studies (binding assay for Bcl-2 proteins and MTT assay) suggested that some active compounds showed potent inhibitory activities on Bcl-2/Mcl-1 without binding on Bcl-XL. Furthermore, Compound 9c and 9h showed better anti-proliferative activity than WL-276.
Hydrolysis mechanisms for indomethacin and acemethacin in perchloric acid
Garcia,Hoyuelos,Ibeas,Leal
, p. 3718 - 3726 (2006)
The acid-catalyzed hydrolysis reactions of the antiinflammatory drugs indomethacin and acemethacin were investigated at 25.0 °C in a number of strongly concentrated perchloric acid media. The reaction rates were evaluated by UV measurements, and the intermediate species were detected by UV-vis, 1H NMR, 13C NMR, and mass spectroscopy measurements. A switchover from an A-2 to an A-1 mechanism as a function of the medium acidity is reported for the acid-catalyzed hydrolyses of the amide group of both indomethacin and acemethacin. In the A-2 hydrolysis, two water molecules are involved in the rate-determining step. An analysis of the kinetic data collected for acemethacin by the different techniques used reveals a complex mechanism, indomethacin being a metabolite intermediate species in the hydrolysis of acemethacin. The rate constants for the hydrolysis of the acemethacin ester group were considerably larger compared to those of the amide group.
Indole compounds with: N-ethyl morpholine moieties as CB2 receptor agonists for anti-inflammatory management of pain: Synthesis and biological evaluation
Ji, Jing,Li, Jiaojiao,Li, Zhengfu,Xu, Ruibo
, p. 1935 - 1947 (2019/11/20)
The CB2 receptor plays a crucial role in analgesia and anti-inflammation. To develop novel CB2 agonists with high efficacy and selectivity, a series of indole derivatives with N-ethyl morpholine moieties (compounds 1-56) were designed, synthesized and biologically evaluated. Compounds 1, 2, 3, 46 and 53 exhibited high CB2 receptor affinity at low nanomolar concentrations and good receptor selectivity (EC50(CB1)/EC50(CB2) greater than 1000). The most active compound, compound 2, was more potent than the standard drug GW405833 for in vitro agonistic action on the CB2 receptor. More importantly, in a rat model for CFA-induced inflammatory hyperalgesia, compound 2 had a potent anti-inflammatory pain effect within 12 hours after administration. At the 1 h time point, compound 2 had a dose-dependent reversal for hyperalgesia with an estimated ED50 value of 1.097 mg kg-1. Moreover, compound 2 significantly suppressed the pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) in CFA-induced lesions. These protective effects of compound 2 on inflammatory pain were superior to those of GW405833, suggesting that compound 2 may be a promising therapeutic drug that needs further validation.
Pd-tBuONO Cocatalyzed Aerobic Indole Synthesis
Ning, Xiao-Shan,Liang, Xin,Hu, Kang-Fei,Yao, Chuan-Zhi,Qu, Jian-Ping,Kang, Yan-Biao
, p. 1590 - 1594 (2018/04/30)
A Pd-tBuONO co-catalyzed scalable and practical synthesis of indoles with molecular oxygen as terminal oxidant is developed. Either terminal or internal 2-vinylanilines could be smoothly converted to desired indoles under one general condition. This method has been evaluated in the large scale synthesis of indomethacin and a potential anti-breast cancer drug candidate 1. (Figure presented.).
Synthesis of Functionalized Indoles via Palladium-Catalyzed Aerobic Cycloisomerization of o-Allylanilines Using Organic Redox Cocatalyst
Ning, Xiao-Shan,Wang, Mei-Mei,Qu, Jian-Ping,Kang, Yan-Biao
, p. 13523 - 13529 (2018/10/25)
A scalable and practical synthesis of functionalized indoles via Pd-tBuONO cocatalyzed aerobic cycloisomerization of o-allylanilines is reported. Using molecular oxygen as a terminal oxidant, a series of substituted indoles were prepared in moderate to good yields. The avoidance of hazardous oxidants, heavy-metal cocatalysts, and high boiling point solvents such as DMF and DMSO enables this method to be applied in pharmaceutical synthesis. A practical gram-scale synthesis of indomethacin demonstrates its application potential.
Bifunctional conjugates with potent inhibitory activity towards cyclooxygenase and histone deacetylase
Raji, Idris,Yadudu, Fatima,Janeira, Emily,Fathi, Shaghayegh,Szymczak, Lindsey,Kornacki, James Richard,Komatsu, Kensei,Li, Jian-Dong,Mrksich, Milan,Oyelere, Adegboyega K.
, p. 1202 - 1218 (2017/02/05)
We herein disclose a series of compounds with potent inhibitory activities towards histone deacetylases (HDAC) and cyclooxygenases (COX). These compounds potently inhibited the growth of cancer cell lines consistent with their anti-COX and anti-HDAC activities. While compound 2b showed comparable level of COX-2 selectivity as celecoxib, compound 11b outperformed indomethacin in terms of selectivity towards COX-2 relative to COX-1. An important observation with our lead compounds (2b, 8, 11b, and 17b) is their enhanced cytotoxicity towards androgen dependent prostate cancer cell line (LNCaP) relative to androgen independent prostate cancer cell line (DU-145). Interestingly, compounds 2b and 17b arrested the cell cycle progression of LNCaP in the S-phase, while compound 8 showed a G0/G1 arrest, similar to SAHA. Relative to SAHA, these compounds displayed tumor-selective cytotoxicity as they have low anti-proliferative activity towards healthy cells (VERO); an attribute that makes them attractive candidates for drug development.
Synthesis of novel indole-benzimidazole derivatives
Wang, Xinying,Liu, Yizhou,Xu, Juan,Jiang, Fanwei,Kang, Congmin
, p. 588 - 590 (2016/10/18)
2-Methylindole-3-acetic acid and its 5-methoxy derivative were prepared from the respective phenylhydrazines and levulinic acid. Indole-3-carboxylic acid was obtained from indole, dimethylformamide and trifluoroacetic acid. These indole carboxylic acids were then condensed with substituted o-phenylenediamines under high temperature conditions in the presence of polyphosphoric acid as a catalyst to give the combined indole-benzimidazoles.
Comparative in vitro metabolism of phospho-tyrosol-indomethacin by mice, rats and humans
Xie, Gang,Zhou, Dingying,Cheng, Ka-Wing,Wong, Chi C.,Rigas, Basil
, p. 1195 - 1202 (2013/05/22)
Phospho-tyrosol-indomethacin (PTI; MPI 621), a novel anti-cancer agent, is more potent and safer than conventional indomethacin. Here, we show that PTI was extensively metabolized in vitro and in vivo. PTI was rapidly hydrolyzed by carboxylesterases to generate indomethacin as its major metabolite in the liver microsomes and rats. PTI additionally undergoes cytochromes P450 (CYP)-mediated hydroxylation at its tyrosol moiety and O-demethylation at its indomethacin moiety. Of the five major human CYPs, CYP3A4 and CYP2D6 catalyze the hydroxylation and O-demethylation reactions of PTI, respectively; whereas CYP1A2, 2C9 and 2C19 are inactive towards PTI. In contrast to PTI, indomethacin is primarily O-demethylated by CYP2C9, which prefers acidic substrates. The hydrolyzed and O-demethylated metabolites of PTI are further glucuronidated and sulfated, facilitating drug elimination and detoxification. We observed substantial inter-species differences in the metabolic rates of PTI. Among the liver microsomes from various species, PTI was the most rapidly hydrolyzed, hydroxylated and O-demethylated in mouse, human and rat liver microsomes, respectively. These results reflect the differential expression patterns of carboxylesterase and CYP isoforms among these species. Of the human microsomes from various tissues, PTI underwent more rapid carboxylesterase- and CYP-catalyzed reactions in liver and intestine microsomes than in kidney and lung microsomes. Together, our results establish the metabolic pathways of PTI, reveal significant inter-species differences in its metabolism, and provide insights into the underlying biochemical mechanisms.
Ortho-Carbaborane derivatives of indomethacin as cyclooxygenase (COX)-2 selective inhibitors
Scholz, Matthias,Blobaum, Anna L.,Marnett, Lawrence J.,Hey-Hawkins, Evamarie
supporting information; experimental part, p. 4830 - 4837 (2012/09/22)
A series of novel indomethacin analogues with carbaboranes as three-dimensional substitutes for the chlorophenyl ring have been prepared. Their cyclooxygenase (COX) inhibition and enzyme selectivity has been tested and compared to the corresponding adamantyl analogues. Surprisingly, only the ortho-carbaborane derivatives were active compounds. Preliminary biological studies gave an interesting insight into the validity of employing carbaboranes as pharmacophores.
