771-50-6Relevant academic research and scientific papers
Substrate orientation and specificity in xanthine oxidase: Crystal structures of the enzyme in complex with indole-3-acetaldehyde and guanine
Cao, Hongnan,Hall, James,Hille, Russ
, p. 533 - 541 (2014)
Xanthine oxidase is a molybdenum-containing hydroxylase that catalyzes the hydroxylation of sp2-hybridized carbon centers in a variety of aromatic heterocycles as well as aldehydes. Crystal structures of the oxidase form of the bovine enzyme in complex with a poor substrate indole-3-acetaldehyde and the nonsubstrate guanine have been determined, both at a resolution of 1.6 A. In each structure, a specific and unambiguous orientation of the substrate in the active site is observed in which the hydroxylatable site is oriented away from the active site molybdenum center. The orientation seen with indole-3-acetaldehyde has the substrate positioned with the indole ring rather than the exocyclic aldehyde nearest the molybdenum center, indicating that the substrate must rotate some 30 in the enzyme active site to permit hydroxylation of the aldehyde group (as observed experimentally), accounting for the reduced reactivity of the enzyme toward this substrate. The principal product of hydroxylation of indole-3-acetaldehyde by the bovine enzyme is confirmed to be indole-3-carboxylic acid based on its characteristic UV-vis spectrum, and the kinetics of enzyme reduction are reported. With guanine, the dominant orientation seen crystallographically has the C-8 position that might be hydroxylated pointed away from the active site molybdenum center, in a configuration resembling that seen previously with hypoxanthine (a substrate that is effectively hydroxylated at position 2). The ～180 reorientation required to permit reaction is sterically prohibited, indicating that substrate (mis)orientation in the active site is a major factor precluding formation of the highly mutagenic 8-hydroxyguanine.
Development of 2-oindolin-3-ylidene-indole-3-carbohydrazide derivatives as novel apoptotic and anti-proliferative agents towards colorectal cancer cells
Abdel-Aziz, Hatem A.,Abdulla, maha,Abo-Ashour, mahmoud f.,Ahmad, Rehan,Al-Khayal, Khayal,Al-Rashood, Sara T.,Al-Warhi, Tarfah,Alharbi, Amal,Ayyad, Rezk R.,El-Haggar, Radwan,Eldehna, Wagdy m.
, p. 319 - 328 (2020/12/23)
Mitochondrial anti-apoptotic Bcl2 and BclxL proteins, are overexpressed in multiple tumour types, and has been involved in the progression and survival of malignant cells. Therefore, inhibition of such proteins has become a validated and attractive target for anticancer drug discovery. In this manner, the present studies developed a series of novel isatin–indole conjugates (7a-j and 9a-e) as potential anticancer Bcl2 and BclxL inhibitors. The progression of the two examined colorectal cancer cell lines was significantly inhibited by all of the prepared compounds with IC50 ranges132–611 nM compared to IC50 = 4.6 μM for 5FU, against HT-29 and IC50 ranges 37–468 nM compared to IC50 = 1.5 μM for 5FU, against SW-620. Thereafter, compounds 7c and 7g were selected for further investigations. Interestingly, both compounds exhibited selective cytotoxicity against both cell lines with high safety to normal fibroblast (HFF-1). In addition, both compounds 7c and 7g induced apoptosis and inhibited Bcl2 and BclxL expression in a dose-dependent manner. Collectively, the high potency and selective cytotoxicity suggested that conjugates 7c and 7g could be a starting point for further optimisation to develop novel pro-apoptotic and antitumor agents towards colon cancer.
Discovery of novel indole-1,2,4-triazole derivatives as tubulin polymerization inhibitors
Wu, Meng-Ke,Man, Ruo-Jun,Liao, Yan-Juan,Zhu, Hai-Liang,Zhou, Zhu-Gui
, p. 1008 - 1020 (2021/03/15)
A series of novel indole-1,2,4-triazole derivatives have been designed, synthesized, and evaluated as potential tubulin polymerization inhibitors. The top hit 12, bearing the 3,4,5-trimethoxyphenyl moiety, exhibited substantial anti-proliferative activity against HepG2, HeLa, MCF-7, and A549 cells in vitro with IC50 values of 0.23 ± 0.08 μM, 0.15 ± 0.18 μM, 0.38 ± 0.12 μM, and 0.30 ± 0.13 μM, respectively. It also inhibited tubulin polymerization with the IC50 value of 2.1 ± 0.12 μM, which was comparable with that of the positive controls. Furthermore, compound 12 regulated the expression of cell cycle-related proteins (Cyclin B1, Cdc25c, and Cdc2) and apoptosis-related proteins (Bcl-2, Bcl-x, and Mcl-1). Mechanistically, compound 12 could arrest cell cycle at the G2/M phase, thus induce an increase of apoptotic cell death. In addition, molecular docking hinted the possible interaction mode of compound 12 into the colchicine binding site of tubulin heterodimers. According to the applications of microtubule-targeting agents in both direct and synergistic cancer therapies, we hope this work might be of significance for future researches.
Cleavage of Carboxylic Esters by Aluminum and Iodine
Sang, Dayong,Yue, Huaxin,Fu, Yang,Tian, Juan
, p. 4254 - 4261 (2021/03/09)
A one-pot procedure for deprotecting carboxylic esters under nonhydrolytic conditions is described. Typical alkyl carboxylates are readily deblocked to the carboxylic acids by the action of aluminum powder and iodine in anhydrous acetonitrile. Cleavage of lactones affords the corresponding ω-iodoalkylcarboxylic acids. Aryl acetylates undergo deacetylation with the participation of the neighboring group. This method enables the selective cleavage of alkyl carboxylic esters in the presence of aryl esters.
Development and Profiling of Inverse Agonist Tools for the Neuroprotective Transcription Factor Nurr1
Zaienne, Daniel,Willems, Sabine,Schierle, Simone,Heering, Jan,Merk, Daniel
, p. 15126 - 15140 (2021/10/25)
The ligand-sensing transcription factor nuclear receptor related 1 (Nurr1) evolves as an appealing target to treat neurodegenerative diseases. Despite its therapeutic potential observed in various rodent models, potent modulators for Nurr1 are lacking as pharmacological tools. Here, we report the structure-activity relationship and systematic optimization of indole-based inverse Nurr1 agonists. Optimized analogues decreased the receptor's intrinsic transcriptional activity by up to more than 90% and revealed preference for inhibiting Nurr1 monomer activity. In orthogonal cell-free settings, we detected displacement of NCoRs and disruption of the Nurr1 homodimer as molecular modes of action. The inverse Nurr1 agonists reduced the expression of Nurr1-regulated genes in T98G cells, and treatment with an inverse Nurr1 agonist mimicked the effect of Nurr1 silencing on interleukin-6 release from LPS-stimulated human astrocytes. The indole-based inverse Nurr1 agonists valuably extend the toolbox of Nurr1 modulators to further probe the role of Nurr1 in neuroinflammation, cancer, and beyond.
Synthesis, anticancer evaluation and molecular docking studies of 2,5-bis(indolyl)-1,3,4-oxadiazoles, Nortopsentin analogues
Sreenivasulu, Reddymasu,Tej, Mandava Bhuvan,Jadav, Surender Singh,Sujitha, Pombala,Kumar, C. Ganesh,Raju, Rudraraju Ramesh
, (2020/02/18)
A series of ten novel 2,5-bis(indolyl)-1,3,4-oxadiazoles were designed and synthesized. All these compounds were evaluated for their cytotoxicity against four cancer cell lines namely A549, MDA-MB-231, MCF-7 and HeLa using MTT reduced assay. Among them, compound 12e exhibited good cytotoxicity on MCF-7 cell line with IC50 value of 1.8 μM and it was identified as a promising drug lead when compared to the standard drug doxorubicin (IC50 value 0.98 μM). Compound, 12h exhibited better antitumor activity against three cancer cell lines i.e., lung (A549), breast (MCF-7) and cervical (HeLa) with IC50 values of 3.3 μM, 2.6 μM and 6.34 μM respectively. The impact of these compounds on colchicine binding site of tubulin polymer was carefully investigated using molecular docking studies and interpretations between actives and inactive were explained.
Efficient construction of diverse 3-cyanoindoles under novel tandem catalysis
Wu, Jun,Liu, Jiabin,Zhou, Kerui,He, Zhenni,Wang, Qian,Wu, Fen,Miao, Tingting,Qian, Jinjie,Shi, Qian
supporting information, p. 12660 - 12663 (2020/11/02)
A novel and rapid construction of 3-cyanoindoles by palladium-catalyzed tandem reactions has been developed. "N-H"free unprotected, N-alkyl and N-aryl 3-cyanoindoles are obtained with good to excellent yields. The usefulness of this synthetic approach is further demonstrated by the successful synthesis of practical compounds such as the therapeutic estrogen receptor ligand A precursor. Mechanism study shows that the tandem catalysis exploits a Suzuki cross-coupling with subsequent base-induced isoxazole fragmentation, followed by the aldimine condensation.
CO2-Folded Single-Chain Nanoparticles as Recyclable, Improved Carboxylase Mimics
Chen, Liang,Yan, Qiang,Zeng, Rongjin
supporting information, p. 18418 - 18422 (2020/08/21)
Emulating the function of natural carboxylases to convert CO2 under atmospheric condition is a great challenge. Herein we report a class of CO2-folded single-chain nanoparticles (SCNPs) that can function as recyclable, function-intensified carboxylase mimics. Lewis pair polymers containing bulky Lewis acidic and basic groups as the precursor, can bind CO2 to drive an intramolecular folding into SCNPs, in which CO2 as the folded nodes can form gas-bridged bonds. Such bridging linkages highly activate CO2, which endows the SCNPs with extraordinary catalytic ability that can not only catalyze CO2-insertion of C(sp3)-H for imitating the natural enzyme's function, it can also act on non-natural carboxylation pathways for C(sp2 and sp)-H substrates. The nanocatalysts are of highly catalytic efficiency and recyclability, and can work at room temperature and near ambient CO2 condition, inspiring a new approach to sustainable C1 utilization.
Design, synthesis, and antitumor activity of novel benzoheterocycle derivatives as inhibitors of vascular endothelial growth factor receptor-2 tyrosine kinase
Ding, Yangyang,Liu, Kai,Zhao, Xinyu,Lv, Yingtao,Yu, Rilei,Kang, Congmin
, p. 286 - 294 (2020/01/28)
The vascular endothelial growth factor receptor-2 signaling pathway promotes the formation of new blood vessels, and vascular endothelial growth factor receptor-2 tyrosine kinase exists in both active and inactive conformations. Novel indole–benzimidazole and indole–benzothiazole derivatives joined by different linkers are designed and synthesized as inhibitors of vascular endothelial growth factor receptor-2 tyrosine kinase. All the synthesized compounds were evaluated for their cytotoxicity against four human cancer cell lines (HeLa, HT29, A549, and MDA-MB-435) and human umbilical vein endothelial cell. Meanwhile, the inhibitory activities against vascular endothelial growth factor receptor-2 are estimated in vitro and the binding interactions with dual conformations of vascular endothelial growth factor receptor-2 tyrosine kinase are evaluated by molecular docking. Compounds 5a–c and 14 show inhibitory activity against vascular endothelial growth factor receptor-2 tyrosine kinase and promising cytotoxicity, specifically with IC50 values ranging between 0.1 and 1 μM, which imply broad-spectrum antitumor activity. These results provide a deep insight into potential structural modifications for developing potent vascular endothelial growth factor receptor-2 tyrosine kinase inhibitors.
Synthesis, antiproliferative and apoptosis induction potential activities of novel bis(indolyl)hydrazide-hydrazone derivatives
Sreenivasulu, Reddymasu,Reddy, Kotthireddy Thirumal,Sujitha, Pombala,Kumar, C. Ganesh,Raju, Rudraraju Ramesh
, p. 1043 - 1055 (2019/02/19)
In recent years, indole-indazolyl hydrazide-hydrazone derivatives with strong cell growth inhibition and apoptosis induction characteristics are being strongly screened for their cancer chemo-preventive potential. In the present study, N-methyl and N,N-dimethyl bis(indolyl)hydrazide-hydrazone analog derivatives were designed, synthesized and allowed to evaluate for their anti-proliferative and apoptosis induction potential against cervical (HeLa), breast (MCF-7 and MDA-MB-231) and lung (A549) cancer cell lines relative to normal HEK293 cells. The MTT assay in conjunction with mitochondrial potential assays and the trypan blue dye exclusion were employed to ascertain the effects of the derivatives on the cancer cells. Further, mechanistic studies were conducted on compound 14a to understand the biochemical mechanisms and functional interactions with various signaling pathways triggered in HeLa and MCF-7 cells. Compound 14a induced apoptosis via caspase independent pathway through the participation of mitogen-activated protein kinases (MAPK) such as extracellular signal related kinase (ERK) and p38 as well as p53 pathways. It originates the activation of pro-apoptotic proteins such as Bak and Mcl-1s and also strongly induced the generation of reactive oxygen species. In downstream signaling pathway, activated p53 protein interacted with MAPK pathways, including SAPK/c-Jun N-terminal protein kinase (JNK), p38 and ERK kinases resulting in apoptotic cell death. The involvement of MAPK cascades such as p38, ERK and p38 on compound 14a induced apoptotic cell death was evidenced by the fact that the inclusion of specific inhibitors of p38, ERK1/2 and JNK MAPK (SB2035809, PD98059 and SP600125) prevented the compound 14a towards induced apoptosis. The results clearly showed that MAP kinase cascades were crucial for apoptotic response in compound 14a induced cellular killing and were dependent on p53 activity. Based on the results, compound 14a was identified as a promising candidate for cancer therapeutics and these findings furnish a basis for further in vivo experiments on anti-proliferative activity.
