3484-35-3Relevant articles and documents
Following Nature’s Footprint: Mimicking the High-Valent Heme-Oxo Mediated Indole Monooxygenation Reaction Landscape of Heme Enzymes
Mondal, Pritam,Rajapakse, Shanuk,Wijeratne, Gayan B.
, p. 3843 - 3854 (2022/02/16)
Pathways for direct conversion of indoles to oxindoles have accumulated considerable interest in recent years due to their significance in the clear comprehension of various pathogenic processes in humans and the multipotent therapeutic value of oxindole pharmacophores. Heme enzymes are predominantly responsible for this conversion in biology and are thought to proceed with a compound-I active oxidant. These heme-enzyme-mediated indole monooxygenation pathways are rapidly emerging therapeutic targets; however, a clear mechanistic understanding is still lacking. Additionally, such knowledge holds promise in the rational design of highly specific indole monooxygenation synthetic protocols that are also cost-effective and environmentally benign. We herein report the first examples of synthetic compound-I and activated compound-II species that can effectively monooxygenate a diverse array of indoles with varied electronic and steric properties to exclusively produce the corresponding 2-oxindole products in good to excellent yields. Rigorous kinetic, thermodynamic, and mechanistic interrogations clearly illustrate an initial rate-limiting epoxidation step that takes place between the heme oxidant and indole substrate, and the resulting indole epoxide intermediate undergoes rearrangement driven by a 2,3-hydride shift on indole ring to ultimately produce 2-oxindole. The complete elucidation of the indole monooxygenation mechanism of these synthetic heme models will help reveal crucial insights into analogous biological systems, directly reinforcing drug design attempts targeting those heme enzymes. Moreover, these bioinspired model compounds are promising candidates for the future development of better synthetic protocols for the selective, efficient, and sustainable generation of 2-oxindole motifs, which are already known for a plethora of pharmacological benefits.
BENZOFURAN-BASED N-ACYLHYDRAZONE DERIVATIVES AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
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Paragraph 0172-0175, (2021/02/02)
A benzofuran-based N-acylhydrazone derivative according to the present invention has an excellent anticancer effect while having low toxicity and excellent solubility, and, thus, a pharmaceutical composition comprising the derivative can be usefully used to prevent or treat a cell proliferative disorder including various cancers. To this end, the present invention provides a compound represented by chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
A novel methodology for the efficient synthesis of 3-monohalooxindoles by acidolysis of 3-phosphate-substituted oxindoles with haloid acids
Liu, Li,Li, Yue,Huang, Tiao,Kong, Dulin,Wu, Mingshu
, p. 2321 - 2328 (2021/09/22)
A novel method for the synthesis of 3-monohalooxindoles by acidolysis of isatin-derived 3-phosphate-substituted oxindoles with haloid acids was developed. This synthetic strategy involved the preparation of 3-phosphate-substituted oxindole intermediates and SN1 reactions with haloid acids. This new procedure features mild reaction conditions, simple operation, good yield, readily available and inexpensive starting materials, and gram-scalability.
Selective formation of γ-lactams via C-H amidation enabled by tailored iridium catalysts
Hong, Seung Youn,Park, Yoonsu,Hwang, Yeongyu,Kim, Yeong Bum,Baik, Mu-Hyun,Chang, Sukbok
, p. 1016 - 1021 (2018/03/09)
Intramolecular insertion of met al nitrenes into carbon-hydrogen bonds to form γ-lactam rings has traditionally been hindered by competing isocyanate formation. We report the application of theory and mechanism studies to optimize a class of pentamethylcyclopentadienyl iridium(III) catalysts for suppression of this competing pathway. Modulation of the stereoelectronic properties of the auxiliary bidentate ligands to be more electron-donating was suggested by density functional theory calculations to lower the C-H insertion barrier favoring the desired reaction. These catalysts transform a wide range of 1,4,2-dioxazol-5-ones, carbonylnitrene precursors easily accessible from carboxylic acids, into the corresponding γ-lactams via sp3 and sp2 C-H amidation with exceptional selectivity. The power of this method was further demonstrated by the successful late-stage functionalization of amino acid derivatives and other bioactive molecules.
Discovery of novel polycyclic spiro-fused carbocyclicoxindole-based anticancer agents
Zhang, Lidan,Ren, Wen,Wang, Xiaoyan,Zhang, Jiaying,Liu, Jie,Zhao, Lifeng,Zhang, Xia
, p. 1071 - 1082 (2016/12/28)
A series of novel polycyclic spiro-fused carbocyclicoxindoles were synthesized and investigated for their in?vitro antiproliferative activities against nine human cancer cell lines. Five compounds (10i, 10l, 10n, 10p, and 10r) demonstrated anticancer activities against A2780s cells with IC50values of less than 30?μM. In particular, compound 10i showed anticancer activities against seven cancer cell lines and stronger activities than cisplatin in A2780s, A2780T, CT26, and HCT116?cells. Further studies illustrated that compound 10i arrested cell cycle in G1 phase and induced apoptosis of HCT116?cells. This compound also effectively increased the protein levels of cleaved caspase-3, p53, and MDM2. Molecular docking results revealed that compound 10i could bind well to the p53-binding site on MDM2, indicating that it might work by blocking the MDM2-p53 interactions.
Natural α-methylenelactam analogues: Design, synthesis and evaluation of α-alkenyl-γ and δ-lactams as potential antifungal agents against Colletotrichum orbiculare
Delong, Wang,Lanying, Wang,Yongling, Wu,Shuang, Song,Juntao, Feng,Xing, Zhang
, p. 286 - 307 (2017/03/09)
In our continued efforts to improve the potential utility of the α-methylene-γ-lactone scaffold, 62 new and 59 known natural α-methylenelactam analogues including α-methylene-γ-lactams, α-arylidene-γ and δ-lactams, and 3-arylideneindolin-2-ones were synthesized as the bioisosteric analogues of the α-methylenelactone scaffold. The results of antifungal and cytotoxic activity indicated that among these derivatives compound (E)-1-(2, 6-dichlorobenzyl)-3-(2-fluorobenzylidene) pyrrolidin-2-one (Py51) possessed good selectivity with the highest antifungal activity against Colletotrichum orbiculare with IC50?=?10.4?μM but less cytotoxic activity with IC50?=?141.2?μM (against HepG2 cell line) and 161.2?μM (against human hepatic L02?cell line). Ultrastructural change studies performed by transmission electron microscope showed that Py51 could cause important cell morphological changes in C.?orbiculare, such as plasma membrane detached from cell wall, cell wall thickening, mitochondria disruption, a dramatic increase in vacuolation, and eventually a complete loss in the integrity of organelles. Significantly, mitochondria appeared one of the primary targets, as confirmed by their remarkably aberrant morphological changes. Analysis of structure–activity relationships revealed that incorporation of the aryl group into the α-exo-methylene and the N-benzyl substitution increased the activity. Meanwhile, the α-arylidene-γ-lactams have superiority in selectivity over the 3-arylideneindolin-2-ones. Based on the results, the N-benzyl substituted α-(2-fluorophenyl)-γ-lactam was identified as the most promising natural-based scaffold for further discovering and developing improved crop-protection agents.
A safe and selective method for reduction of 2-nitrophenylacetic acid systems to N-aryl hydroxamic acids using continuous flow hydrogenation
Ichire, Ogar,Jans, Petra,Parfenov, Galina,Dounay, Amy B.
, p. 582 - 585 (2017/01/16)
The cyclic hydroxamic acid functional group is critical to the biological activity of numerous natural products and drug candidates. Efficient, reliable, and green synthetic methods to produce cyclic hydroxamic acids are needed. Herein, flow hydrogenation has been explored as a novel approach toward achieving the selective partial reduction of 2-nitrophenylacetic acid to 1-hydroxyindolin-2-one. The bidentate ligand, 1,10-phenanthroline, has been identified as a unique inhibitor for modulating product selectivity in this Pt/C-catalyzed process. Under the newly optimized reaction conditions, the targeted hydroxamic acid is produced with high selectivity (49:1) over the lactam by-product. The scope of the reaction is demonstrated for a variety of 2-nitrophenylacetic acid derivatives.
Nickel-catalyzed methylation of aryl halides/tosylates with methyl tosylate
Wang, Jiawang,Zhao, Jianhong,Gong, Hegui
supporting information, p. 10180 - 10183 (2017/09/23)
This work describes the cross-electrophile methylation of aryl bromides and aryl tosylates with methyl tosylate. The mild reaction conditions allow effective methylation of a wide set of heteroaryl electrophiles and dimethylation of dibromoarenes.
Method for preparing indole and derivatives thereof
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, (2017/08/24)
The invention discloses a method for preparing indole and derivatives of indole. The method for preparing indole and the derivatives of indole is characterized by comprising the following two steps that (1) a catalyst, a ligand and alkali are added in a reaction tube, under the protection of nitrogen, beta-hydroxy ketone or ester is reacted with a mixed solution of o-nitro aryl halides for 3 to 8h in an oil bath pan at the temperature of 90 to 120 DEG C, and then cooled to room temperature after reaction, and extracted, washed, dried and subjected to chromatography to obtain a product of o-nitro alpha-aryl ketone or ester; (2) o-nitro alpha-aryl ketone or ester obtained in the step (1), a reducing agent system and a solvent are added to the reaction tube, and reacted for 3 to 8h at the temperature of 60 to 100 DEG C, and then extracted, washed, dried and subjected to chromatography after being reacted to obtain a target product of indole and the derivatives of indole. Reaction raw materials, the catalyst, the ligand, the alkali and the solvent used in the invention are all industrial commodities, and simple and readily available, wide in sources, cheap in price, and further very stable in performances, and with no need for special storage conditions; in addition, the method for preparing indole and the derivatives of indole disclosed by the invention has the characteristics of low cost, high yield, simple process, less pollution and the like.
Design, synthesis and apoptosis inducing effect of novel (Z)-3-(3′-methoxy-4′-(2-amino-2-oxoethoxy)-benzylidene)indolin-2-ones as potential antitumour agents
Senwar, Kishna Ram,Reddy, T. Srinivasa,Thummuri, Dinesh,Sharma, Pankaj,Naidu,Srinivasulu, Gannoju,Shankaraiah, Nagula
, p. 34 - 46 (2016/05/09)
A series of new (Z)-3-(3′-methoxy-4′-(2-amino-2-oxoethoxy)benzylidene)indolin-2-one derivatives has been synthesized and evaluated for their cytotoxic activity against selected human cancer cell lines of prostate (PC-3 and DU-145), breast (BT-549 and MDA-MB-231) and non-tumorigenic prostate epithelial cells (RWPE-1). Among the tested, one of the compounds 4p exhibited potent cytotoxicity selectively on prostate cancer cell lines (PC-3 and DU-145; IC50: 1.89 ± 0.6 and 1.94 ± 0.2 μM, respectively). Further experiments were conducted with 4p on PC-3 cancer cells to study the mechanisms of growth inhibition and apoptosis inducing effect. Treatment of PC-3 cells with test compound 4p resulted in inhibition of cell migration through disorganization of F-actin protein. The flow-cytometry analysis results showed that the compound arrested PC-3 cancer cells in the G2/M phase of cell cycle in a dose dependent manner. Hoechst staining and annexin-V binding assay revealed that the compound 4p inhibited tumor cell proliferation through induction of apoptosis. Western blot studies demonstrated that the compound 4p treatment led to activation of caspase-3, increased expression of pro-apoptotic Bax and significantly decreased expression of anti-apoptotic Bcl-2 in human prostate cancer PC-3 cells. In addition, the mitochondrial membrane potential (ΔΦm) was also affected and the levels of intracellular Ca2+ were raised.
