- Synthesis of novel 5-substituted indirubins as protein kinases inhibitors
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In an effort to identify new pharmacological inhibitors of disease-relevant protein kinases with increased potency and selectivity, we synthesized and evaluated new 5-substituted indirubins. The effects of 34 indirubin derivatives on CDK1/cyclin B, CDK5/p25, and GSK-3, as well as on SH-SY5Y human neuroblastoma cell survival, were investigated.
- Beauchard, Anne,Ferandin, Yoan,Frere, Stephane,Lozach, Olivier,Blairvacq, Melina,Meijer, Laurent,Thiery, Valerie,Besson, Thierry
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- Synthesis of new 3-(Trifluoromethyl)-1H-indoles by reduction of trifluoromethyloxoindoles
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(Chemical Equation Presented) This work describes the synthesis of new 3-trifluoromethylindoles. Different isatins were trifluoromethylated using (trifluoromethyl)trimethylsilane (Me3SiCF3) as a nucleophilic agent giving new 3-hydroxy-3-(trifluoromethyl)indolin-2-one. Different "one-step" procedures to transform the latter compounds into the reduced indoles were attempted, but failed. For the synthesis of the new trifluoromethylindoles the corresponding 2-oxo-3-(trifluoromethyl)indoles were reduced using borane/THF complex to furnish 3-(trifluoromethyl)indolin-3-ol that additionally were dehydrated using thionyl chloride in pyridine to give excellent yields of the desired products.
- Bastos, Monica M.,Mayer, Lucia M. U.,Figueira, Elza C. S.,Soares, Marcio,Kover, Warner B.,Boechat, Nubia
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- AcOH-mediated dichloroimination of indoles using chloramine-B: A facile access to 2,3-functionalized indolines
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A new and mild method for the efficient synthesis of 3,3-dichloro-2-sulfonyliminoindolines via AcOH-mediated dichloroimination of indoles using chloramine-B is presented. Application of this method to the efficient construction of pyrrolidinoindoles and N-C3 linked pyrrolidinoindolines is demonstrated.
- Liu, Xiaozu,Hu, Qinghong,Yuan, Zeli,Liu, Peijun
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- Formation of indole trimers in Vilsmeier type reactions
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The reaction of indole with the complex formed from 1,3-dimethylimidazolidin-2-one or N-methyloxindole with phosphorus oxychloride (phosphoryl chloride), was studied. In similar reactions of five-membered tertiary amide rings, 3-(1-alkyl-pyrrolidin-2-ylidene)-3H-indoles or ring opening products were obtained but in these cases, new products N1,N2-dimethyl-N1-[tri-(1H-indol-3-yl)methyl]ethane-1,2-diamine and N-methyl-2-(3,3,3-tri-(1H-indol-3-yl)propyl)aniline as trimers of indole were obtained. (Formula presented).
- Aghazadeh, Masomeh
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- C-H Activation Relay (CHAR): An Efficient Construction of Isatin Skeleton by Aerobic Oxidation of Glycine Esters
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Directed by the strategy of C-H activation relay (CHAR), an efficient construction of isatin skeleton was developed through catalytic oxidation of glycine esters. The mechanistic study reveals that the oxidation of the relatively active C-H bonds initiated the followed activation of remote and inert C-H bonds, and an intramolecular 1,6-hydrogen shift was involved as a key step.
- Jia, Xiaodong,Zhu, Yingzu,Yuan, Yu,Zhang, Xuewen,Lü, Shiwei,Zhang, Liang,Luo, Liangliang
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- Novel indolin-2-one-substituted methanofullerenes bearing long N-alkyl chains: Synthesis and application in bulk-heterojunction solar cells
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An easy, high-yield and atom-economic procedure of a C60 fullerene modification using a reaction of fullerene C60 with N-alkylisatins in the presence of tris(diethylamino)phosphine to form novel long-chain alkylindolinone-substituted methanofullerenes (AIMs) is described. Optical absorption, electrochemical properties and solubility of AIMs were studied. Poly(3-hexylthiophene-2,5-diyl) (P3HT)/AIMs solar cells were fabricated and the effect of the AIM alkyl chain length and the P3HT:AIM ratio on the solar cell performance was studied. The power conversion efficiencies of about 2% were measured in the P3HT/AIM devices with 1:0.4 P3HT:AIM weight ratio for the AIMs with hexadecyl and dodecyl substituents. From the optical and AFM data, we suggested that the AIMs, in contrast to [6,6]-phenyl-C61-butyric acid methyl ester (PCBM), do not disturb the P3HT crystalline domains. Moreover, the more soluble AIMs do not show a better miscibility with the P3HT crystalline phase.
- Romanova, Irina P.,Bogdanov, Andrei V.,Izdelieva, Inessa A.,Trukhanov, Vasily A.,Shaikhutdinova, Gulnara R.,Yakhvarov, Dmitry G.,Latypov, Shamil K.,Mironov, Vladimir F.,Dyakov, Vladimir A.,Golovnin, Ilya V.,Paraschuk, Dmitry Yu,Sinyashin, Oleg G.
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- New and efficient one-pot synthesis of functionalized γ-spirolactones mediated by vinyltriphenylphosphonium salts
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The addition of dimethyl acetylenedicarboxylate to isatin derivatives in the presence of triphenylphosphine leading to new highly functionalized γ-spirolactones is reported.
- Esmaili, Abbas Ali,Bodaghi, Asghar
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- Aqueous tert-Butyl Hydroperoxide Mediated Regioselective Ring-Opening Reactions of Spiro-aziridine-epoxy Oxindoles: Synthesis of 3-Peroxy-3-substituted Oxindoles and Their Acid-Mediated Rearrangement
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A highly efficient regioselective C3-peroxylation of spiro-aziridine and spiro-epoxy oxindoles has been developed with commercially available 70% aqueous tert-butyl hydroperoxide under solvent-free and metal/catalyst-free conditions. The protocol provides an easy access of 3-peroxyoxindoles, which undergo acid-mediated rearrangement to afford unprecedented 2-hydroxy-2-substituted-2H-benzo[b][1,4]oxazin-3(4H)-ones. The protocol is also equally effective for the ring opening of simple phenyl aziridine with excellent regio-selectivity.
- Hajra, Saumen,Hazra, Atanu,Saleh, Sk Abu,Mondal, Ananda Shankar
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- First X-ray structural characterization of isatin Schiff base derivative. NMR and theoretical conformational studies
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Isatin (1H-indole-2,3-dione) is an endogenous natural compound under intense development in medicinal chemistry. Here, we characterize isatin Schiff base derivative by X-ray crystallography. We describe a derivative that crystallizes E-isomer form in the triclinic space group P 1ˉ; a = 5.9580 (4) A?, b = 8.4184 (7) A?, c = 14.1801 (14) A?, α = 73.962 (8)°, β = 83.184 (7)°, γ = 81.143 (6)°. NMR data show that E-conformer interconverts to the Z-conformer when dissolved, this equilibrium weakly depends on the solvent type. The Z-isomer geometry and the energetics of ΔEE-Zinterconversion barriers were determined by quantum chemical calculations. The isomers are further characterized by means of FT-IR and UV-Vis spectroscopy.
- Davidovich, Pavel,Novikova, Daria,Tribulovich, Vyacheslav,Smirnov, Sergey,Gurzhiy, Vlad,Melino, Gerry,Garabadzhiu, Alexander
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- Reaction of 1-substituted 3-(2-hydroxyethylamino)quinoline-2,4(1H,3H)-diones with isothiocyanic acid
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[Figure not available: see fulltext.] 3-Chloroquinoline-2,4-diones react with ethanolamine to form 3-(3-hydroxyethylamino)quinoline-2,4-diones. These compounds afford, depending on substituents in positions 1 and 3, four different products from their reac
- Klásek, Antonín,Ly?ka, Antonín,Rouchal, Michal,Barto?ík, Radek
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- [3 + 3] Formal Cycloadditions of Nitrones from Isatins and Azaoxyallyl Cations for Construction of Spirooxindoles
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A [3 + 3] formal cycloaddition reaction between in situ formed azaoxyallyl cations and nitrones from isatins has been developed, furnishing a spectrum of spiro[1,2,4-oxadiazinan-5-one]oxindoles in good to excellent yields with excellent diastereoselectivity. This method provides direct and efficient access to potentially bioactive spirooxindoles incorporating a six-membered heterocyclic scaffold.
- Lin, Weijia,Zhan, Gu,Shi, Minglin,Du, Wei,Chen, Yingchun
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- Modular Catalytic Synthesis of 3-Amino-3-aryl-2-oxindoles: Rh Catalysis with Isatin-Derived N-Boc-Protected Ketimines
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Chiral 3-amino-3-aryloxindoles are important biologically active compounds. Using a catalytic modular approach, 31 new 3-amino-3-aryl-2-oxindoles were prepared by a simple Rh-catalysed addition of arylboronic acids to isatin-derived N-Boc-protected ketimines (Boc = tert-butoxycarbonyl). A low catalyst loading of 3 mol-% was used, and the reaction showed a wide scope with high functional-group compatibility, and gave good yields. We report the first catalytic enantioselective reactions with this substrate. Deprotection of the Boc group was easily accomplished in good yields.
- Marques, Carolina S.,Burke, Anthony J.
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- Synthesis and biological evaluation of new [1,2,4]triazino[5,6-b]indol-3-ylthio-1,3,5-triazines and [1,2,4]triazino[5,6-b]indol-3-ylthio-pyrimidines against Leishmania donovani
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A series of [1,2,4]triazino[5,6-b]indol-3-ylthio-1,3,5-triazines and [1,2,4]triazino[5,6-b]indol-3-ylthio-pyrimidines were synthesized and screened for their in vitro antileishmanial activity against Leishmania donovani. Among all, 8 compounds have shown more than 90% inhibition against promastigotes and IC50 in the range of 4.01-57.78 μM against amastigotes. Compound 5, a triazino[5,6-b]indol-3-ylthio-1,3,5-triazine derivative was found to be the most active and least toxic with 20- & 10-fold more selectivity (S.I. = 56.61) as compared to that of standard drugs pentamidine and sodium stibogluconate (SSG), respectively.
- Gupta, Leena,Sunduru, Naresh,Verma, Aditya,Srivastava, Saumya,Gupta, Suman,Goyal, Neena,Chauhan, Prem M.S.
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- Synthesis of novel MT3 receptor ligands via an unusual Knoevenagel condensation
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New 5-acetamido-substituted melatonin derivatives were efficiently synthesized in excellent yields via Knoevenagel condensation. The relative binding affinity of new synthesized compounds to MT3 receptor was tested via enzymatic assays and the X-ray struc
- Volkova, Maria S.,Jensen, Katherine C.,Lozinskaya, Natalia A.,Sosonyuk, Sergey E.,Proskurnina, Marina V.,Mesecar, Andrew D.,Zefirov, Nikolay S.
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- Construction of spiro[indoline]oxindoles through one-pot thermal-induced [3+2] cycloaddition/silica gel-promoted fragmentation sequence between isatin ketonitrones and electron-deficient alkynes
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One-pot thermal-induced [3+2] cycloaddition/silica gel-promoted fragmentation sequence between isatin ketonitrones and electron-deficient alkynes affords spiro[indoline]oxindoles in moderate to excellent yields along with good diastereoselectivities. The
- Yang, Hai-Bin,Wei, Yin,Shi, Min
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- Formation Kinetics of an Amino Carboxy Type Merostabilized Free Radical
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The reduction of isatin (5) and N-methylisatin (6) by the merostabilized free radical 3,5,5-trimethyl-2-morpholinon-3-yl (4) to isatide (7) and N,N'-dimethylisatide (8) is described.The reaction rates are first order in the meso and dl dimers (2 and 3) of 4 and zero order in N-methylisatin.The rate of reaction is a measure of the rate of bond homolysis of the meso or dl dimer.Rate constants and activation parameters are reported.The free energies of activation for homolysis of 2 and 3 in chloroform solvent are 24.6+/-0.3 and 25.1+/-0.2 kcal/mol, respectively.The enthalpy of activation for recombination of 4 is estimated at 4-5 kcal/mol.Measured rate constants for bond homolysis were consistent within one standard deviation with the observed kinetics of isomerization of the meso dimer (2) to the equilibrium mixture of the meso and dl dimers.The activation parameters in part are a measure of the effect of merostabilization on radical stability.
- Bennett, Richard W.,Wharry, Donald L.,Koch, Tad H.
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- TBHP Mediated Substrate Controlled Oxidative Dearomatization of Indoles to C2/C3-Quaternary Indolinones
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Oxidative dearomatization of indoles with 70 % aqueous tert-butylhydroperoxide (TBHP) in the absence of any metal salts/organic solvents gave the corresponding C2/C3-quaternary indolinones under open-air reaction conditions. The nature of substituent on the indole nitrogen dictates the type of product formed in these reactions. Free (NH)-indoles gave C2-quaternary indolinone derivatives whilst (NR)-indoles yielded C3-quaternary indolinones as the major product. Moreover, the addition of an excess amount of TBHP also facilitated the one-pot transformation of (NR)-indoles to the corresponding isatin derivatives.
- Kothandapani, Jagatheeswaran,Reddy, Singarajanahalli Mundarinti Krishna,Thamotharan, Subbiah,Kumar, Shankar Madan,Byrappa, Kullaiah,Ganesan, Subramaniapillai Selva
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- Copper-catalyzed aerobic oxidative intramolecular amidation of 2-aminophenylacetylenes: A domino process for the synthesis of isatin
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A novel CuI-catalyzed oxidative amidation of 2-aminophenylacetylenes leading to the formation of isatins by using open air as an oxygen source has been developed. The reaction proceeded smoothly and provided a variety of isatin derivatives in good yields. The advantages of this one-pot reaction protocol include the use of a green oxidant, low-price catalyst and facile conditions, and easy handling.
- Salvanna,Ramesh, Perla,Santosh Kumar,Das, Biswanath
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- Synthesis of novel functionalized 3-spiropyrrolizidine and 3-spiropyrrolidine oxindoles from Baylis-Hillman adducts of iatin and heteroaldehydes with azomethine ylides via [3+2]-cycloaddition
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A novel regioselective synthesis of a number of functionalized 3-spiropyrrolizidine and 3-spiropyrrolidine oxindoles from Baylis-Hillman adducts of satin and heteroaldehydes via [3+2] cycloaddition of azomethine ylides in excellent yields has been reported.
- Shanmugam, Ponnusamy,Viswambharan, Baby,Madhavan, Suchithra
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- Organocatalytic and Late-Stage CH-Functionalization Enabled Asymmetric Synthesis of Communesin F and Putative Communesins
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Herein we report the total syntheses of communesin F and putative members of the communesin family of polycyclic bis-aminal alkaloids. The successful strategy featured a novel organocatalytic reaction between two oxindole subunits to cast, after extensive optimization, the all-carbon vicinal quaternary stereocenters of the target molecule with high enantiocontrol. The resulting bis-oxindole intermediate further underwent a Ti(OiPr)4-mediated dehydrative skeletal rearrangement to furnish the communesin core structure. Consider the ready availability and low-cost of unsubstituted isatin, and the inferior organocatalytic reaction employing a bromo-substituted substrate, a Pd(OAc)2-catalyzed and oxalamide-directed aryl CH-alkenylation reaction was implemented to assemble the complete skeletal backbone of the target molecule. Collectively, the synthetic technologies disclosed herein constitute the first asymmetric organocatalytic approach to the communesins, together with a highly effective late-stage CH-functionalization in stark contrast to the bromoarene substrates employed in all of the past synthetic work.
- Park, Jisook,Jean, Alexandre,Chen, David Y.-K.
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- The application of Morita-Baylis-Hillman reaction: Synthetic studies on perophoramidine
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A new concise methodology was developed for the synthesis of the two vicinal quaternary centers of the natural product perophoramidine. Key steps involved the Morita–Baylis–Hillman reaction, reductive cyclization and allylic alkylation. Moreover, most con
- Wu, Lin,Zhang, Qian-Ru,Huang, Ji-Rong,Li, Yang,Su, Fu,Dong, Lin
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- Base-mediated allylation of N-2,2,2-trifluoroethylisatin ketimines and its application in aza-Prins reactions
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The aza-Prins reaction of allylic imines triggered by N-2,2,2-trifluoroethylisatin ketimine is accomplished for the synthesis of spirooxindole derivatives involving trifluoromethyl group in the presence of TMSX. This cyclization reaction is operationally simple and proceeds under mild conditions using non-toxic reagents. Notably, while the previous our work could not be compatible with TMSX (X = Cl, I, etc) in one-pot process, this work describes successful aza-Prins reaction with TMSX (X = Cl, I, etc) via step-by-step process.
- Kim, Jaehwan,Yeon Park, Se,Jung, Myeongjin,Jang, Woo Cheol,Ko, Haye Min
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supporting information
(2021/12/01)
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- Organocatalytic Asymmetric Synthesis of Cyclic Acetals with Spirooxindole Skeleton
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An organocatalytic asymmetric synthesis of cyclic acetal with spirooxindole skeleton has been developed via a domino reaction between isatin and γ-hydroxy enones. Bifunctional squaramide catalyst with adamantyl motif was found to be the most effective for the cascade reaction. With 10 mol% of the catalyst, the desired products were obtained in 1.8:1 to 9:1 diastereo- and 86% to >99% enantioselectivities from a range of substituted isatins and γ-hydroxy enones. (Figure presented.).
- Shikari, Amit,Mandal, Koushik,Chopra, Deepak,Pan, Subhas Chandra
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supporting information
p. 58 - 63
(2021/11/09)
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- Oxidative Cleavage of Indoles Mediated by Urea Hydrogen Peroxide or H2O2 in Polar Solvents
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The oxidative cleavage of indoles (Witkop oxidation) involving the use of H2O2 or urea hydrogen peroxide in combination with a polar solvent has been described. Among these solvents, 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) stands out as the one affording the corresponding 2-ketoacetanilides generally in higher yields The protocol described has also enabled the oxidation of different pyrroles and furans derivatives. Furthermore, the procedure was implemented in a larger-scale and HFIP was distilled from the reaction mixture and reused (up to 4 cycles) without a significant detriment in the reaction outcome, which remarks its sustainability and applicability. (Figure presented.).
- Llopis, Natalia,Gisbert, Patricia,Baeza, Alejandro
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supporting information
p. 3245 - 3249
(2021/06/08)
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- Novel quinolone-based potent and selective HDAC6 inhibitors: Synthesis, molecular modeling studies and biological investigation
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In this work we describe the synthesis of potent and selective quinolone-based histone deacetylase 6 (HDAC6) inhibitors. The quinolone moiety has been exploited as an innovative bioactive cap-group for HDAC6 inhibition; its synthesis was achieved by applying a multicomponent reaction. The optimization of potency and selectivity of these products was performed by employing computational studies which led to the discovery of the diethylaminomethyl derivatives 7g and 7k as the most promising hit molecules. These compounds were investigated in cellular studies to evaluate their anticancer effect against colon (HCT-116) and histiocytic lymphoma (U9347) cancer cells, showing good to excellent potency, leading to tumor cell death by apoptosis induction. The small molecules 7a, 7g and 7k were able to strongly inhibit the cytoplasmic and slightly the nuclear HDAC enzymes, increasing the acetylation of tubulin and of the lysine 9 and 14 of histone 3, respectively. Compound 7g was also able to increase Hsp90 acetylation levels in HCT-116 cells, thus further supporting its HDAC6 inhibitory profile. Cytotoxicity and mutagenicity assays of these molecules showed a safe profile; moreover, the HPLC analysis of compound 7k revealed good solubility and stability profile.
- Relitti, Nicola,Saraswati, A. Prasanth,Chemi, Giulia,Brindisi, Margherita,Brogi, Simone,Herp, Daniel,Schmidtkunz, Karin,Saccoccia, Fulvio,Ruberti, Giovina,Ulivieri, Cristina,Vanni, Francesca,Sarno, Federica,Altucci, Lucia,Lamponi, Stefania,Jung, Manfred,Gemma, Sandra,Butini, Stefania,Campiani, Giuseppe
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- Microwave-assisted synthesis and antimicrobial activity of novel spiro 1,3,4-thiadiazolines from isatin derivatives
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This work describes the synthesis of spiro 1,3,4-thiadiazolines from isatin-β-thiosemicarbazone acetylation, using microwave irradiation as a source of heating the reaction medium. N-substituted isatin derivatives were used as substrates to obtain thiosemicarbazones by adding thiosemicarbazide to the isatin ketone carbonyl. The final synthetic step was the reaction of thiosemicarbazones with acetic anhydride under microwave irradiation to get the spiro compounds. Reaction times ranged from 6 to 18 minutes resulting in yields of up to 90%. Biological assays have shown promising antibacterial and antifungal activity, especially spiro thiadiazolines derived from allylated isatins. All the proposed molecules proved to be potential drug candidates based on the results of the in silico investigation, with satisfactory drug-likeness and drug-score, respecting Lipinski's rule. The use of the microwave reactor was efficient for the synthesis of thiosemicarbazones and spiro compounds, resulting in a significant reduction in reaction times with conventional heating. Taking into account the threat of antimicrobial resistance, this work presents a series of bioactive molecules that are easily obtained via microwave reaction.
- da Costa, Daniel Pereira,de Castro, Aleff Cruz,da Silva, Girlyanderson Araújo,Lima-Junior, Claudio Gabriel,de Andrade Júnior, Francisco Patricio,de Oliveira Lima, Edeltrudes,Vaz, Boniek Gontijo,da Silva, Lidya Cardoso
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p. 766 - 776
(2020/12/31)
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- BIOMASS DERIVED DIKETONES AS EFFICIENT VISIBLE LIGHT PHOTOINITIATORS
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Isatin derivatives, and methods of using isatin and isatin derivatives as photoinitiators, are described.
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Paragraph 00202-00205
(2021/11/26)
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- Applications of Ytterbium(II) Reagent as Grignard Reagent and Single-Electron Transfer Reagent in the Synthesis of 3-Substituted 2-Oxindoles
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The use of ytterbium(II) reagent as both nucleophilic reagent and single-electron transfer reagent in the reaction of isatin derivatives with ytterbium(II) reagent is reported. From a synthetic point of view, a general, efficient, and experimentally simple one-pot method for the preparation of 3-substituted 2-oxindoles was developed.
- Wang, Pengkai,Cao, Xuyan,Zhang, Songlin
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supporting information
p. 3836 - 3846
(2021/07/02)
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- Palladium-Catalyzed Allenamide Carbopalladation/Allylation with Active Methine Compounds
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A palladium-catalyzed allenamide carbopalladation/allylation with active methine compounds has been developed. Various indoles and isoquinolinones bearing a quaternary carbon center were achieved with good efficiency, a broad substrate scope and good functional group tolerance. This reaction underwent cascade oxidative addition, carbopalladation, and allylic alkylation, and two new C-C bonds were formed in one pot.
- Zhu, Xiaoyi,Li, Ruibo,Yao, Hequan,Lin, Aijun
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supporting information
p. 4630 - 4634
(2021/06/28)
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- Synthesis, in silico, in vitro and in vivo evaluations of isatin aroylhydrazones as highly potent anticonvulsant agents
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In this study, a series of new isatin aroylhydrazones (5a-e and 6a-e) was synthesized and evaluated for their anticonvulsant activities. The (Z)-configuration of compounds was confirmed by 1H NMR. In vivo studies using maximal electroshock (MES) and pentylenetetrazole (PTZ) models of epilepsy in mice revealed that while most of compounds had no effect on chemically-induced seizures at the higher dose of 100 mg/kg but showed significant protection against electrically-induced seizures at the lower dose of 5 mg/kg. Certainly, N-methyl analogs 6a and 6e were found to be the most effective compounds, displaying 100% protection at the dose of 5 mg/kg. Protein binding and lipophilicity (logP) of the selected compounds (6a and 6e) were also determined experimentally. In silico evaluations of title compounds showed acceptable ADME parameters, and drug-likeness properties. Distance mapping and docking of the selected compounds with different targets proposed the possible action of them on VGSCs and GABAA receptors. The cytotoxicity evaluation of 6a and 6e against SH-SY5Y and Hep-G2 cell lines indicated safety profile of compounds on the neuronal and hepatic cells.
- Emami, Saeed,Valipour, Mehdi,Kazemi Komishani, Fatemeh,Sadati-Ashrafi, Fatemehsadat,Rasoulian, Maria,Ghasemian, Majid,Tajbakhsh, Mahmood,Honarchian Masihi, Patrick,Shakiba, Aidin,Irannejad, Hamid,Ahangar, Nematollah
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- Development of isatin-thiazolo[3,2-a]benzimidazole hybrids as novel CDK2 inhibitors with potent in vitro apoptotic anti-proliferative activity: Synthesis, biological and molecular dynamics investigations
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In the current medical era, human health is experiencing numerous challenges, particularly the human malignancies. Therefore, the therapeutic arsenal for these malignancies is to be inexorably enhanced with new treatments that target tumor cells in a selective manner. In this regard, the present work aims at developing a new set of small molecules featuring the privileged isatin scaffold conjugated with a thiazolo[3,2-a]benzimidazole (TBI) motif through a cleavable hydrazide linker (7a-e and 10a-i) as potential anticancer CDK2 inhibitors. The large tricyclic TBI motif is anticipated to achieve a plethora of hydrophobic interactions within the CDK2 binding site. The growth of the two examined cell lines was significantly inhibited by most the prepared hybrids with IC50 ranges; (2.60 ± 1.47–20.90 ± 1.17 μM, against MDA-MB-231) and (1.27 ± 0.06–16.83 ± 0.95 μM, against MCF-7). In particular, hybrids 7a, 7d and 10a displayed potent dual activity against the examined cell lines, and thus selected for further investigations. They exerted a significance alteration in the cell cycle progression, in addition to an apoptosis induction within both MDA-MB-231 and MCF-7 cells. Furthermore, 7a, 7d and 10a displayed potent CDK2 inhibitory action (IC50 = 96.46 ± 5.3, 26.24 ± 1.4 and 42.95 ± 2.3 nM, respectively). The docking simulations unveiled, as expected, the ability of the TBI ring to well-accommodate and establish several hydrophobic interactions within a hydrophobic pocket in the CDK2 binding site. Also, the docking simulations highlighted the significance of incorporation of the hydrazide linker and isatin unsubstituted (NH) functionality in the H-bonding interactions. Interestingly, the most potent CDK2 inhibitor 7d achieved the best binding score (-11.2 Kcal/mole) and formed the most stable complex with CDK2 enzyme (RMSD = 1.24 ?) in a 100 ns MD simulation. In addition, the MM-PBSA calculations ascribed the lowest binding free energy to the 7d–CDK2 complex (?323.69 ± 15.17 kJ/mol). This could be attributed to an incorporation of the 5-OCH3 group that was engaged in an extra hydrogen bonding with key THR14 amino acid residue. Finally, these results suggested hybrid 7d as a good candidate for further optimization as promising breast cancer antitumor agent and CDK2 inhibitor.
- Eldehna, Wagdy M.,El Hassab, Mahmoud A.,Abo-Ashour, Mahmoud F.,Al-Warhi, Tarfah,Elaasser, Mahmoud M.,Safwat, Nesreen A.,Suliman, Howayda,Ahmed, Marwa F.,Al-Rashood, Sara T.,Abdel-Aziz, Hatem A.,El-Haggar, Radwan
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supporting information
(2021/03/15)
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- Novel oxindole/benzofuran hybrids as potential dual CDK2/GSK-3β inhibitors targeting breast cancer: design, synthesis, biological evaluation, and in silico studies
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The serine/threonine protein kinases CDK2 and GSK-3β are key oncotargets in breast cancer cell lines, therefore, in the present study three series of oxindole-benzofuran hybrids were designed and synthesised as dual CDK2/GSK-3β inhibitors targeting breast cancer (5a–g, 7a–h, and 13a–b). The N1 -unsubstituted oxindole derivatives, series 5, showed moderate to potent activity on both MCF-7 and T-47D breast cancer cell lines. Compounds 5d–f showed the most potent cytotoxic activity with IC50 of 3.41, 3.45 and 2.27 μM, respectively, on MCF-7 and of 3.82, 4.53 and 7.80 μM, respectively, on T-47D cell lines, in comparison to the used reference standard (staurosporine) IC50 of 4.81 and 4.34 μM, respectively. On the other hand, the N1 -substituted oxindole derivatives, series 7 and 13, showed moderate to weak cytotoxic activity on both breast cancer cell lines. CDK2 and GSK-3β enzyme inhibition assay of series 5 revealed that compounds 5d and 5f are showing potent dual CDK2/GSK-3β inhibitory activity with IC50 of 37.77 and 52.75 nM, respectively, on CDK2 and 32.09 and 40.13 nM, respectively, on GSK-3β. The most potent compounds 5d–f caused cell cycle arrest in the G2/M phase in MCF-7 cells inducing cell apoptosis because of the CDK2/GSK-3β inhibition. Molecular docking studies showed that the newly synthesised N1 -unsubstituted oxindole hybrids have comparable binding patterns in both CDK2 and GSK-3β. The oxindole ring is accommodated in the hinge region interacting through hydrogen bonding with the backbone CO and NH of the key amino acids Glu81 and Leu83, respectively, in CDK2 and Asp133 and Val135, respectively, in GSK-3β. Whereas, in series 7 and 13, the N1 -substitutions on the oxindole nucleus hinder the compounds from achieving these key interactions with hinge region amino acids what rationalises their moderate to low anti-proliferative activity.
- Eldehna, Wagdy M.,Al-Rashood, Sara T.,Al-Warhi, Tarfah,Eskandrani, Razan O.,Alharbi, Amal,El Kerdawy, Ahmed M.
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p. 270 - 285
(2020/12/18)
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- Development of 2-oindolin-3-ylidene-indole-3-carbohydrazide derivatives as novel apoptotic and anti-proliferative agents towards colorectal cancer cells
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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.
- 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.
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p. 319 - 328
(2020/12/23)
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- Development of novel benzofuran-isatin conjugates as potential antiproliferative agents with apoptosis inducing mechanism in Colon cancer
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In the current work, a new set of carbohydrazide linked benzofuran-isatin conjugates (5a–e and 7a–i) was designed and synthesised. The anticancer activity for compounds (5b–d, 7a, 7b, 7d and 7g) was measured against NCI-55 human cancer cell lines. Compound 5d was the most efficient, and thus subjected to the five-dose screen where it showed excellent broad activity against almost all tested cancer subpanels. Furthermore, all conjugates (5a–e and 7a–i) showed a good anti-proliferative activity towards colorectal cancer SW-620 and HT-29 cell lines, with an excellent inhibitory effect for compounds 5a and 5d (IC50 = 8.7 and 9.4 μM (5a), and 6.5 and 9.8 μM for (5d), respectively). Both compounds displayed selective cytotoxicity with good safety profile. In addition, both compounds provoked apoptosis in a dose dependent manner in SW-620 cells. Also, they significantly inhibited the anti-apoptotic Bcl2 protein expression and increased the cleaved PARP level that resulted in SW-620 cells apoptosis.
- Eldehna, Wagdy M.,Salem, Rofaida,Elsayed, Zainab M.,Al-Warhi, Tarfah,Knany, Hamada R.,Ayyad, Rezk R.,Traiki, Thamer Bin,Abdulla, Maha-Hamadien,Ahmad, Rehan,Abdel-Aziz, Hatem A.,El-Haggar, Radwan
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p. 1424 - 1435
(2021/07/02)
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- Lanthanide Silylamide-Catalyzed Synthesis of Pyrano[2,3- b]indol-2-ones
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A lanthanide silylamide-catalyzed tandem reaction of isatins, diethyl phosphite, and 2,3-diarylcyclopropenones has been developed. A series of pyrano[2,3-b]indol-2-ones were synthesized in high yields. The cooperation of the Lewis acidity of the lanthanide center and the Bronsted basicity of the N(SiMe3)2 anion may be the key factor affecting the catalytic activity of lanthanide amides.
- Chen, Qifa,Teng, Yue,Xu, Fan
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supporting information
p. 4785 - 4790
(2021/06/28)
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- Design, synthesis,: In silico molecular modelling studies and biological evaluation of novel indole-thiazolidinedione hybrid analogues as potential pancreatic lipase inhibitors
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Pancreatic lipase (PL) is a key enzyme responsible for the digestion of dietary triglycerides; hence its inhibition is considered as a promising target for the management and/or treatment of obesity. A new series of indole-thiazolidinedione (TZD) hybrid analogues were synthesized using a molecular hybridisation approach and evaluated for their anti-obesity effects via PL inhibition. The targeted analogues were synthesized via the condensation reaction between various substituted isatin with TZD in the presence of aqueous KOH in methanol. Amongst the synthesized analogues, 7k and 7m exhibited a potential PL inhibitory activity (IC50-7.30 and 9.51 μM, respectively). Kinetic study of these potent analogues revealed their competitive mode of enzyme inhibition. This fact was confirmed via fluorescence spectroscopy which further suggested the presence of one binding site for the synthesized analogues. Molecular docking of the synthesized analogues was performed using human PL (PDB ID: 1LPB). The obtained MolDock scores were aligned with the in vitro PL inhibitory activity (Pearson's r = 0.9108, p 0.05). Moreover, a stable conformation of the 1LPB-ligands suggested the stability of these complexes in the dynamic environment. These studies provided a basis for the potential role of the indole-TZD hybrids in PL inhibition and further optimization might result in the development of new lead candidates for obesity treatment.
- George, Ginson,Auti, Prashant S.,Paul, Atish T.
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p. 1381 - 1394
(2021/02/06)
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- Bismuth(iii)-catalyzed regioselective alkylation of tetrahydroquinolines and indolines towards the synthesis of bioactive core-biaryl oxindoles and CYP19 inhibitors
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Bismuth(iii)-catalyzed regioselective functionalization at the C-6 position of tetrahydroquinolines and the C-5 position of indolines has been demonstrated. For the first time, one pot symmetrical and unsymmetrical arylation of isatins with tetrahydroquinolines was accomplished giving a completely new product skeleton in good to excellent yields. Most importantly, this protocol leads to the formation of a highly strained quaternary carbon stereogenic center, which is a challenging task. Benzhydryl and 1-phenylethyl trichloroacetimidates have been used as the alkylating partners to functionalize the C-6 and C-5 positions of tetrahydroquinolines and indolines, respectively. The scope of the developed methodology has been extended for the synthesis of the bioactive CYP19-inhibitor and its analogue.
- Prusty, Namrata,Kinthada, Lakshmana K.,Meena, Rohit,Chebolu, Rajesh,Ravikumar, Ponneri Chandrababu
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p. 891 - 905
(2021/02/09)
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- Synthesis of Azacarbolines via PhIO2-Promoted Intramolecular Oxidative Cyclization of α-Indolylhydrazones
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An unprecedented synthesis of polysubstituted indole-fused pyridazines (azacarbolines) from α-indolylhydrazones under oxidative conditions using a combination of iodylbenzene (PhIO2) and trifluoroacetic acid (TFA) has been developed. This transformation is conducted without the need for transition metals, harsh conditions, or an inert atmosphere.
- Corrieri, Matteo,De Crescentini, Lucia,Mantellini, Fabio,Mari, Giacomo,Santeusanio, Stefania,Favi, Gianfranco
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p. 17918 - 17929
(2021/12/17)
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- Dynamic Kinetic Asymmetric Transformation of Racemic Diastereomers: Diastereo- and Enantioconvergent Michael–Henry Reactions to Afford Spirooxindoles Bearing Furan-Fused Rings
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Dynamic kinetic asymmetric transformation (DYKAT) reactions of racemic diastereomer mixtures that afford the products as essentially single diastereomers with high enantioselectivities are described. We demonstrated the DYKAT in the diastereo- and enantio
- Sohail, Muhammad,Tanaka, Fujie
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supporting information
p. 21256 - 21260
(2021/08/23)
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- Synthesis, characterization and anticancer activity of (5,1-substituted)-3-(indoline-4-(thiophene- 2-yl-methylene)-2-(p-tolyl)-2-methylene)-4,3-dihydro-1h-imidazole-5-one derivatives
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The synthesis of novel imidazole-5-one derivatives (5a-j) was allowed in a conventional method by way of Erlenmeyer and Schiff base mechanism. Compound 2a was synthesized by Erlenmeyer reaction of N-(4-methoxy benzoyl)glycine with 2-thiophene-carboxaldehyde in the presence of acetic anhydride and anhydrous sodium acetate. Finally, it undergoes dehydration reaction with Schiff bases of isatin derivatives (4a-j) to yield final compounds 5a-j. The organic potentials of the newly synthesized imidazole-5-one derivatives have been evaluated for their in vitro anticancer activity by MTT assay method. It against MCF-7 cells as comparison with doxorubicin popular drug. The synthesized compounds 5e, 5f and 5j exhibited excellent anticancer activity against MCF-7 cell lines.
- BAYYA, CHANDRAPRAKASH,MANDA, SARANGAPANI
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p. 2027 - 2032
(2021/08/24)
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- Visible-Light-Mediated Dearomatisation of Indoles and Pyrroles to Pharmaceuticals and Pesticides
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Dearomatisation of indole derivatives to the corresponding isatin derivatives has been achieved with the aid of visible light and oxygen. It should be noted that isatin derivatives are highly important for the synthesis of pharmaceuticals and bioactive compounds. Notably, this chemistry works excellently with N-protected and protection-free indoles. Additionally, this methodology can also be applied to dearomatise pyrrole derivatives to generate cyclic imides in a single step. Later this methodology was applied for the synthesis of four pharmaceuticals and a pesticide called dianthalexin B. Detailed mechanistic studies revealed the actual role of oxygen and photocatalyst.
- Schilling, Waldemar,Zhang, Yu,Riemer, Daniel,Das, Shoubhik
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supporting information
p. 390 - 395
(2019/12/15)
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- A Bifunctional Iron Nanocomposite Catalyst for Efficient Oxidation of Alkenes to Ketones and 1,2-Diketones
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We herein report the fabrication of a bifunctional iron nanocomposite catalyst, in which two catalytically active sites of Fe-Nx and Fe phosphate, as oxidation and Lewis acid sites, were simultaneously integrated into a hierarchical N,P-dual doped porous carbon. As a bifunctional catalyst, it exhibited high efficiency for direct oxidative cleavage of alkenes into ketones or their oxidation into 1,2-diketones with a broad substrate scope and high functional group tolerance using TBHP as the oxidant in water under mild reaction conditions. Furthermore, it could be easily recovered for successive recycling without appreciable loss of activity. Mechanistic studies disclose that the direct oxidation of alkenes proceeds via the formation of an epoxide as intermediate followed by either acid-catalyzed Meinwald rearrangement to give ketones with one carbon shorter or nucleophilic ring-opening to generate 1,2-diketones in a cascade manner. This study not only opens up a fancy pathway in the rational design of Fe-N-C catalysts but also offers a simple and efficient method for accessing industrially important ketones and 1,2-diketones from alkenes in a cost-effective and environmentally benign fashion.
- Ma, Zhiming,Ren, Peng,Song, Tao,Xiao, Jianliang,Yang, Yong,Yuan, Youzhu
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p. 4617 - 4629
(2020/05/19)
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- Discovery of 3,3′-pyrrolidinyl-spirooxindoles as cardioprotectant prohibitin ligands
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The scaffold proteins prohibitins-1 and 2 (PHB1/2) play many important roles in coordinating many cell signaling pathways and represent emerging targets in cardiology and oncology. We previously reported that a family of natural products derivatives, flavaglines, binds to PHB1/2 to exert cardioprotectant and anti-cancer effects. However, flavaglines also target the initiation factor of translation eIF4A, which doesn't contribute to cardioprotection and may even induce some adverse effects. Herein, we report the development of a convenient and robust synthesis of the new PHB2 ligand 2′-phenylpyrrolidinyl-spirooxindole, and its analogues. We discovered that these compounds displays cardioprotective effect against doxorubicin mediated cardiotoxicity and uncovered the structural requirement for this activity. We identified in particular some analogues that are more cardioprotectant than flavaglines. Pull-down experiments demonstrated that these compounds bind not only to PHB2 but also PHB1. These novel PHB ligands may provide the basis for the development of new drugs candidates to protect the heart against the adverse effects of anticancer treatments.
- Elderwish, Sabria,Audebrand, Ana?s,Nebigil, Canan G.,Désaubry, Laurent
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supporting information
(2019/11/26)
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- Preparation method of Spiro[oxindole-3,2'-pyrrolidine] Derivatives
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The present invention relates to a novel spiro[oxyindole-3,2andprime;-pyrrolidine] derivative and a method for manufacturing the same. In order to achieve the aforementioned objective, the present invention provides the spiro[oxyindole-3,2andprime;-pyrrol
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Paragraph 0108-0109
(2020/07/29)
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- Annulation reaction of cyclic pyridinium ylides with: In situ generated azoalkenes for the construction of spirocyclic skeletons
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Two new types of cyclic pyridinium ylides were designed and further used in reactions with azoalkenes to access structurally diverse spirocyclic compounds. A range of spiropyrazoline oxindoles could be smoothly obtained in up to 99% yield via a [4 + 1] annulation process with oxindole 3-pyridinium ylides as C1 synthons. Similarly, a series of spiropyrazoline indanones could be prepared with indanone 2-pyridinium ylides as C1 synthons. This work represents the first example of cyclic pyridinium ylides as C1 synthons for the efficient construction of spirocyclic compounds.
- Quan, Bao-Xue,Yuan, Wei-Cheng,Zhang, Ming-Liang,Zhang, Xiao-Mei,Zhao, Jian-Qiang,Zhou, Ming-Qiang,Zhuo, Jun-Rui
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supporting information
p. 1886 - 1891
(2020/03/23)
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- Accessing New 5-α-(3,3-Disubstituted Oxindole)-Benzylamine Derivatives from Isatin: Stereoselective Organocatalytic Three Component Petasis Reaction
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A one-step, three-component Petasis reaction of isatin derived 5-arylboronate-3-substituted oxindole derivatives with salicylaldehydes and secondary amines affords new enantiomerically pure structurally diverse 5-α-(3-substituted-oxindole)-benzylamine derivatives. The reaction shows good substrate and reagent scope affording the products with good to excellent yields (up to >99 % yield) and enantioselectivities (up to 99 % ee) using cheap and readily available (R)-BINOL as the organocatalyst. A diastereoselective version of the reaction was also developed where moderate yields (37 to 55 % yield), excellent enantioselectivities (up to 99 % ee) and good diastereoselectivities (up to 86 % de) were obtained for new 5-α-(3-hydroxy-oxindole)-benzylamine derivatives, having two stereocenters. The reaction is also feasible on gram-scale.
- Burke, Anthony J.,Erxleben, Andrea,Marques, Carolina S.,McArdle, Patrick
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supporting information
(2020/06/30)
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- Enantio- And Diastereoselective Synthesis of Homoallylic α-Trifluoromethyl Amines by Catalytic Hydroalkylation of Dienes
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We describe a strategy for the enantio- and diastereoselective synthesis of homoallylic α-trifluoromethyl amines by the catalytic hydroalkylation of terminal dienes. Trifluoromethyl-substituted isatin-derived azadienolate nucleophiles undergo γ-selective alkylation with a Pd-DTBM-SEGPHOS catalyst, which additionally promotes regioselective addition to the diene and delivers products in up to 86% yield, 10:1 dr, and 97.5:2.5 er.
- Onyeagusi, Chibueze I.,Shao, Xinxin,Malcolmson, Steven J.
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supporting information
p. 1681 - 1685
(2020/02/22)
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- The selective condensation of pyrazolones to isatins in aqueous medium
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The selective condensation of pyrazolones with isatins using water as the reaction medium is presented. This strategy provides an environmentally benign synthetic route to synthesize various potentially bioactive pyrazolone substituted oxindoles.
- Zhang, Yong,Nie, Long-Jun,Luo, Liang,Mao, Jia-Xin,Liu, Jin-Xiang,Xu, Guo-Hai,Chen, Deliang,Luo, Hai-Qing
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supporting information
(2020/01/08)
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- Synthesis, biological evaluation and in silico studies of certain oxindole–indole conjugates as anticancer CDK inhibitors
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On account of their overexpression in a wide range of human malignancies, cyclin-dependent kinases (CDKs) are among the most validated cancer targets, and their inhibition has been featured as a valuable strategy for anticancer drug discovery. In this study, a hybrid pharmacophore approach was adopted to develop two series of oxindole–indole conjugates (6a–i and 9a–f) and carbocycle–indole conjugates (11a,b) as efficient antitumor agents with potential inhibitory action toward CDK4. All oxindole–indole conjugates, except 6i, 9b, and 9c efficiently affected the growth of the human breast cancer MCF-7 (IC50: 0.39 ± 0.05–21.40 ± 1.58 μM) and/or MDA-MB-231 (IC50: 1.03 ± 0.04–22.54 ± 1.67 μM) cell lines, whereas bioisosteric replacement of the oxindole nucleus with indane or tetralin rings (compounds 11a,b) diminished the anti-proliferative activity. In addition, hybrids 6e and 6f displayed effective cell cycle disturbance and proapoptotic capabilities in MCF-7 cells. Furthermore, the efficient anti-proliferative agents towards MCF-7 and/or MDA-MB-231 cell lines (6a–h, 9a, and 9e) were investigated for their potential inhibitory action toward CDK4. Hybrids 6a and 6e displayed good CDK4 inhibitory activity with IC50s equal 1.82 and 1.26 μM, respectively. The molecular docking study revealed that oxindole moiety is implicated in two H-bonding interactions via both (NH) and (C=O) groups with the key amino acids Glu94 and Val96, respectively, whereas the indole framework is stably accommodated in a hydrophobic sub-pocket establishing hydrophobic interactions with the amino acid residues of Ile12, Val20, and Gln98 lining this sub-pocket. Collectively, these results highlighted hybrids 6a and 6e as good leads for further optimization as promising antitumor drugs toward breast malignancy and CDK inhibitors.
- Abdel-Aziz, Hatem A.,Al-Ansary, Ghada H.,Al-Warhi, Tarfah,Aljaeed, Nada,Ayyad, Rezk R.,El Kerdawy, Ahmed M.,Eldehna, Wagdy M.,Ismael, Omnia E.
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- Palladium-Catalyzed Allylation of Cyclopropyl Acetylenes with Oxindoles to Construct 1,3-Dienes
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A novel palladium-catalyzed allylic alkylation of oxindoles with cyclopropyl acetylenes has been developed. Various 1,3-diene oxindole framework bearing a quaternary stereocenter at the C3 position were synthesized straightforwardly in good to excellent yields with high regio-, and stereoselectivities. The reaction exhibited high atom economy and good functional group tolerance.
- Lu, Chuan-Jun,Yu, Xin,Chen, Yu-Ting,Song, Qing-Bao,Yang, Zhen-Ping,Wang, Hong
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p. 680 - 688
(2020/02/11)
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- Synthesis and selective inhibitory effects of some 2-oxindole benzenesulfonamide conjugates on human carbonic anhydrase isoforms CA I, CA II, CA IX and CAXII
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Three series of 2-oxindole benzenesulfonamide conjugates with different linkers were prepared by the condensation reaction of isatin derivatives 1a-e with different benzenesulfonamides. They were screened for their ability to inhibit human (h) carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I, hCA II, hCA IX and hCA XII. Many compounds revealed promising activity and selectivity toward CAI, CAII and CAIX compared to acetazolamide (AAZ) especially compounds 2b (KI = 97.6, 8.0 nM against hCA I, hCA II, respectively) and 3a (KI = 90.2, 6.5 and 21.4 nM against hCA I, hCA II and hCA IX, respectively) relative to AAZ (KI = 250, 12 and 25 nM). Additionally, compound 4a revealed the highest activity against hCA II and hCA IX with KI of 3.0 and 13.9 nM, respectively. Docking of 2b, 3a and 4a into the active site of CA I, II, IX and XII revealed binding mode comparable to AAZ confirming the inhibition results.
- George, Riham F.,Said, Mona F.,Bua, Silvia,Supuran, Claudiu T.
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- Syntheses of 2-Iminoindolin-3-ones and 2-Alknyl-2,3-dihydroquinazolin-4(1 H)-ones from 3-Diazoindolin-2-imines
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3-Diazoindolin-2-imines reacted with nitrones to furnish 2-iminoindolin-3-ones through a Au(I)-catalyzed cascade oxygen transfer/imine exchange process. The prepared 2-iminoindolin-3-ones could be further transformed into 2-Alknyl-2,3-dihydroquinazolin-4(1H)-ones through a Ag(I)-catalyzed reaction with terminal alkynes. A MeOH-Triggered ring expansion mechanism involving cyclic iminium formation and nucleophilic addition is proposed for this novel alkynylation reaction. This two-step procedure provides a general and convenient approach to 2-Alknyl-2,3-dihydroquinazolin-4(1H)-ones, which are privileged structures in medicinal chemistry.
- Lin, Zhenwei,Qian, Jing,Lu, Ping,Wang, Yanguang
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p. 11766 - 11777
(2020/10/23)
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- Synthesis method of isatin derivatives
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The invention relates to a synthesis method of isatin derivatives. The synthesis method comprises following steps: taking a compound represented by a formula (I) as a raw material, and carrying out reactions in the presence of a copper salt catalyst and an oxidant to obtain isatin derivatives represented by a formula (II); wherein R1 represents a C1-C3 alkyl group, and R2 represents H, a halogen atom, a C1-C3 alkyl group, a C1-C3 alkoxyl group, a nitro group, a naphthyl group, or an ester group. According to the synthesis method, the compound represented by the formula (I) is taken as the rawmaterial to synthesize isatin derivatives in one step in the presence of a copper salt catalyst and an oxidant; the synthesis route is simple; moreover, the subsequent purification and separation areconvenient; the obtained product purity is high, and the application prospect is good.
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Paragraph 0054-0057
(2020/02/27)
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- Transformations of N-arylpropiolamides to indoline-2,3-diones and acids via C≡C triple bond oxidative cleavage and C(sp2)–H functionalization
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A new palladium-catalyzed oxidative conversion of N-arylpropiolamides and H2O to various indoline-2,3-diones and acids through the C≡C triple bond cleavage and C(sp2)–H functionalization is described, which is promoted by a cooperative action of catalytic CuBr2, 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) and O2. The method provides a practical tool for transformations of alkynes by means of a C–H functionalization strategy, which enables the formation of one C–C bond and multiple C–O bonds in a single reaction with high substrates compatibility and excellent functional group tolerance.
- Zhou, Ming-Bo,Li, Yang,Ouyang, Xuan-Hui,Li, Jin-Heng
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p. 222 - 227
(2019/11/13)
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- POLYMORPHIC FORM OF MEISOINDIGO AND MODIFIED FORMULATION OF MEISOINDIGO
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The present invention relates to a novel crystal form, manufacturing procedures, pharmaceutical compositions, formulations and medicaments comprising a N-methylisoindigo crystalline, methods of preparation, and the use of the N-methylisoindigo crystalline to prepare a medicament to prevent cancer, or treat cancer or an inflammatory-related disease associated with pro-inflammatory cytokine expression and/or reduced expression of anti-inflammatory cytokines.
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- Facile synthesis of isatins by direct oxidation of indoles and 3-iodoindoles using NIS/IBX
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A facile one-pot access to a broad range of isatins by direct oxidation of indoles using NIS/IBX reagent in DMSO at 25 °C in very good isolated yields is reported. It is shown by mechanistic investigations that a number of substituted indoles react rapidly with NIS in DMSO to produce intermediary 3-iodoindoles, which undergo oxidation subsequently to isatins with IBX.
- Chandra, Ajeet,Yadav, Navin R.,Moorthy, Jarugu Narasimha
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supporting information
p. 2169 - 2174
(2019/03/04)
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- Metal-free synthesis of benzimidazo[1,2-c]quinazolin-6-ones with indole and benzenediamine oxidized by I2/TBHP
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A variety of benzimidazo[1,2-c]quinazolin-6-ones derivatives can be accessed in moderate to good yields under simple and metal-free reaction conditions using indoles and o-benzenediamines oxidized by iodine and TBHP. This procedure works in reasonable yields for different indoles as well as o-benzenediamines thus may provide a good synthesis of quinazolinones. A TBHP oxidized ring expansion reaction mechanism that explains the synthesis of benzimidazo[1,2-c]quinazolin-6-ones were reported.
- Dai, Zhen,Li, Songhua,Li, Yunyi,Feng, Lei,Ma, Chen
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supporting information
p. 2012 - 2017
(2019/02/20)
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- MnO2?Fe3O4 Magnetic Nanoparticles as Efficient and Recyclable Heterogeneous Catalyst for Benzylic sp3 C?H Oxidation
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Herein, we report a highly chemoselective and efficient heterogeneous MnO2?Fe3O4 MNP catalyst for the oxidation of benzylic sp3 C?H group of ethers using TBHP as a green oxidant to afford ester derivatives in high yield under batch/continuous flow module. This catalyst was also effective for the benzylic sp3 C?H group of methylene derivatives to furnish the ketone in high yield which can be easily integrated into continuous flow condition for scale up. The catalyst is fully characterized by spectroscopic techniques and it was found that 0.424 % MnO2?Fe3O4 catalyzes the reaction; the magnetic nanoparticles of this catalyst could be easily recovered from the reaction mixture. The recovered catalyst was recycled for twelve cycles without any loss of the catalytic activity. The advantages of MnO2?Fe3O4 MNP are its catalytic activity, easy preparation, recovery, and recyclability, gram scale synthesis with a TOF of up to 14.93 h?1 and low metal leaching during the reaction.
- Pandey, Akanksha M.,Agalave, Sandip G.,Vinod, Chathakudath P.,Gnanaprakasam, Boopathy
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supporting information
p. 3414 - 3423
(2019/10/19)
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- Transition-metal-free addition reaction for the synthesis of 3-(aminobenzylidene/aminoalkylidene)indolin-2-ones and its synthetic applications
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A novel and efficient transition-metal-free approach for the exclusive synthesis of Z-3-(aminobenzylidene/aminoalkylidene)indolin-2-ones in high yield from 2-oxindole and aryl/alkyl nitrile in the presence of LiOtBu and 2,2′-bipyridine system is described. In addition, we disclosed a new approach towards the metal-free fluorination using selectfluor and the C=C bond cleavage using CuI and environmentally benign O2.
- Bisht, Girish Singh,Gnanaprakasam, Boopathy
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p. 13516 - 13527
(2019/10/19)
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- Vinyl Fluorides: Competent Olefinic Counterparts in the Intramolecular Pauson-Khand Reaction
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Despite the great advances achieved in the Pauson-Khand reaction and the ever-increasing demand for fluorinated compounds, the use of vinyl fluorides as olefinic counterparts in the above-mentioned transformation had been completely overlooked. Herein, we
- Román, Raquel,Mateu, Natalia,López, Inés,Medio-Simon, Mercedes,Fustero, Santos,Barrio, Pablo
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supporting information
p. 2569 - 2573
(2019/04/16)
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- Spiro indolone compound as well as, preparation, method and pharmaceutical composition and application thereof
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Spiro indolone compounds, a preparing method, a medicine composition and uses of the compounds are disclosed. In particular, the invention provide spiro indolone compounds shown as a formula I or II, a preparing method of the spiro indolone compounds and
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Paragraph 0194-0197
(2020/01/11)
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- "on Water" Direct Organocatalytic Cyanoarylmethylation of Isatins for the Diastereoselective Synthesis of 3-Hydroxy-3-cyanomethyl Oxindoles
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An "on water" organocatalytic cyanoarylmethylation of aryl acetonitrile to isatins is developed, giving products in high yields and up to excellent diastereoselectivities. A remarkable enhancement of reaction rates and diastereoselectivities by water was observed under mild conditions. Moreover, this approach provides a highly efficient and environmentally benign access to thermodynamic 3-hydroxy-3-cyanomethyl oxindoles.
- Zhang, Yong,Luo, Liang,Ge, Jin,Yan, Su-Qiong,Peng, Yan-Xin,Liu, Ya-Ru,Liu, Jin-Xiang,Liu, Chong,Ma, Tianqiong,Luo, Hai-Qing
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p. 4000 - 4008
(2019/03/29)
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- Synthesis and anticancer activity evaluation of azepinobisindoles;the isomeric iheyamine A-derivatives
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Azepinobisindole derivatives, the isomeric Iheyamine skeleton, were prepared and their anticancer activity evaluation were investigated against two human cancer cell lines, Hepatocellular carcinoma (HepG2) and human cervical cancer line (HeLa) as well as the normal cell line (Vero cell line) using MTT assay. The anticancer activity results indicated that 2-methoxy-5-methyl-5H-azepino[2,3-b:4,5-b]diindole was the most active derivative against tested cell lines. Additionally, molecular docking study in silico the possible inhibitory effect of cyclin-dependent kinase 2 (CDK2) by the azepinoindole revealed that all synthesized compounds fit well in the binding cavity of CDK2.
- Phutdhawong, Weerachai,Rattanopas, Sopita,Sirirak, Jitnapa,Taechowisan, Thongchai,Phutdhawong, Waya S.
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p. 723 - 731
(2019/06/07)
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- Site-Selective C–H Functionalization of (Hetero)Arenes via Transient, Non-symmetric Iodanes
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Fosu, Hambira, and colleagues describe the direct C–H functionalization of medicinally relevant arenes or heteroarenes. This strategy is enabled by transient generation of reactive, non-symmetric iodanes from anions and PhI(OAc)2. The site-selective incorporation of Cl, Br, OMs, OTs, and OTf to complex molecules, including within medicines and natural products, can be conducted by the operationally simple procedure included herein. A computational model for predicting site selectivity is also included. The discovery of new medicines is a time- and labor-intensive process that frequently requires over a decade to complete. A major bottleneck is the synthesis of drug candidates, wherein each complex molecule must be prepared individually via a multi-step synthesis, frequently requiring a week of effort per molecule for thousands of candidates. As an alternate strategy, direct, post-synthetic functionalization of a lead candidate could enable this diversification in a single operation. In this article, we describe a new method for direct manipulation of drug-like molecules by incorporation of motifs with either known pharmaceutical value (halides) or that permit subsequent conversion (pseudo-halides) to medicinally relevant analogs. This user-friendly strategy is enabled by combining commercial iodine reagents with salts and acids. We expect this simple method for selective, post-synthetic incorporation of molecular diversity will streamline the discovery of new medicines. A strategy for C–H functionalization of arenes and heteroarenes has been developed to allow site-selective incorporation of various anions, including Cl, Br, OMs, OTs, and OTf. This approach is enabled by in situ generation of reactive, non-symmetric iodanes by combining anions and bench-stable PhI(OAc)2. The utility of this mechanism is demonstrated via para-selective chlorination of medicinally relevant arenes, as well as site-selective C–H chlorination of heteroarenes. Spectroscopic, computational, and competition experiments describe the unique nature, reactivity, and selectivity of these transient, unsymmetrical iodanes.
- Fosu, Stacy C.,Hambira, Chido M.,Chen, Andrew D.,Fuchs, James R.,Nagib, David A.
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supporting information
p. 417 - 428
(2019/02/14)
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- Enhancement of the tail hydrophobic interactions within the carbonic anhydrase IX active site via structural extension: Design and synthesis of novel N-substituted isatins-SLC-0111 hybrids as carbonic anhydrase inhibitors and antitumor agents
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Herein we report the design and synthesis of novel N-substituted isatins-SLC-0111 hybrids (6a-f and 9a-l). A structural extension approach was adopted via N-alkylation and N-benzylation of isatin moiety to enhance the tail hydrophobic interactions within the carbonic anhydrase (CA) IX active site. Thereafter, a hybrid pharmacophore approach was utilized via merging the pharmacophoric elements of isatin and SLC-0111 in a single chemical framework. As planned, a substantial improvement of inhibitory profile of the target hybrids (KIs: 4.7–86.1 nM) towards hCA IX in comparison to N-unsubstituted leads IVa-c (KIs: 192–239 nM), was achieved. Molecular docking of the designed hybrids in CA IX active site unveiled, as planned, the ability of N-alkylated and N-benzylated isatin moieties to accommodate in a wide hydrophobic pocket formed by T73, P75, P76, L91, L123 and A128, establishing strong van der Waals interactions. Hybrid 6c displayed good anti-proliferative activity under hypoxic conditions towards breast cancer MDA-MB-231 and MCF-7 cell lines (IC50 = 7.43 ± 0.28 and 12.90 ± 0.34 μM, respectively). Also, 6c disrupted the MDA-MB-231 cell cycle via alteration of the Sub-G1 phase and arrest of G2-M stage. Additionally, 6c displayed significant increase in the percent of annexinV-FITC positive apoptotic cells from 1.03 to 18.54%. Furthermore, 6c displayed potent VEGFR-2 inhibitory activity (IC50 = 260.64 nM). Collectively, these data suggest 6c as a promising lead molecule for the development of effective anticancer agents.
- Eldehna, Wagdy M.,Abo-Ashour, Mahmoud F.,Nocentini, Alessio,El-Haggar, Radwan S.,Bua, Silvia,Bonardi, Alessandro,Al-Rashood, Sara T.,Hassan, Ghada S.,Gratteri, Paola,Abdel-Aziz, Hatem A.,Supuran, Claudiu T.
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p. 147 - 160
(2018/11/23)
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- Organocatalytic double arylation of 3-isothiocyanato oxindoles: Stereocontrolled synthesis of complex spirooxindoles
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Quinones, precursors of aromatic structures, were firstly employed as the electrophiles for the organocatalytic Michael addition/cyclization cascade reaction with versatile 3-isothiocyanato oxindoles. Chiral bifunctional organocatalyst was appropriate for this enantioselective transformation to afford a variety of novel spirooxindoles, possessing a spirocyclic stereocenter adjacent to the aromatic ring, via asymmetric double arylation. These synthesized spirooxindoles are very difficult to access by the reported methods and were obtained in excellent chemical yields with excellent enantioselectivities.
- Zhang, Lin-Lin,Da, Bing-Chao,Xiang, Shao-Hua,Zhu, Shuai,Yuan, Zi-Yun,Guo, Zhen,Tan, Bin
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supporting information
p. 1689 - 1696
(2018/11/25)
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- Click-chemistry approach to synthesis of functionalized isatin-ferrocenes and their biological evaluation against the human pathogen Trichomonas vaginalis
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Copper-promoted azide-alkyne cycloadditions were attempted to synthesize a series of variedly functionalized 1H-1,2,3-triazole-linked isatin-ferrocene, ferrocenylmethoxy-isatin and isatin-ferrocenyl-chalcone conjugates. The synthesized scaffolds were assayed for their inhibitory activity against T. vaginalis as well as several common normal human flora bacteria. The observed inhibitory activities against T. vaginalis and undetectable inhibition of microflora bacteria suggest that these compounds may be specific against trichomonad protozoa and could serve as a new scaffold for synthesis of novel compounds against this important human pathogen.
- Singh, Amandeep,Zhang, David,Tam, Christina C.,Cheng, Luisa W.,Land, Kirkwood M.,Kumar, Vipan
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- Electrosynthesis of N-methylisatin
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Isatin in a solution of dry N,N-dimethylformamide/NaClO4 is electroreduced in the presence of CH3I. N-methylisatin (NMI) is obtained in quantitative molar yield and high current efficiency by controlled potential electrolysis (CPE). NMI and N-methylisatoic anhydride are the reaction products when CPE is performed in the absence of CH3I, but adding it once the CPE was completed. The water effect on the identity and yield of the reaction product(s) is investigated. Reaction pathways are proposed.
- Martínez Suárez, Jaime F.,Caram, José A.,Echeverriá, Gustavo. A.,Piro, Oscar E.,Gennaro, Ana. M.,Mirífico, Mariá. V.
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p. 6879 - 6885
(2019/06/14)
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- 3-Hydrazinoisatin-based benzenesulfonamides as novel carbonic anhydrase inhibitors endowed with anticancer activity: Synthesis, in vitro biological evaluation and in silico insights
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Herein we describe the design and synthesis of two series of sulfonamides featuring N-unsubstituted (4a-c) or N-substituted (7a-o) isatin moieties (as tails) connected to benzenesulfonamide moiety via a hydrazine linker. All the prepared sulfonamides (4a-c and 7a-o) showed potent inhibitory activities toward transmembrane tumor-associated human (h) carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, IX and XII with KI range (8.3–65.4 nM) and (11.9–72.9 nM), respectively. Furthermore, six sulfonamides (7e, 7i, 7j, 7m, 7n and 7o) were assessed for their anti-proliferative activity, according to US-NCI protocol, toward a panel of sixty cancer cell lines. Compounds 7j and 7n were the most promising counterparts in this assay displaying broad spectrum anti-proliferative activity toward diverse cell lines. Also, sulfonamide 7n significantly inhibited clonogenicity of HCT-116 cells in a concentration dependent manner in the colony forming assay. Moreover, molecular modeling studies were performed to gain insights for the plausible binding interactions and affinities for the target isatin-based sulfonamides (4a-c and 7a-o) within hCA isoforms II and IX active sites.
- Abo-Ashour, Mahmoud F.,Eldehna, Wagdy M.,Nocentini, Alessio,Bonardi, Alessandro,Bua, Silvia,Ibrahim, Hany S.,Elaasser, Mahmoud M.,Kry?tof, Vladimír,Jorda, Radek,Gratteri, Paola,Abou-Seri, Sahar M.,Supuran, Claudiu T.
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