- Discovery of New 4-Indolyl Quinazoline Derivatives as Highly Potent and Orally Bioavailable P-Glycoprotein Inhibitors
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The major drawbacks of P-glycoprotein (P-gp) inhibitors at the clinical stage make the development of new P-gp inhibitors challenging and desirable. In this study, we reported our structure-activity relationship studies of 4-indolyl quinazoline, which led to the discovery of a highly effective and orally active P-gp inhibitor, YS-370. YS-370 effectively reversed multidrug resistance (MDR) to paclitaxel and colchicine in SW620/AD300 and HEK293T-ABCB1 cells. YS-370 bound directly to P-gp, did not alter expression or subcellular localization of P-gp in SW620/AD300 cells, but increased the intracellular accumulation of paclitaxel. Furthermore, YS-370 stimulated the P-gp ATPase activity and had moderate inhibition against CYP3A4. Significantly, oral administration of YS-370 in combination with paclitaxel achieved much stronger antitumor activity in a xenograft model bearing SW620/Ad300 cells than either drug alone. Taken together, our data demonstrate that YS-370 is a promising P-gp inhibitor capable of overcoming MDR and represents a unique scaffold for the development of new P-gp inhibitors.
- Chen, Zhe-Sheng,Dai, Qing-Qing,Li, Guo-Bo,Liu, Hong-Min,Liu, Hui,Wang, Bo,Wang, Shaomeng,Yu, Bin,Yuan, Shuo,Zhang, Jing-Ya,Zhang, Xiao-Nan,Zuo, Jia-Hui
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p. 14895 - 14911
(2021/10/12)
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- Application of Fluorine- And Nitrogen-Walk Approaches: Defining the Structural and Functional Diversity of 2-Phenylindole Class of Cannabinoid 1 Receptor Positive Allosteric Modulators
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Cannabinoid 1 receptor (CB1R) allosteric ligands hold a far-reaching therapeutic promise. We report the application of fluoro- and nitrogen-walk approaches to enhance the drug-like properties of GAT211, a prototype CB1R allosteric agonist-positive allosteric modulator (ago-PAM). Several analogs exhibited improved functional potency (cAMP, β-arrestin 2), metabolic stability, and aqueous solubility. Two key analogs, GAT591 (6r) and GAT593 (6s), exhibited augmented allosteric-agonist and PAM activities in neuronal cultures, improved metabolic stability, and enhanced orthosteric agonist binding (CP55,940). Both analogs also exhibited good analgesic potency in the CFA inflammatory-pain model with longer duration of action over GAT211 while being devoid of adverse cannabimimetic effects. Another analog, GAT592 (9j), exhibited moderate ago-PAM potency and improved aqueous solubility with therapeutic reduction of intraocular pressure in murine glaucoma models. The SAR findings and the enhanced allosteric activity in this class of allosteric modulators were accounted for in our recently developed computational model for CB1R allosteric activation and positive allosteric modulation.
- Garai, Sumanta,Kulkarni, Pushkar M.,Schaffer, Peter C.,Leo, Luciana M.,Brandt, Asher L.,Zagzoog, Ayat,Black, Tallan,Lin, Xiaoyan,Hurst, Dow P.,Janero, David R.,Abood, Mary E.,Zimmowitch, Anaelle,Straiker, Alex,Pertwee, Roger G.,Kelly, Melanie,Szczesniak, Anna-Maria,Denovan-Wright, Eileen M.,Mackie, Ken,Hohmann, Andrea G.,Reggio, Patricia H.,Laprairie, Robert B.,Thakur, Ganesh A.
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p. 542 - 568
(2020/02/04)
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- Chiral Br?nsted Acid from Chiral Phosphoric Acid Boron Complex and Water: Asymmetric Reduction of Indoles
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A new chiral Br?nsted acid, generated in situ from a chiral phosphoric acid boron (CPAB) complex and water, was successfully applied to asymmetric indole reduction. This “designer acid catalyst”, which is more acidic than TsOH as suggested by DFT calculations, allows the unprecedented direct asymmetric reduction of C2-aryl-substituted N-unprotected indoles and features good to excellent enantioselectivities with broad functional group tolerance. DFT calculations and mechanistic experiments indicates that this reaction undergoes C3-protonation and hydride-transfer processes. Besides, bulky C2-alkyl-substituted N-unprotected indoles are also suitable for this system.
- Yang, Kai,Lou, Yixian,Wang, Chenglan,Qi, Liang-Wen,Fang, Tongchang,Zhang, Feng,Xu, Hetao,Zhou, Lu,Li, Wangyang,Zhang, Guan,Yu, Peiyuan,Song, Qiuling
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supporting information
p. 3294 - 3299
(2020/01/21)
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- Pd-catalyzed C–H bond activation of Indoles for Suzuki reaction
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Abstract: We present a practical method for Suzuki coupling by which unprotected or N-protected indoles may be selectively arylated in the C2-position through direct C–H bond activation by electrophilic Pd(TFA) 2 catalyst. The protocol is operationally simple as it is carried out in dioxane/water mixture, and air as the sole oxidant at room temperature. Various 2-arylated indoles were obtained in good yields. The protocol works for benzofuran, pyrrole and thiophene also. Graphic abstract: Selective C-2 arylation of heterocycles using Pd(II) catalyst via C–H activation was performed under ambient condition. C3–C2 migration of organopalladium intermediate controls the reaction pathway.[Figure not available: see fulltext.].
- Banerjee, Isita,Ghosh, Keshab Ch,Sinha, Surajit
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- Regioselective Synthesis of 2-Arylindoles via Palladium-Catalyzed Cyclization of Phenylglyoxal and 2-Anilinoacetophenones with Anilines
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A versatile route has been developed for the synthesis of 2-arylindoles using a Pd-catalyzed tandem process. Under reductive conditions, different 2-arylindoles were synthesized from phenylglyoxal and aniline. This synthetic methodology involves a tandem reaction of four steps with high regioselectivity. Alternatively, 2-anilinoacetophenones intermediates also can be using to give access to the corresponding 2-arylindoles.
- Benitez-Medina, G. Eliad,Ortiz-Soto, Sofía,Cabrera, Armando,Amézquita-Valencia, Manuel
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p. 3763 - 3770
(2019/06/24)
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- Synthetic method of 2-substituted indoles compounds
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The invention discloses a synthetic method of 2-substituted indoles compounds, and belongs to the organic synthesis field. 2-fluorotoluene compound shown in formula 1 and nitrile compound shown in formula 2 mix with an organic solvent in the presence of strong alkali and cesium salt additives, and react to synthesize the 2-substituted indoles compounds shown in formula 3. The synthesis method of 2-substituted indoles compounds is simple, economical and has wider applicability, is suitable for large-scale production, and has a very important influence on the synthesis of indoles compounds.
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Paragraph 0010; 0035-0037; 0041; 0043; 0052
(2019/05/02)
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- Synthesis of Indoles through Domino Reactions of 2-Fluorotoluenes and Nitriles
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Indoles are essential heterocycles in medicinal chemistry, and therefore, novel and efficient approaches to their synthesis are in high demand. Among indoles, 2-aryl indoles have been described as privileged scaffolds. Advanced herein is a straightforward, practical, and transition-metal-free assembly of 2-aryl indoles. Simply combining readily available 2-fluorotoluenes, nitriles, LiN(SiMe3)2, and CsF enables the generation of a diverse array of indoles (38 examples, 48–92 % yield). A range of substituents can be introduced into each position of the indole backbone (C4 to C7, and aryl groups at C2), providing handles for further elaboration.
- Mao, Jianyou,Wang, Zhiting,Xu, Xinyu,Liu, Guoqing,Jiang, Runsheng,Guan, Haixing,Zheng, Zhipeng,Walsh, Patrick J.
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supporting information
p. 11033 - 11038
(2019/07/08)
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- Gold(i)-catalyzed synthesis of 2-substituted indoles from 2-alkynylnitroarenes with diboron as reductant
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An efficient method for the synthesis of 2-substituted indoles via a diboron/base promoted tandem reductive cyclization of o-alkynylnitroarene under Au catalysis conditions has been disclosed. This reaction is efficient and convenient, affording 2-substituted indoles with broad functional groups tolerance and excellent yields.
- Fu, Wenqiang,Yang, Kai,Chen, Jinglong,Song, Qiuling
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p. 8354 - 8360
(2017/10/19)
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- Palladium-catalyzed tandem addition/cyclization in aqueous medium: Synthesis of 2-arylindoles
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An efficient protocol to construct 2-arylindoles was developed through palladium-catalyzed tandem addition/cyclization of potassium aryltrifluoroborates with aliphatic nitriles in aqueous medium. The use of water as the reaction medium makes the synthesis process environmentally benign. A plausible mechanism for the formation of 2-arylindoles involving sequential nucleophilic addition followed by an intramolecular cyclization is proposed. Moreover, the utility of this catalytic tandem transformation was also demonstrated in an efficient gram-scale synthesis. This method provides an alternative synthetic tool for accessing a more diverse array of 2-arylindoles.
- Yu, Shuling,Hu, Kun,Gong, Julin,Qi, Linjun,Zhu, Jianghe,Zhang, Yetong,Cheng, Tianxing,Chen, Jiuxi
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p. 4300 - 4307
(2017/07/10)
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- Palladium-catalyzed direct C2-arylation of free (N–H) indoles via norbornene-mediated regioselective C–H activation
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A palladium-catalyzed direct C2-arylation reaction of free (N–H) indoles has been developed. This reaction relies on a norbornene-mediated C–H activation process on the indole ring, which features high regioselectivity and excellent functional group tolerance.
- Gao, Yadong,Zhu, Wangying,Yin, Long,Dong, Bo,Fu, Jingjing,Ye, Zhiwen,Xue, Fengtian,Jiang, Chao
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supporting information
p. 2213 - 2216
(2017/05/16)
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- Toward highly potent cancer agents by modulating the C-2 group of the arylthioindole class of tubulin polymerization inhibitors
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New arylthioindole derivatives having different cyclic substituents at position 2 of the indole were synthesized as anticancer agents. Several compounds inhibited tubulin polymerization at submicromolar concentration and inhibited cell growth at low nanomolar concentrations. Compounds 18 and 57 were superior to the previously synthesized 5. Compound 18 was exceptionally potent as an inhibitor of cell growth: it showed IC50 = 1.0 nM in MCF-7 cells, and it was uniformly active in the whole panel of cancer cells and superior to colchicine and combretastatin A-4. Compounds 18, 20, 55, and 57 were notably more potent than vinorelbine, vinblastine, and paclitaxel in the NCI/ADR-RES and Messa/Dx5 cell lines, which overexpress P-glycoprotein. Compounds 18 and 57 showed initial vascular disrupting effects in a tumor model of liver rhabdomyosarcomas at 15 mg/kg intravenous dosage. Derivative 18 showed water solubility and higher metabolic stability than 5 in human liver microsomes.
- La Regina, Giuseppe,Bai, Ruoli,Rensen, Whilelmina Maria,Di Cesare, Erica,Coluccia, Antonio,Piscitelli, Francesco,Famiglini, Valeria,Reggio, Alessia,Nalli, Marianna,Pelliccia, Sveva,Da Pozzo, Eleonora,Costa, Barbara,Granata, Ilaria,Porta, Amalia,Maresca, Bruno,Soriani, Alessandra,Iannitto, Maria Luisa,Santoni, Angela,Li, Junjie,Miranda Cona, Marlein,Chen, Feng,Ni, Yicheng,Brancale, Andrea,Dondio, Giulio,Vultaggio, Stefania,Varasi, Mario,Mercurio, Ciro,Martini, Claudia,Hamel, Ernest,Lavia, Patrizia,Novellino, Ettore,Silvestri, Romano
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p. 123 - 149
(2013/03/13)
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- Pd-Catalyzed cascade reaction for the synthesis of 2-substituted indoles
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An efficient cascade methodology toward the synthesis of 2-substituted indoles has been developed. The transformation proceeds via a palladium-catalyzed cross-coupling reaction of o-nitrobenzyl cyanides with boronic acids. The use of Fe as co-catalyst during the course of reaction employs significant enhancement in reaction rates. The developed protocol allows for the unprecedented use of arylboronic acids as coupling partners for constructing 2-substituted indoles.
- Jadhav, Jagannath,Gaikwad, Vipul,Kurane, Rajanikant,Salunkhe, Rajashri,Rashinkar, Gajanan
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p. 2511 - 2515,5
(2012/12/11)
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- Pd-Catalyzed cascade reaction for the synthesis of 2-substituted indoles
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An efficient cascade methodology toward the synthesis of 2-substituted indoles has been developed. The transformation proceeds via a palladium-catalyzed cross-coupling reaction of o-nitrobenzyl cyanides with boronic acids. The use of Fe as co-catalyst during the course of reaction employs significant enhancement in reaction rates. The developed protocol allows for the unprecedented use of arylboronic acids as coupling partners for constructing 2-substituted indoles. Georg Thieme Verlag Stuttgart · New York.
- Jadhav, Jagannath,Gaikwad, Vipul,Kurane, Rajanikant,Salunkhe, Rajashri,Rashinkar, Gajanan
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p. 2511 - 2515
(2013/01/13)
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- Palladium-catalyzed direct C-2 arylation of indoles with potassium aryltrifluoroborate salts
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(Chemical Equation Presented) Mild conditions have been developed to achieve Pd(OAc)2-catalyzed regioselective cross-coupling between indoles and potassium aryltrifluoroarylborates in the presence of Cu(OAc) 2 in acetic acid at room temperature. A variety of potassium aryltrifluoroborates selectively undergo the direct arylation across indoles and afford 2-aryl indoles in moderate to good yields.
- Zhao, Jinlong,Zhang, Yuhong,Cheng, Kai
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supporting information; experimental part
p. 7428 - 7431
(2009/05/07)
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- One-pot/four-step/palladium-catalyzed synthesis of indole derivatives: The combination of heterogeneous and homogeneous systems
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One-pot, four-step syntheses of indoles using both solid-supported heterogeneous and homogeneous palladium catalysts and reagents were carried out. Such a combination of these two-phase catalysts and reagents causes a dramatic increase in yield, and it is a simple process. The presented methodology is effective for four-step reactions to provide various functionalized indoles.
- Sakai, Hayato,Tsutsumi, Ken,Morimoto, Tsumoru,Kakiuchia, Kiyomi
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supporting information; experimental part
p. 2498 - 2502
(2009/08/14)
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- Dirhodium(II)-catalyzed intramolecular C-H amination of aryl azides
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(Chemical Equation Presented) Azides to indoles: Dirhodium(II)-catalyzed decomposition of aryl azides was developed as a mild, functional group tolerant method for the synthesis of indoles (see scheme).
- Shen, Meihua,Leslie, Brooke E.,Driver, Tom G.
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supporting information; experimental part
p. 5056 - 5059
(2009/03/11)
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- Palladium-catalysed cyclization of 2-alkynylanilines to 2-substituted indoles under an acidic two-phase system
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The cyclization of 2-alkynylanilines in the presence of PdCl2 and n-Bu4NCl under an acidic CH2Cl2-HCl two-phase system affords 2-substituted indoles in good to high yield, at room temperature.The reaction is particularly suited to the one-flask preparatio
- Cacchi, Sandro,Carnicelli, Veronica,Marinelli, Fabio
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p. 289 - 296
(2007/10/02)
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- PALLADIUM-CATALYSED COUPLING OF ARYL AND VINYL TRIFLATES OR HALIDES WITH 2-ETHYNYLANILINE: AN EFFICIENT ROUTE TO FUNCTIONALIZED 2-SUBSTITUTED INDOLES
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The palladium(O)-catalysed coupling of aryl and vinyl triflates or halides with the easily available 2-ethynylaniline, followed by a palladium(II)-catalysed cyclization step, provides an efficient and very versatile procedure for the synthesis of function
- Arcadi, A.,Cacchi, S.,Marinelli, F.
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p. 2581 - 2584
(2007/10/02)
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