- Virtual screening-driven discovery of dual 5-HT6/5-HT2A receptor ligands with pro-cognitive properties
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A virtual screening campaign aimed at finding structurally new compounds active at 5-HT6R provided a set of candidates. Among those, one structure, 4-(5-{[(2-{5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)amino]methyl}furan-2-yl)phenol (1, 5-HT6R Ki = 91 nM), was selected as a hit for further optimization. As expected, the chemical scaffold of selected compound was significantly different from all the serotonin receptor ligands published to date. Synthetic efforts, supported by molecular modelling, provided 43 compounds representing different substitution patterns. The derivative 42, 4-(5-{[(2-{5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)amino]methyl}furan-2-yl)phenol (5-HT6R Ki = 25, 5-HT2AR Ki = 32 nM), was selected as a lead and showed a good brain/plasma concentration profile, and it reversed phencyclidine-induced memory impairment. Considering the unique activity profile, the obtained series might be a good starting point for the development of a novel antipsychotic or antidepressant with pro-cognitive properties.
- Staroń, Jakub,Kurczab, Rafa?,Warszycki, Dawid,Sata?a, Grzegorz,Krawczyk, Martyna,Bugno, Ryszard,Lenda, Tomasz,Popik, Piotr,Hogendorf, Adam S.,Hogendorf, Agata,Dubiel, Krzysztof,Mat?oka, Miko?aj,Moszczyński-P?tkowski, Rafa?,Pieczykolan, Jerzy,Wieczorek, Maciej,Zajdel, Pawe?,Bojarski, Andrzej J.
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- Design, synthesis and biological evaluation of tryptamine salicylic acid derivatives as potential antitumor agents
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A series of tryptamine salicylic acid derivatives were synthesized and their antiproliferative activity against MGC-803, MCF-7, HepG2, A549 and HeLa cell lines was evaluated. The structure-activity relationship (SAR) study revealed that different substitutions of the C5 and C3′-C5′ positions have certain effects on the anti-proliferation activity. The growth assay revealed that N-[2-(5-bromo-1H-indol-3-yl)-ethyl]-2-hydroxy-3-methyl-benzamide (E20) showed the most potent and broad-spectrum anticancer inhibition of all the cell lines evaluated, and was only more potent than 5-Fu for the gastric cancer cell line. Preliminary studies indicated that compound E20 could inhibit colony formation and migration of MGC-803 cells. The flow cytometry (FCM) results showed that compound E20 arrested the cell cycle in the G2/M phase and induced apoptosis of MGC-803 cells in a concentration-dependent manner. In addition, the western blot results showed that E20 can down-regulate the expression of hexokinase 2. Our studies suggest that the framework of N-[2-(5-bromo-1H-indol-3-yl)-ethyl]-2-hydroxy-3-methyl-benzamide may be consider as a new type of chemical for designing effective anti-cancer drugs targeting gastric cancer cells.
- Xiong, Runde,He, Dongxiu,Deng, Xiangping,Liu, Juan,Lei, Xiaoyong,Xie, Zhizhong,Cao, Xuan,Chen, Yanming,Peng, Junmei,Tang, Guotao
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p. 573 - 583
(2019/04/30)
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- Anti-cancer indole alkaloid compound, preparation method and application thereof
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The invention relates to an anti-cancer compound, which is an indole alkaloid series compound and has a general formula (I). Indole alkaloids have a very good inhibitory effect on multiple solid tumors, such as human breast cancer cells, and further have an inhibitory effect on tumor growth. The compound has an inhibitory effect on the growth of cancer cells, but has no inhibitory effect on the growth of normal cells. The compound can be used alone or in combination with other drugs.
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Paragraph 0039; 0046-0048; 0068; 0075-0077
(2019/06/30)
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- Indole derivative and uses thereof
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The present invention relates to an indole derivative and uses thereof, wherein the compound and the pharmaceutical composition comprising the compound can be used for antagonizing orexin receptors. The present invention further relates to a method for preparing the compound and the pharmaceutical composition, and uses of the compound and the pharmaceutical composition in treatment or prevention of diseases associated with orexin receptors.
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Paragraph 0236; 0237
(2017/09/01)
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- Chiral anion phase transfer of aryldiazonium cations: An enantioselective synthesis of C3-diazenated pyrroloindolines
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Herein is reported the first asymmetric utilization of aryldiazonium cations as a source of electrophilic nitrogen. This is achieved through a chiral anion phase-transfer pyrroloindolinization reaction that forms C3-diazenated pyrroloindolines from simple tryptamines and aryldiazonium tetrafluoroborates. The title compounds are obtained in up to 99% yield and 96% ee. The air- and water-tolerant reaction allows electronic and steric diversity of the aryldiazonium electrophile and the tryptamine core. Live and let diazene: Chiral anion phase transfer of aryldiazonium cations has been utilized to prepare C3-diazenated pyrroloindolines. The air- and water-tolerant reaction allows electronic and steric diversity in the aryldiazonium electrophile and the tryptamine core, with the products being obtained in up to 99% yield and 96% ee (MTBE=methyl tert-butyl ether).
- Nelson, Hosea M.,Reisberg, Solomon H.,Shunatona, Hunter P.,Patel, Jigar S.,Toste, F. Dean
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supporting information
p. 5600 - 5603
(2014/06/10)
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- Synthesis and structureactivity relationship of novel conformationally restricted analogues of serotonin as 5-HT6 receptor ligands
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5-Hydroxytryptamine 6 receptors (5-HT6R) are being perceived as the possible target for treatment of cognitive disorders as well as obesity. The present article deals with the design, synthesis, in vitro binding and structureactivity relationship of a novel series of tetracyclic tryptamines with the rigidized N-arylsulphonyl, N-arylcarbonyl and N-benzyl substituents as 5-HT6 receptor ligands. The chiral sulphonyl derivatives 15a and 17a showed high affinity at 5-HT6R with the Ki of 23.4 and 20.5nM, respectively. The lead compound from the series 15a has acceptable ADME properties, adequate brain penetration and is active in animal models of cognition like Novel Object Recognition Task (NORT) and water maze.
- Nirogi, Ramakrishna V.S.,Kambhampati, Ramasastri,Kothmirkar, Prabhakar,Konda, Jagadishbabu,Bandyala, Thrinath Reddy,Gudla, Parandhama,Arepalli, Sobhanadri,Gangadasari, Narasimhareddy P.,Shinde, Anil K.,Deshpande, Amol D.,Dwarampudi, Adireddy,Chindhe, Anil K.,Dubey, Pramod Kumar
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scheme or table
p. 443 - 450
(2012/08/28)
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- Structure-based design, synthesis, and pharmacological evaluation of 3-(Aminoalkyl)-5-fluoroindoles as myeloperoxidase inhibitors
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Oxidized low-density lipoproteins (LDLs) accumulate in the vascular wall and promote local inflammation, which contributes to the progression of the atheromatous plaque. The key role of myeloperoxidase (MPO) in this process is related to its ability to modify APO B-100 in the intima and at the surface of endothelial cells. A series of 3-(aminoalkyl)-5-fluoroindole analogues was designed and synthesized by exploiting the structure-based docking of 5-fluorotryptamine, a known MPO inhibitor. In vitro assays were used to study the effects of these compounds on the inhibition of MPO-mediated taurine chlorination and oxidation of LDLs. The kinetics of the interaction between the MPO redox intermediates, Compounds I and II, and these inhibitors was also investigated. The most potent molecules possessed a 4- or 5-carbon aminoalkyl side chain and no substituent on the amino group. The mode of binding of these analogues and the mechanism of inhibition is discussed with respect to the structure of MPO and its halogenation and peroxidase cycles.
- Soubhye, Jalal,Prévost, Martine,Van Antwerpen, Pierre,Zouaoui Boudjeltia, Karim,Rousseau, Alexandre,Furtmüller, Paul G.,Obinger, Christian,Vanhaeverbeek, Michel,Ducobu, Jean,Nève, Jean,Gelbcke, Michel,Dufrasne, Fran?ois
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supporting information; experimental part
p. 8747 - 8759
(2011/02/23)
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- The discovery of tetrahydro-β-carbolines as inhibitors of the kinesin Eg5
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A series of tetrahydro-β-carbolines were identified by HTS as inhibitors of the kinesin Eg5. Molecular modeling and medicinal chemistry techniques were employed to explore the SAR for this series with a focus of removing potential metabolic liabilities and improving cellular potency.
- Barsanti, Paul A.,Wang, Weibo,Ni, Zhi-Jie,Duhl, David,Brammeier, Nathan,Martin, Eric,Bussiere, Dirksen,Walter, Annette O.
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scheme or table
p. 157 - 160
(2010/04/02)
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- Enantioselective Bronsted acid-catalyzed N-acyliminium cyclization cascades
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(Chemical Equation Presented) An enantioselective Bronsted acid-catalyzed N-acyliminium cyclization cascade of tryptamines with enol lactones to form architecturally complex heterocycles in high enantiomeric excess has been developed. The reaction is technically simple to perform as well as atom-efficient and may be coupled to a gold(I)-catalyzed cycloisomerization of alkynoic acids whereby the key enol lactone reaction partner is generated in situ. Employing up to 10 mol % bulky chiral phosphoric acid catalysts in boiling toluene allowed the product materials to be generated in good overall yields (63-99%) and high enantioselectivities (72-99% ee). With doubly substituted enol lactones, high diastereo- and enantioselectivities were obtained, thus providing a new example of a dynamic kinetic asymmetric cyclization reaction.
- Muratore, Michael E.,Holloway, Chloe A.,Pilling, Adam W.,Storer, R. Ian,Trevitt, Graham,Dixon, Darren J.
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supporting information; experimental part
p. 10796 - 10797
(2009/12/03)
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- New synthetic technologies for the construction of heterocycles and tryptamines
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New synthetic methods for the construction of novel heterocycles and tryptamines are described. Thus, N-Boc anilines (I) are sequentially converted to heterocycles II ((3-(2-aminophenyl)pyrrolidin-3-ol) derivatives),III (substituted 2-oxo-1,2-dihydrospirobenzo[d][1,3]oxazine-4,3'-pyrrol idines), and VI (2-(4,5-dihydro-1H-pyrrol-3-yl)aniline) derivatives through a route involving t-BuLi induced ortho-metalation/ LaCl3 2LiCl metalexchange, reaction with N-Boc pyrrolidin-3-one (5), and subsequent deca rboxylative fragmentation. Labile intermediates VI are effectively converted to tryptamines Xa and Xb under controlled proticacidconditions.Inadditiontoprovidingexpedientaccesstothe2-oxo- 1,2-dihydrospirobenzo[d][1,3]oxazine-4,3'-pyrrolidines (III), the method is applicable to the synthesis of the corresponding 2-oxo-1,2-dihydrospirobenzo[d] [1,3]oxazine-4,3'-piperidine series of spirocycles (e.g., 42) and their precursors (3-(2-aminophenyl)piperidin-3-ol derivatives, e.g., 43) by using N-Boc-protected piperidin-3-one (40). Applications of the developed synthetic technologies to the synthesis of regioisomeric spirocycles 87 and 90, tryptamines 88 and 91, Corey's aspidophytine tryptamine (97), and efavirenz (1) are also described.
- Nicolaou, K. C.,Krasovskiy, Arkady,Majumder, Utpal,Trepanier, Vincent E.,Chen, David Y.-K.
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supporting information; experimental part
p. 3690 - 3699
(2009/09/24)
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- An expedient strategy for the synthesis of tryptamines and other heterocycles
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(Chemical Equation Presented) Making many from one: N-Boc-protected anilines are converted into an array of useful N-heterocycles and tryptamines through an expedient, cascade-based synthetic sequence involving ortho metalation and subsequent coupling wit
- Nicolaou,Krasovskiy, Arkady,Trepanier, Vincent E.,Chen, David Y.-K.
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supporting information; experimental part
p. 4217 - 4220
(2009/03/12)
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- CXCR3 ANTAGONISTS
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CXCR3 ANTAGONISTS Compounds, compositions and methods are provided that are useful in the treatment of conditions and diseases mediated by a chemokine receptor. In particular, the compounds of the invention modulate the CXCR3 chemokine receptor. The subject methods are useful for the treatment of inflammatory and immunoregulatory disorders and diseases, such as multiple sclerosis, rheumatoid arthritis and type I diabetes.
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Page/Page column 26
(2008/06/13)
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- NOVEL BETA-CARBOLINES AS GROWTH HORMONE SECRETAGOGUE RECEPTOR (GHSR) ANTAGONISTS
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The present invention relates to compounds of Formula (I): Formula (I) wherein R-R, X, and Y are as described herein, processes for preparing the compounds, pharmaceutical compositions comprising the compounds, and use of the compounds and compositions in the prophylaxis or treatment of a GHSR receptor-related disorder. Examples of such disorders are obesity and related disorders such as diabetes type II, dyslipidemia and the metabolic syndrome Prader-Willi syndrome, cardiovascular diseases such as atherosclerotic vascular disease, angina pectoris, myocardial infarction and stroke, acromegaly and cancer, in particular breast, lung, prostate, thyroid and endocrine pituary carcinomas.
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Page/Page column 64
(2008/06/13)
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- Melatonin receptor ligands: Synthesis of new melatonin derivatives and comprehensive comparative molecular field analysis (CoMFA) study
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The CoMFA methodology was applied to melatonin receptor ligands in order to establish quantitative structure-affinity relationships. One hundred thirty-three compounds were considered: they were either collected from literature or newly synthesized in order to gain information about the less explored positions. To this end, various melatonin derivatives were prepared and their affinity for quail optic tecta melatonin receptor was tested. Compounds were aligned on the putative active conformation of melatonin proposed by our previously reported pharmacophore search, and their relative affinities were calculated from the displacement of 2-[125I]-iodomelatonin on different tissues expressing aMT receptors. Compounds were grouped into three sets according to their topology. Subset A: melatonin-like compounds; subset B: N-acyl-2-amino-8-methoxytetralins and related compounds; subset C: N-acyl-phenylalkylamines and related compounds. CoMFA models were derived for each set, using the steric, electrostatic, and lipophilic fields as structural descriptors; the PLS analyses were characterized by good statistical parameters, taking into account the heterogeneity of the binding data, obtained with different experimental protocols. From the CoMFA model for the melatonin-like compounds, besides the well-known positive effect of 2-substitution, a low steric tolerance for substituents in 1, 6, and 7, and a negative effect of electron-rich 4-substituents were observed; the information provided by the newly synthesized compounds was essential for these results. Moreover, a comprehensive model for the 133 compounds, accounting for a common alignment and a common mode of interaction at the melatonin receptor, was derived (Q2 = 0.769, R2 = 0.905). This model validates our previously reported pharmacophore search and offers a clear depiction of the structure-affinity relationships for the melatonin receptor ligands.
- Mor, Marco,Rivara, Silvia,Silva, Claudia,Bordi, Fabrizio,Plazzi, Pier Vincenzo,Spadoni, Gilberto,Diamantini, Giuseppe,Balsamini, Cesarino,Tarzia, Giorgio,Fraschini, Franco,Lucini, Valeria,Nonno, Romolo,Stankov, Bojidar Michaylov
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p. 3831 - 3844
(2007/10/03)
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- N-acyl-5- and -2,5-substituted tryptamines: Synthesis, activity and affinity for human mt1 and mt2 melatonin receptors
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The synthesis and in vitro evaluation of a number of N-acyltryptamines are reported. Structural changes include the N-acyl group and the 5- (H,CH3,Halogen), and 2- (Br, Ph) substituents. 5Br (6d) and 2,5-diBr (6j) proved to be high affinity melatonin agonists, thus proving that Br can substitute for the 5-OMe group without loss of affinity to melatonin receptors (mt1, MT2). 6j is the first example of a melatonin agonist devoid of the 5-OMe group and endowed with better affinity for mt1 and MT2 receptors than that of melatonin itself. SAR for selectivity and intrinsic activity of the title compounds were also drawn.
- Spadoni, Gilberto,Balsamini, Cesarino,Bedini, Annalida,Carey, Aedin,Diamantini, Giuseppe,Di Giacomo, Barbara,Tontini, Andrea,Tarzia, Giorgio,Nonno, Romolo,Lucini, Valeria,Pannacci, Marilou,Michaylov Stankov, Bojidar,Fraschini, Franco
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p. 487 - 498
(2007/10/03)
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- Aromatic L-Amino Acid Decarboxylase from Micrococcus percitreus Purification, Crystallization and Properties
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An aromatic L-amino acid decarboxylase was crystallized from the cell free extract of Micrococcus percitreus.The purification procedure included protamine sulfate treatment, ammonium sulfate fractionation, DEAE-Sephadex column chromatography and Sephadex G-200 filtration.Crystals were obtained from a solution of the purified enzyme by addition of ammonium sulfate.The crystalline enzyme preparation was homogeneous as judged by ultracentrifugation and SDS-polyacrylamide gel electrophoresis.The molecular weight was determined to be approximately 101,000.The enzyme was evidently composed of two identical subunits of a molecular weight of 48,000.The enzyme catalyzed the stoichiometric conversion of L-tryptophan to tryptamine and CO2 in the presence of pyridoxal phosphate.The optimum pH was 9.0 for the conversion.The Km value and the maximum velocity of L-tryptophan decarboxylation were 2.4E-3 M and 44 μmol/min/mg of protein, respectively.This enzyme also catalyzed decarboxylation of 5-hydroxy-L-tryptophan, L-phenylalanine, L-tyrosine, 3,4-dihydroxy-L-phenylalanine, L-kynurenine and thier α-methyl amino acid derivatives.
- Nakazawa, Hidetsugu,Kumagai, Hidehiko,Yamada, Hideaki
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p. 2543 - 2552
(2007/10/02)
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