- Synthesis of Vinca Alkaloids and Related Compounds, XXXIV: Synthesis of (3S,14S,16S)-Bromovincamines and Bromoapovincamines by Regioselective Bromination
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By bromimation of the iminium salt 2a (X=Cl), the 9-bromo derivative 2c (X=ClO4) is obtained in isomer-free state.Bromination of the lactam 8d leads to ca. 7.5:1 mixture of 11-bromo (8c) and 9-bromo (8a) lactams.These precursors have been used to synthesize 9-, 10- and 11-bromovincamines (11a-c), and 9-, 10- and 11-bromoapovincamines (12a-c).
- Szabo, Lajos,Dobay, Laszlo,Kalaus, Gyoergy,Gacs-Baitz, Eszter,Tamas, Jozsef,Szantay, Csaba
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- 1-BENZYLSPIRO[PIPERIDINE-4,1′-PYRIDO[3,4-b]indole] ‘co-potentiators’ for minimal function CFTR mutants
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We previously identified a spiro [piperidine-4,1-pyrido [3,4-b]indole] class of co-potentiators that function in synergy with existing CFTR potentiators such as VX-770 or GLGP1837 to restore channel activity of a defined subset of minimal function cystic fibrosis transmembrane conductance regulator (CFTR) mutants. Here, structure-activity studies were conducted to improve their potency over the previously identified compound, 20 (originally termed CP-A01). Targeted synthesis of 37 spiro [piperidine-4,1-pyrido [3,4-b]indoles] was generally accomplished using versatile two or three step reaction protocols with each step having high efficiency. Structure-activity relationship studies established that analog 2i, with 6′-methoxyindole and 2,4,5-trifluorobenzyl substituents, had the greatest potency for activation of N1303K-CFTR, with EC50 ~600 nM representing an ~17-fold improvement over the original compound identified in a small molecule screen.
- Son, Jung-Ho,Phuan, Puay-Wah,Zhu, Jie S.,Lipman, Elena,Cheung, Amy,Tsui, Ka Yi,Tantillo, Dean J.,Verkman, Alan S.,Haggie, Peter M.,Kurth, Mark J.
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- Metal-Free Dearomatization: Direct Access to Spiroindol(en)ines in Batch and Continuous-Flow
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A metal-free, phosphine-catalyzed intramolecular “umpolung Michael addition” on alkynes to form spiroindol(en)ines is reported. This nucleophilic catalysis enables the formation of a wide scope of five- and six-membered spiroindol(en)ines in moderate to excellent yields in batch as well as under continuous-flow conditions. Triphenylphosphine-catalyzed nucleophilic activation of alkynes allows the exclusive formation of exo-product under mild reaction conditions.
- Ranjan, Prabhat,Ojeda, Gerardo M.,Sharma, Upendra K.,Van der Eycken, Erik V.
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p. 2442 - 2446
(2019/01/29)
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- Synthesis of 1-methoxyindoles and related analogs of pimprinine, (±)-chelonin A and B, based on 1-hydroxy-indole chemistry
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The total synthesis of pimprinine, (±)-chelonin A and B, and their analogs are achieved based on 1-hydroxyindole chemistry.
- Aoki, Kazuko,Nagahama, Yoshiyuki,Sugaya, Katsuko,Maeda, Yuki,Sato, Haruhiko,Nakagawa, Kyoko,Somei, Masanori
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p. 236 - 270
(2019/08/01)
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- Facile in Vitro Biocatalytic Production of Diverse Tryptamines
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Tryptamines are a medicinally important class of small molecules that serve as precursors to more complex, clinically used indole alkaloid natural products. Typically, tryptamine analogues are prepared from indoles through multistep synthetic routes. In the natural world, the desirable tryptamine synthon is produced in a single step by l-tryptophan decarboxylases (TDCs). However, no TDCs are known to combine high activity and substrate promiscuity, which might enable a practical biocatalytic route to tryptamine analogues. We have now identified the TDC from Ruminococcus gnavus as the first highly active and promiscuous member of this enzyme family. RgnTDC performs up to 96 000 turnovers and readily accommodates tryptophan analogues with substituents at the 4, 5, 6, and 7 positions, as well as alternative heterocycles, thus enabling the facile biocatalytic synthesis of >20 tryptamine analogues. We demonstrate the utility of this enzyme in a two-step biocatalytic sequence with an engineered tryptophan synthase to afford an efficient, cost-effective route to tryptamines from commercially available indole starting materials.
- McDonald, Allwin D.,Perkins, Lydia J.,Buller, Andrew R.
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p. 1939 - 1944
(2019/07/08)
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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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- Preparation method of 5-bromoindole derivative
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The invention discloses a preparation method of a 5-bromoindole derivative tert-butyl 2-(5-bromo-1H-indole-3-yl)ethyl carbamate. The preparation method comprises the following steps: taking 5-bromoindole as an initial raw material, and performing a Friedel-Craft reaction, amidation, reduction and a tert-butyloxycarbonyl protection reaction to obtain the target product. The compound is an important medical intermediate compound.
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- Marine AChE inhibitors isolated from Geodia barretti: Natural compounds and their synthetic analogs
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Barettin, 8,9-dihydrobarettin, bromoconicamin and a novel brominated marine indole were isolated from the boreal sponge Geodia barretti collected off the Norwegian coast. The compounds were evaluated as inhibitors of electric eel acetylcholinesterase. Barettin and 8,9-dihydrobarettin displayed significant inhibition of the enzyme, with inhibition constants (Ki) of 29 and 19 μM respectively towards acetylcholinesterase via a reversible noncompetitive mechanism. These activities are comparable to those of several other natural acetylcholinesterase inhibitors of marine origin. Bromoconicamin was less potent against acetylcholinesterase, and the novel compound was inactive. Based on the inhibitory activity, a library of 22 simplified synthetic analogs was designed and prepared to probe the role of the brominated indole, common to all the isolated compounds. From the structure-activity investigation it was shown that the brominated indole motif is not sufficient to generate a high acetylcholinesterase inhibitory activity, even when combined with natural cationic ligands for the acetylcholinesterase active site. The four natural compounds were also analysed for their butyrylcholinesterase inhibitory activity in addition and shown to display comparable activities. The study illustrates how both barettin and 8,9-dihydrobarettin display additional bioactivities which may help to explain their biological role in the producing organism. The findings also provide new insights into the structure-activity relationship of both natural and synthetic acetylcholinesterase inhibitors.
- Olsen, Elisabeth K.,Hansen, Espen,Moodie, Lindon W. K.,Isaksson, Johan,Sep?i?, Kristina,Cergolj, Marija,Svenson, Johan,Andersen, Jeanette H.
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p. 1629 - 1640
(2016/02/09)
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- Asymmetric dearomatization of indoles through a Michael/Friedel-Crafts-Type cascade to construct polycyclic spiroindolines
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A highly efficient asymmetric dearomatization of indoles was realized through a cascade reaction between 2-isocyanoethylindole and alkylidene malonates catalyzed by a chiral N,N-dioxide/MgII catalyst. Fused polycyclic indolines containing three stereocenters were afforded in good yields with excellent diastereo- and enantioselectivities through a Michael/Friedel-Crafts/Mannich cascade. When 2-substituted 2-isocyanoethylindoles were used, spiroindoline derivatives were obtained through a Michael/Friedel-Crafts reaction.
- Zhao, Xiaohu,Liu, Xiaohua,Mei, Hongjiang,Guo, Jing,Lin, Lili,Feng, Xiaoming
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p. 4032 - 4035
(2015/03/30)
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- Alpha-ethyltryptamines as dual dopamine-serotonin releasers
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The dopamine (DA), serotonin (5-HT), and norepinephrine (NE) transporter releasing activity and serotonin-2A (5-HT2A) receptor agonist activity of a series of substituted tryptamines are reported. Three compounds, 7b, (+)-7d and 7f, were found to be potent dual DA/5-HT releasers and were >10-fold less potent as NE releasers. Additionally, these compounds had different activity profiles at the 5-HT2Areceptor. The unique combination of dual DA/5-HT releasing activity and 5-HT2Areceptor activity suggests that these compounds could represent a new class of neurotransmitter releasers with therapeutic potential.
- Blough, Bruce E.,Landavazo, Antonio,Partilla, John S.,Decker, Ann M.,Page, Kevin M.,Baumann, Michael H.,Rothman, Richard B.
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p. 4754 - 4758
(2015/01/09)
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- Total synthesis and biological activity of marine alkaloid eudistomins Y1-Y7 and their analogues
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Eudistomin Y class compounds are a series of β-carbolines which was originally isolated from a marine turnicate or ascidian near the South Korea Sea. These compounds contain bromo-substituted groups, which is one of the typical characters of marine natural products. We report herein the chemical synthesis and biological evaluation of seven new β-carboline-based metabolites, Eudistomins Y1-Y7, and their hydroxyl-methylated phenyl derivatives. Using bromo-substituted tryptamines and bromo-substituted phenylglyoxals as the key intermediates, Eudistomins Y 1-Y7 and their derivatives were synthesized via the acid-catalyzed Pictet-Spengler reaction and fully characterized by 1H- and 13C-NMR and mass spectroscopy. Biological studies revealed that all of the compounds showed moderate growth inhibitory activity against breast carcinoma cell line MDA-231 with IC50 of 15-63 μM and the inhibitory activities of hydroxyl-methylated phenyl products were higher than that of the corresponding natural products Eudistomins Y 1-Y7.
- Jin, Huijuan,Zhang, Puyong,Bijian, Krikor,Ren, Sumei,Wan, Shengbiao,Alaoui-Jamali, Moulay A.,Jiang, Tao
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p. 1427 - 1439
(2013/07/11)
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- Enantioselective total synthesis of eudistomidins G, H, and I
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Asymmetric first total synthesis of eudistomidins G, H, and I, tetrahydro-β-carboline alkaloids from the Okinawan marine tunicate Eudistoma glaucus, has been accomplished with the Bischler-Napieralski reaction and the Noyori catalytic asymmetric hydrogen-transfer reaction. The absolute configurations of eudistomidins G, H, and I were confirmed from comparison of the 1H and 13C NMR, and CD spectral data of synthetic and natural eudistomidins G, H, and I, respectively.
- Ishiyama, Haruaki,Yoshizawa, Kazuaki,Kobayashi, Jun'ichi
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p. 6186 - 6192
(2012/08/27)
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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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- Asymmetric total synthesis of reported structure of eudistomidin B, an indole alkaloid isolated from a marine tunicate
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Eudistomidin B, isolated from a marine tunicate, was originally assigned a tetrahydro-β-carboline structure with a 2-p-tolylethanamine residue. Asymmetric total synthesis of the reported structure of natural product, which features an intramolecular diast
- Ito, Takeshi,Kitajima, Mariko,Takayama, Hiromitsu
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experimental part
p. 4506 - 4508
(2009/11/30)
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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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- A versatile linkage strategy for solid-phase synthesis of N,N-dimethyltryptamines and β-carbolines
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(matrix presented) Various tryptamines are captured by a vinylsulfonylmethyl polystyrene resin, generating a safety-catch linkage. β-Carbolines can be formed from 4 by a Pictet-Spengler reaction with the introduction of R1. Tryptamine 4 can also be derivatized by acylation or copper-mediated coupling to introduce R2. If X = Br, Suzuki coupling can be used to introduce R3. After derivatization, the indole derivatives are activated with methyl iodide and released under mild basic condition.
- Wu, Tom Y. H.,Schulte, Peter G.
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p. 4033 - 4035
(2007/10/03)
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- A novel methodology for preparing 5-chloro- and 5-bromotryptamines and tryptophans, and its application to the synthesis of (±)-bromochelonin B
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A novel methodology for introducing chlorine or bromine into the 5- position of tryptamines was found through 1-hydroxytryptamines. The chemistry was applied to the syntheses of (±)-5-chloro-, -5-bromotryptophan derivatives, and (±)-bromochelonin B.
- Hasegawa, Masakazu,Yamada, Koji,Nagahama, Yoshiyuki,Somei, Masanori
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p. 2815 - 2821
(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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- 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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- Synthesis of the brominated marine alkaloids (±)-arborescidine A, B and C
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A straightforward synthesis of the brominated marine alkaloids arborescidine A (1), B (2) and C (3), starting from 6-bromo-(N-methyl) trypatamine is described. An equilibrium, under both basic and acidic conditions was found to exist between the trans- and cis-isomers 3 and 4. Spectral data indicated that the structure of isomer 4 does not correspond with the compound identified as arborescidine D recently isolated from the marine tunicate Pseudodistoma arborescens.
- Burm, Brigitte E.A.,Meijler, Michael M.,Korver, Jacco,Wanner, Martin J.,Koomen, Gerrit-Jan
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p. 6135 - 6146
(2007/10/03)
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- Approaches to the tetracyclic eudistomins: the synthesis of N(10)-acetyleudistomin L
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The successful synthesis of the tetracyclic ring system present in eudistomins C, E, K, and L involves a convergent approach to N(10)-acetyleudistomin L from 5-bromo-N'-hydroxytryptamine and a suitably protected cysteinal derivate.Ring C in the eudistomin was constructed by a modified Pictet-Spengler reaction and the unique 1,3,7-oxathiazepine ring (ring D) by an unprecedented intramolecular sila-Pummerer reaction.An interesting diastereoselectivity is observed in the former process.The formation of an alternative seven-membered ring cyclization product under certain conditions in the sila-Pummerer reaction is also described.
- Still, Ian W. J.,Strautmanis, Juris R.
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p. 1408 - 1419
(2007/10/02)
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- SYNTHESIS OF N(10)-ACETYLEUDISTOMIN L
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The marine indole alkaloid derivative N(10)-acetyleudistomin L has been prepared in a convergent synthesis, starting from 5-bromoindole and L-cysteine.
- Still, Ian W. J.,Strautmanis, Juris R.
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p. 1041 - 1044
(2007/10/02)
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- 1-Alkyl-9-bromohexahydroindolo quinolizium salts and use thereof to increase blood flow
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The invention is directed to 1-alkyl-9-bromohexagydro indoloquinolizium salts and a method for their use to increase blood circulation and decrease in blood vessel resistance.
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