- Structural spectroscopic study of enantiomerically pure synthetic cathinones and their major metabolites
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New psychoactive substances (NPSs) have become a popular alternative to illicit drugs of abuse. However, to determine their metabolic pathways in the human organism, a detailed knowledge of their structure is crucial. Here, we present a comprehensive spectroscopic structural study of synthetic cathinones (clephedrone, flephedrone, and brephedrone) and their major human metabolites, desmethyl derivatives. Chiral high-performance liquid chromatography was utilized to obtain the individual enantiomers of the parent synthetic cathinones and their assumed major metabolites synthesized de novo. The developed chromatographic method made it possible to obtain the target optically pure substances on a multimilligram scale. Electronic and vibrational circular dichroism, combined with infrared and ultraviolet spectroscopy and supported by DFT calculations, were used to determine their absolute configuration and the chiroptical methods to elucidate their molecular structure in detail. Two stable conformers of each substance were found in aqueous solution. Their relative abundances were estimated based on the Boltzmann distribution and the population weighted spectra were obtained. Very good agreement was achieved between the experimental and simulated spectra, enabling the 3D structures of the studied substances to be determined in aqueous solution. This journal is
- Spálovská, Dita,Pa?kan, Martin,Jurásek, Bronislav,Kucha?, Martin,Kohout, Michal,Setni?ka, Vladimír
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supporting information
p. 850 - 860
(2021/01/25)
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- α-PPP and its derivatives are selective partial releasers at the human norepinephrine transporter: A pharmacological characterization of interactions between pyrrolidinopropiophenones and uptake1 and uptake2 monoamine transporters
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While classical cathinones, such as methcathinone, have been shown to be monoamine releasing agents at human monoamine transporters, the subgroup of α-pyrrolidinophenones has thus far solely been characterized as monoamine transporter reuptake inhibitors. Herein, we report data from previously undescribed α-pyrrolidinopropiophenone (α-PPP) derivatives and compare them with the pharmacologically well-researched α-PVP (α-pyrrolidinovalerophenone). Radiotracer-based in vitro uptake inhibition assays in HEK293 cells show that the investigated α-PPP derivatives inhibit the human high-affinity transporters of dopamine (hDAT) and norepinephrine (hNET) in the low micromolar range, with α-PVP being ten times more potent. Similar to α-PVP, no relevant pharmacological activity was found at the human serotonin transporter (hSERT). Unexpectedly, radiotracer-based in vitro release assays reveal α-PPP, MDPPP and 3Br-PPP, but not α-PVP, to be partial releasing agents at hNET (EC50 values in the low micromolar range). Furthermore, uptake inhibition assays at low-affinity monoamine transporters, i.e., the human organic cation transporters (hOCT) 1–3 and human plasma membrane monoamine transporter (hPMAT), bring to light that all compounds inhibit hOCT1 and 2 (IC50 values in the low micromolar range) while less potently interacting with hPMAT and hOCT3. In conclusion, this study describes (i) three new hybrid compounds that efficaciously block hDAT while being partial releasers at hNET, and (ii) highlights the interactions of α-PPP-derivatives with low-affinity monoamine transporters, giving impetus to further studies investigating the interaction of drugs of abuse with OCT1-3 and PMAT.
- Blough, Bruce E.,Gannon, Brenda M.,Holy, Marion,Maier, Julian,Murnane, Kevin S.,Niello, Marco,Rauter, Laurin,Rudin, Deborah,Schmid, Diethart,Sitte, Harald H.,Wilson, Joseph
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- Enantioselective Synthesis of Nitrogen-Nitrogen Biaryl Atropisomers via Copper-Catalyzed Friedel-Crafts Alkylation Reaction
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Nitrogen-nitrogen bonds containing motifs are ubiquitous in natural products and bioactive compounds. However, the atropisomerism arising from a restricted rotation around an N-N bond is largely overlooked. Here, we describe a method to access the first enantioselective synthesis of N-N biaryl atropisomers via a Cu-bisoxazoline-catalyzed Friedel-Crafts alkylation reaction. A wide range of axially chiral N-N bisazaheterocycle compounds were efficiently prepared in high yields with excellent enantioselectivities via desymmetrization and kinetic resolution. Heating experiments showed that the axially chiral bisazaheterocycle products have high rotational barriers.
- Guo, Chang-Qiu,Liu, Ren-Rong,Lu, Chuan-Jun,Wang, Xiao-Mei,Xu, Qi,Zhang, De-Bing,Zhang, Peng
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supporting information
p. 15005 - 15010
(2021/09/30)
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- Unique Sulfur-Aromatic Interactions Contribute to the Binding of Potent Imidazothiazole Indoleamine 2,3-Dioxygenase Inhibitors
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Indoleamine 2,3-dioxygenase (IDO1) inhibitors are speculated to be useful in cancer immunotherapy, but a phase III clinical trial of the most advanced IDO1 inhibitor, epacadostat, did not meet its primary end point and was abandoned. In previous work, we identified the novel IDO1 inhibitor N-(4-chlorophenyl)-2-((5-phenylthiazolo[2,3-c][1,2,4]triazol-3-yl)thio)acetamide 1 through high-throughput screening (HTS). Herein, we report a structure-activity relationship (SAR) study of this compound, which resulted in the potent IDO1 inhibitor 1-(4-cyanophenyl)-3-(3-(cyclopropylethynyl)imidazo[2,1-b]thiazol-5-yl)thiourea 47 (hIDO IC50 = 16.4 nM). X-ray cocrystal structural analysis revealed that the basis for this high potency is a unique sulfur-aromatic interaction network formed by the thiourea moiety of 47 with F163 and F226. This finding is expected to inspire new approaches toward the discovery of potent IDO1 inhibitors in the future.
- Peng, Yi-Hui,Liao, Fang-Yu,Tseng, Chen-Tso,Kuppusamy, Ramajayam,Li, An-Siou,Chen, Chi-Han,Fan, Yu-Shiou,Wang, Sing-Yi,Wu, Mine-Hsine,Hsueh, Ching-Cheng,Chang, Jia-Yu,Lee, Lung-Chun,Shih, Chuan,Shia, Kak-Shan,Yeh, Teng-Kuang,Hung, Ming-Shiu,Kuo, Ching-Chuan,Song, Jen-Shin,Wu, Su-Ying,Ueng, Shau-Hua
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p. 1642 - 1659
(2020/03/17)
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- Novel benzene-based carbamates for ache/bche inhibition: Synthesis and ligand/structure-oriented sar study
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A series of new benzene-based derivatives was designed, synthesized and comprehensively characterized. All of the tested compounds were evaluated for their in vitro ability to potentially inhibit the acetyl-and butyrylcholinesterase enzymes. The selectivity index of individual molecules to cholinesterases was also determined. Generally, the inhibitory potency was stronger against butyryl-compared to acetylcholinesterase; however, some of the compounds showed a promising inhibition of both enzymes. In fact, two compounds (23, benzyl ethyl(1-oxo-1-phenylpropan-2-yl)carbamate and 28, benzyl (1-(3-chlorophenyl)-1-oxopropan-2-yl) (methyl)carbamate) had a very high selectivity index, while the second one (28) reached the lowest inhibitory concentration IC50 value, which corresponds quite well with galanthamine. Moreover, comparative receptor-independent and receptor-dependent structure–activity studies were conducted to explain the observed variations in inhibiting the potential of the investigated carbamate series. The principal objective of the ligand-based study was to comparatively analyze the molecular surface to gain insight into the electronic and/or steric factors that govern the ability to inhibit enzyme activities. The spatial distribution of potentially important steric and electrostatic factors was determined using the probability-guided pharmacophore mapping procedure, which is based on the iterative variable elimination method. Additionally, planar and spatial maps of the host–target interactions were created for all of the active compounds and compared with the drug molecules using the docking methodology.
- Bak, Andrzej,Kozik, Violetta,Kozakiewicz, Dariusz,Gajcy, Kamila,Strub, Daniel Jan,Swietlicka, Aleksandra,Stepankova, Sarka,Imramovsky, Ales,Polanski, Jaroslaw,Smolinski, Adam,Jampilek, Josef
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- Synthesis of α,β-dibromo ketones by photolysis of α-bromo ketones with N-bromosuccinimide: Photoinduced β-bromination of α-bromo ketones
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Irradiation of α-bromopropiophenones in the presence of NBS results in the formation of α,β-dibromopropiophenones, which can be viewed as β-bromination of α-bromopropiophenones. The reaction is believed to go through a series of reactions; photoinduced C–Br bond cleavage, elimination of HBr to give α,β-unsaturated ketone intermediates, and addition of Br2, which are formed by the reaction between HBr and NBS. From mechanistic studies of the reaction, we have also found a very convenient method for α-debromination of the α,β-dibromopropiophenones which is by simple irradiation of the dibromo ketones in acetone or 2-propanol without the use of any additives. Our results demonstrate that bromine can be added into or eliminated from the alpha, beta, or both positions to the carbonyl group by photochemical methods, which make synthetic options of bromine containing carbonyl compounds versatile.
- Moon, Da Yoon,An, Sejin,Park, Bong Ser
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- INDOLE DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS
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The present disclosure relates to compounds and a pharmaceutically acceptable salt thereof, compositions, combinations and medicaments containing the compounds, and processes for their preparation. The disclosure also relates to the use of the compounds, combinations, compositions and medicaments, for example as inhibitors of the activity of the estrogen receptor, including degrading the estrogen receptor, the treatment of diseases and conditions mediated by the estrogen receptor.
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Paragraph 0444; 0445
(2018/04/21)
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- Synthesis and biological evaluation of novel thiazole- VX-809 hybrid derivatives as F508del correctors by QSAR-based filtering tools
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The most common CF mutation, F508del, impairs the processing and gating of CFTR protein. This deletion results in the improper folding of the protein and its degradation before it reaches the plasma membrane of epithelial cells. Present correctors, like VX809 only induce a partial rescue of the mutant protein. Our previous studies reported a class of compounds, called aminoarylthiazoles (AATs), featuring an interesting activity as correctors. Some of them show additive effect with VX809 indicating a different mechanism of action. In an attempt to construct more interesting molecules, it was thought to generate chemically hybrid compounds, blending a portion of VX809 merged to the thiazole scaffold. This approach was guided by the development of QSAR analyses, which were performed based on the F508del correctors so far disclosed in the literature. This strategy was aimed at exploring the key requirements turning in the corrector ability of the collected derivatives and allowed us to derive a predictive model guiding for the synthesis of novel hybrids as promising correctors. The new molecules were tested in functional and biochemical assays on bronchial CFBE41o-cells expressing F508del-CFTR showing a promising corrector activity.
- Liessi, Nara,Cichero, Elena,Pesce, Emanuela,Arkel, Maria,Salis, Annalisa,Tomati, Valeria,Paccagnella, Matteo,Damonte, Gianluca,Tasso, Bruno,Galietta, Luis J.V.,Pedemonte, Nicoletta,Fossa, Paola,Millo, Enrico
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p. 179 - 200
(2017/12/28)
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- Annulation Cascades of 2-Bromo-1-arylpropan-1-ones with Terminal Alkynes Involving C-Br/C-H Functionalization
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Straightforward access to various substituted naphthalenones by copper-catalyzed [4 + 2] annulation cascades of 2-bromo-1-arylpropan-1-ones with terminal alkynes is presented. Employing a Cu(MeCN)4PF4 catalyst and 1,10-phenanthroline (1,10-Phen) ligand enables the formation of three new C-C bonds in a single reaction via [4 + 2] annulation of a 2-bromo-1-arylpropan-1-one with an alkyne followed by α-alkylation with the other 2-bromo-1-arylpropan-1-one with excellent functional group tolerance and step efficiency.
- Ouyang, Xuan-Hui,Hu, Chao,Song, Ren-Jie,Li, Jin-Heng
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supporting information
p. 4659 - 4662
(2018/08/09)
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- Solvent free, light induced 1,2-bromine shift reaction of α-bromo ketones
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Photolysis of α-bromopropiophenones in acetonitrile results in formation of β-bromopropiophenones with good product selectivity, which can be coined as 1,2-Br shift reaction. The product selectivity increases when the reaction is done in neat or solid state, where only the 1,2-Br shift product is formed in some cases. The reaction is suggested to proceed by C–Br bond homolysis to give a radical pair, followed by disproportionation and conjugate addition of HBr to the α,β-unsaturated ketone intermediate. When the unsaturated intermediate is stabilized by an extra conjugation, the reaction stops at the stage, in which the unsaturated ketone becomes a major product. The synthetic method described in this research fits in a category of eco-friendly organic synthesis nicely since the reaction does not use volatile organic solvents and any other additives such as acid, base or metal catalysts, etc. Besides, the method fits into perfect atom economy, which does not give any side products. The synthetic method should find much advantage over other alternative methods to obtain β-bromo carbonyl compounds.
- An, Sejin,Moon, Da Yoon,Park, Bong Ser
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p. 6922 - 6928
(2018/10/24)
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- PURINONES AS UBIQUITIN-SPECIFIC PROTEASE 1 INHIBITORS
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The application relates to inhibitors of USP1 useful in the treatment of cancers, and other USP1 associated diseases and disorders, having the Formula: (I), where R1, R2, R3, R3', R4, R5, X1, X2, X3, X4, and n are described herein.
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Paragraph 00363; 00436
(2017/06/12)
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- Substituted 2-aminothiazoles are exceptional inhibitors of neuronal degeneration in tau-driven models of Alzheimer's disease
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A novel series of 2-aminothiazoles with strong protection in an Alzheimer's disease (AD) model comprising tau-induced neuronal toxicity is disclosed. These derivatives can be synthesized in one-pot and a small SAR of the substitution within these series afforded several compounds that counteracted tau-induced cell toxicity at nanomolar concentrations. These congeners therefore have strong potential as possible treatment for Alzheimer's disease and other related tauopathies.
- Lagoja, Irene,Pannecouque, Christophe,Griffioen, Gerard,Wera, Stefaan,Rojasdelaparra, Veronica Maria,Van Aerschot, Arthur
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p. 386 - 392
(2012/05/31)
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- Copper-catalyzed amination of (bromophenyl)ethanolamine for a concise synthesis of aniline-containing analogues of NMDA NR2B antagonist ifenprodil
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An operationally simple and concise synthesis of anilinoethanolamines, as NMDA NR2B receptor antagonist ifenprodil analogues, was developed via a copper-catalyzed amination of the corresponding bromoarene. Coupling was achieved with linear primary alkylamines, α,ω-diamines, hexanolamine and benzophenone imine, as well as with aqueous ammonia, in good yields using CuI and N,N-diethylsalicylamide, 2,4-pentadione or 2-acetylcyclohexanone as catalytic systems. Amination with ethylene diamine was efficient even in the absence of an additive ligand, whereas no reaction occurred with ethanolamine whatever the conditions used. The anilinoethanolamines were evaluated as NR2B receptor antagonists in a functional inhibition assay. Aminoethylanilines displayed inhibition effects close to that of ifenprodil. The Royal Society of Chemistry.
- Bouteiller, Cedric,Becerril-Ortega, Javier,Marchand, Patrice,Nicole, Olivier,Barre, Louisa,Buisson, Alain,Perrio, Cecile
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supporting information; experimental part
p. 1111 - 1120
(2010/06/16)
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- MONOAM1NE REUPTAKE INHIBITORS
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The invention provides bupropion analogue compounds capable of inhibiting the reuptake of one or more monoamines. The compounds may selectively bind to one or more monoamine transporters, including those for dopamine, norepinephrine,and serotonin. Such compounds may be used to treat conditions that are responsive to inhibition of the reuptake of monoamines, including addiction, depression, and obesity
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Page/Page column 67
(2010/11/04)
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- An expedient protocol for conversion of olefins to α-bromo/iodoketones using IBX and NBS/NIS
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A variety of olefins have been shown to undergo conversion to the corresponding α-bromo/iodoketones when reacted with NBS/NIS and IBX in DMSO at room temperature. While the reaction is found to occur rapidly with e-rich arylolefins leading to the corresponding haloketones in 65-95% yields in 0.3-3.0 h, those containing e-withdrawing groups are found to yield diketones concomitantly, such that the latter are the exclusive products over extended duration of the reactions.
- Moorthy, Jarugu Narasimha,Senapati, Kalyan,Singhal, Nidhi
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experimental part
p. 2493 - 2496
(2009/08/17)
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- Synthesis and biological evaluation of bupropion analogues as potential pharmacotherapies for cocaine addiction
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A series of bupropion (1a) analogues (1b-1ff) were synthesized, and their in vitro and in vivo pharmacological properties evaluated with the goal of developing a 1a analogue that had better properties for treating addictions. Their in vitro pharmacological properties were examined by [3H] dopamine ([3H]DA), [3H]serotonin ([3H]5HT), and [3H]norepinephrine ([3H]NE) uptake inhibition studies, and by binding studies at the dopamine, serotonin, and norepinephrine transporters using [125I]RTI-55 in cloned transporters. Several analogues showed increased [3H]DAuptake inhibition with reduced or little change in [3H]5HT and [3H]NE uptake inhibition relative to bupropion. Thirty-five analogues were evaluated in a 1 h locomotor activity observation test and 32 in an 8 h locomotor activity observation test and compared to the locomotor activity of cocaine. Twenty-four analogues were evaluated for generalization to cocaine drug discrimination after i.p. administration, and twelve analogues were tested in a time course cocaine discrimination study using oral administration. 2-(N-Cyclopropylamino)-3- chloropropiophenone (1x) had the most favorable in vitro efficacy and in vivo pharmacological profile for an indirect dopamine agonist pharmacotherapy for treating cocaine, methamphetamine, nicotine, and other drugs of abuse addiction. 2009 American Chemical Society.
- Carroll, F. Ivy,Blough, Bruce E.,Abraham, Philip,Mills, Andrew C.,Holleman, J. Ashley,Wolckenhauer, Scott A.,Decker, Ann M.,Landavazo, Antonio,McElroy, K. Timothy,Navarro, Hernán A.,Gatch, Michael B.,Forster, Michael J.
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supporting information; experimental part
p. 6768 - 6781
(2010/04/06)
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- IMIDAZOPYRIMIDINE-BASED COMPOUND AND ORGANIC LIGHT-EMITTING DEVICE EMPLOYING ORGANIC LAYER INCLUDING THE SAME
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Imidazopyrimidine-based compounds and organic light-emitting devices employing organic layers including the imidazopyrimidine-based compounds are provided. Organic light-emitting devices employing organic layers including the imidazopyrimidine-based compounds feature low driving voltages, high efficiency, high brightness, long lifetimes, and low power consumption.
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- COMPOUND FOR INHIBITING TYROSINE KINASE ACTIVITY OF DDR2 PROTEIN
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A new furopyrimidine compound, their pharmaceutically acceptable salt, and a tyrosine kinase activity inhibitor. The furopyrimidine compound is a compound defined by chemical formula 1, 2, 3 or 4, on their precursor, and can exist as a form of free base or in an acid-addition salt. Since the furopyrimidine compound has an effect of inhibiting activity of DDR2 tyrosine kinase, it can be used in treating illnesses caused by the DDR2 tyrosine kinase activity such as hepatocirrhosis, rheumatoid arthritis or cancer.
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Page/Page column 28; 31
(2010/02/14)
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- NITROGENOUS HETEROCYCLIC DERIVATIVE AND ORGANIC ELECTROLUMINESCENT ELEMENT EMPLOYING THE SAME
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A specific derivative of heterocyclic compound having nitrogen atom and an organic electroluminescence device comprising the compound. An organic electroluminescence device comprising at least one of organic compound layers including a light emitting layer sandwiched between an anode and a cathode, wherein said at least one of the organic compound layers comprises the derivative of the heterocyclic compound having nitrogen atom as a sole component or as mixed component. The organic electroluminescence device achieves elevation of luminance and excellent efficiency of light emission, and also achieves long lifetime by an improvement of an electrode adhesion.
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Page/Page column 84
(2008/06/13)
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- Efficient microwave induced direct α-halogenation of carbonyl compounds
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A novel and direct method for the synthesis of α-halocarbonyl compounds using sequential treatment of carbonyl compounds with [hydroxy(tosyloxy)iodo]benzene followed by magnesium halides under solvent-free microwave irradiation conditions is described.
- Lee, Jong Chan,Park, Jin Young,Yoon, So Young,Bae, Yong Hun,Lee, Seung Jun
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p. 191 - 193
(2007/10/03)
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- N-aminoimidazole derivatives inhibiting retroviral replication via a yet unidentified mode of action
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The synthesis of a series of N-aminoimidazoles (NAIMs) with an uncommon spectrum of antiretroviral activity is described. From a group of 60 closely related molecules, we were able to subdivide the molecules in different groups based on their anti-HIV and anti-SIV activity in vitro: (i) molecules acting on a new, immediate postintegration step, (ii) molecules acting on both postintegration and HIV-1 reverse transcriptase (RT) as NNRTI, and (iii) molecules that mainly act at the HIV-1 RT according to an NNRTI-type mode of action.
- Lagoja, Irene M.,Pannecouque, Christophe,Van Aerschot, Arthur,Witvrouw, Myriam,Debyser, Zeger,Balzarini, Jan,Herdewijn, Piet,De Clercq, Erik
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p. 1546 - 1553
(2007/10/03)
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- Pyrrole derivatives and medicinal composition
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The invention relates to a pharmaceutical composition comprising a pyrrole derivative of the following formula [1] or a pharmaceutically acceptable salt thereof, or a solvate of either of them, as an active ingredient. STR1 (wherein R1 represents hydrogen or alkoxycar91 bonylamino, R2 represents alkyl, aryl which may be substituted, aromatic heterocyclyl which may be substituted, unsubstituted amino, monoalkylamino, dialkylamino, or cyclic amino which may be substituted; R3 represents cyano or carbamoyl; R4 represents hydrogen or alkyl; E represents alkylene; q is equal to 0 or 1, A represents methyl, aryl which may be substituted, or aromatic heterocyclyl which may be substituted). The pharmaceutical composition of the invention is effective for the treatment of pollakiuria or urinary incontinence.
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- Application of Oxidative Aryl Migration in Organo-selenium and -tellurium Compounds to the Synthesis of 2-Arylpropanoic Acids
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The ethylene acetals of aryl α-phenylseleno- and α-phenyltelluro-ethyl ketones i, Ph, Br) and 5-bromo-6-methoxy-2-naphthyl> have been prepared in 12-83percent yields by treating the corresponding α-bromo compounds with diphenyl diselenide-sodium or diphenyl ditelluride-sodium, respectively, in tetrahydrofuran-dimethylformamide under reflux for 6-10 h, during which the bromine is substituted by the PhSe or PhTe group.This substitution is not observed when the (PhM)2-NaBH4-EtOH (M=Se, Te) system which is known as a source of PhM- anion is used.Oxidation of the acetals thus formed with an excess of meta-chloroperbenzoic acid at 20-25 deg C for 1 h affords hydroxy-ethyl 2-arylpropanoates in 56-86percent yields via aryl group migration which are hydrolysed to 2-arylpropanoic acids, some of which are pharmaceutically important compounds.Overall isolated yields of 2-arylpropanoic acids are around 30-42percent based on the starting propiophenones over 5 steps.
- Uemura, Sakae,Fukuzawa, Shin-ichi,Yamauchi, Takayoshi,Hattori, Kaneaki,Mizutaki, Shoichi,Tamaki, Kentaro
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p. 1983 - 1987
(2007/10/02)
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- New Preparative Method for 2-Arylpropanoic Acids by Oxidative Aryl Migration in Aryl α-Seleno- and Aryl α-Telluro-ethyl Ketones
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Oxidation with m-chloroperbenzoic acid of the ethylene acetals of aryl α-phenylseleno- or aryl α-phenyltelluro-ethyl ketones prepared by treating the corresponding α-bromo compounds with diphenyl diselenide-sodium or diphenyl ditelluride-sodium, respectively, affords hydroxyethyl 2-arylpropanoates in moderate to good yields via aryl group migration.
- Uemura, Sakae,Fukuzawa, Shin-ichi,Yamauchi, Takayoshi,Hattori, Kaneaki,Mizutaki, Shoichi,Tamaki, Kentaro
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p. 426 - 427
(2007/10/02)
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