- Identification of First-in-Class Inhibitors of Kallikrein-Related Peptidase 6 That Promote Oligodendrocyte Differentiation
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Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS) that causes severe motor, sensory, and cognitive impairments. Kallikrein-related peptidase (KLK)6 is the most abundant serine protease secreted in the CNS, mainly by oligodendrocytes, the myelin-producing cells of the CNS, and KLK6 is assumed to be a robust biomarker of MS, since it is highly increased in the cerebrospinal fluid (CSF) of MS patients. Here, we report the design and biological evaluation of KLK6's low-molecular-weight inhibitors, para-aminobenzyl derivatives. Interestingly, selected hit compounds were selective of the KLK6 proteolytic network encompassing KLK1 and plasmin that also participate in the development of MS physiopathology. Moreover, hits were found noncytotoxic on primary cultures of murine neurons and oligodendrocyte precursor cells (OPCs). Among them, two compounds (32 and 42) were shown to promote the differentiation of OPCs into mature oligodendrocytes in vitro constituting thus emerging leads for the development of regenerative therapies.
- A?t Amiri, Sabrina,Deboux, Cyrille,Soualmia, Feryel,Chaaya, Nancy,Louet, Maxime,Duplus, Eric,Betuing, Sandrine,Nait Oumesmar, Brahim,Masurier, Nicolas,El Amri, Chahrazade
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supporting information
p. 5667 - 5688
(2021/05/29)
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- Synthesis and evaluation of 7-substituted-5,6-dihydrobenzo[c]acridine derivatives as new c-KIT promoter G-quadruplex binding ligands
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It has been shown that treatment of cancer cells with c-KIT G-quadruplex binding ligands can reduce their c-KIT expression levels thus inhibiting cell proliferation and inducing cell apoptosis. Herein, a series of new 7-substituted-5,6-dihydrobenzo[c]acri
- Guo, Qian-Liang,Su, Hua-Fei,Wang, Ning,Liao, Sheng-Rong,Lu, Yu-Ting,Ou, Tian-Miao,Tan, Jia-Heng,Li, Ding,Huang, Zhi-Shu
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supporting information
p. 458 - 471
(2017/03/16)
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- Highly enantioselective [3+2] coupling of cyclic enamides with quinone monoimines promoted by a chiral phosphoric acid
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Enantioselective [3+2] coupling of cyclic enamides with quinone monoimines was realised using a chiral phosphoric acid as a catalyst. This transformation allowed for the synthesis of highly enantioenriched polycyclic 2,3-dihydrobenzofurans (up to 99.9% ee). The absolute configuration of one product was determined by an X-ray crystal structural analysis. We also found a possible mechanism for this reaction.
- Zhang, Minmin,Yu, Shuowen,Hu, Fangzhi,Liao, Yijun,Liao, Lihua,Xu, Xiaoying,Yuan, Weicheng,Zhang, Xiaomei
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supporting information
p. 8757 - 8760
(2016/07/15)
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- Intramolecular Friedel-Crafts Acylation Reaction Promoted by 1,1,1,3,3,3-Hexafluoro-2-propanol
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Simple dissolution of an arylalkyl acid chloride in 1,1,1,3,3,3-hexafluoro-2-propanol promotes an intramolecular Friedel-Crafts acylation without additional catalysts or reagents. This reaction is operationally trivial in both execution and product isolation (only requiring concentration followed by purification) and accommodates a broad range of substrates. Preliminary studies that bear upon potential reaction mechanisms are reported.
- Motiwala, Hashim F.,Vekariya, Rakesh H.,Aubé, Jeffrey
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p. 5484 - 5487
(2015/11/18)
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- Borontribromide-mediated C-C bond formation in cyclic ketones: A transition metal free approach
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Borontribromide (BBr3) is a well-known demethylating agent. The current investigation was focused on a new application of borontribromide as a C-C bond forming agent in cyclic ketones. In this study, borontribromide mediated C-C bond formation reactions of tetralones, chromenone, thiochromenone and indanones were explored. A methoxy group containing ketones showed selective C-C bond formation reaction instead of demethylation of the methoxy group. MM2 steric energy calculations for the final products showed that the reaction favored the formation of exo- or endo-cyclic double bond containing products, depending upon their low MM2 steric energy in a specific frame structure, as observed in X-ray crystallography. A comprehensive crystallographic and pi-stacking analysis of product 10a demonstrated the formation of 10a as an enantiomeric mixture, and its centre of inversion was stabilized by a set of three unique pi-pi interactions.
- Ahmad, Imran,Pathak, Vinay,Vasudev, Prema G.,Maurya, Hardesh K.,Gupta, Atul
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p. 24619 - 24634
(2014/07/07)
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- Sustainable flow oppenauer oxidation of secondary benzylic alcohols with a heterogeneous zirconia catalyst
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A flow chemistry process for the Oppenauer oxidation of benzylic secondary alcohols using partially hydrated zirconium oxide and a simple carbonyl containing oxidant such as acetone, cyclohexanone, and neopentanal is reported. The heterogeneous oxidative system could be applied to a wide range of functionalized alcohol substrates, allowing clean and fast delivery of ketone products within a few minutes between 40 and 100 C.
- Chorghade, Rajeev,Battilocchio, Claudio,Hawkins, Joel M.,Ley, Steven V.
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supporting information
p. 5698 - 5701
(2013/12/04)
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- Expeditious approach to pyrrolophenanthridones, phenanthridines, and benzo[ c ]phenanthridines via organocatalytic direct biaryl-coupling promoted by potassium tert -butoxide
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A methodology involving a "transition metal-free" intramolecular biaryl-coupling of o-halo-N-arylbenzylamines has been developed in the presence of potassium tert-butoxide and an organic molecule as catalyst. The reaction appears to proceed through KOtBu-promoted intramolecular homolytic aromatic substitution (HAS). Interestingly, this biaryl coupling also works in the presence of potassium tert-butoxide as sole promoter. On extending our approach further, we found that N-acyl 2-bromo-N-arylbenzylamines undergo a one-pot N-deprotection/biaryl coupling followed by oxidation, thus offering an expeditious route to the phenanthridine and benzo[c]phenanthridine skeletons. The strategy has been applied to a concise synthesis of Amaryllidaceae alkaloids viz. oxoassoanine (1b), anhydrolycorinone (1d), 5,6-dihydrobicolorine (2d), trispheridine (2b), and benzo[c]phenanthridines alkaloids dihydronitidine (3b), dihydrochelerythidine (3d), dihydroavicine (3f), nornitidine (3h), and norchelerythrine (3j).
- De, Subhadip,Mishra, Sourabh,Kakde, Badrinath N.,Dey, Dhananjay,Bisai, Alakesh
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p. 7823 - 7844
(2013/09/12)
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- 12-N-Methylated 5,6-dihydrobenzo[c]acridine derivatives: A new class of highly selective ligands for c-myc G-quadruplex DNA
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12-N-Methylated and non-methylated 5,6-dihydrobenzo[c]acridine derivatives were designed and synthesized as new series of c-myc G-quadruplex binding ligands. Their interactions with c-myc G-quadruplex were evaluated using fluorescence resonance energy tra
- Liao, Sheng-Rong,Zhou, Chen-Xi,Wu, Wei-Bin,Ou, Tian-Miao,Tan, Jia-Heng,Li, Ding,Gu, Lian-Quan,Huang, Zhi-Shu
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experimental part
p. 52 - 63
(2012/08/08)
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- COMPOUNDS FOR THE INHIBITION OF CELLULAR PROLIFERATION
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Compositions and methods for inhibiting translation are provided. Compositions, methods and kits for treating (1) cellular proliferative disorders, (2) non-proliferative, degenerative disorders, (3) viral infections, (4) disorders associated with viral infections, and/or (5) non-proliferative metabolic disorders such as type II diabetes where inhibition of translation initiation is beneficial using the compounds disclosed herein.
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Page/Page column 108; 110
(2012/02/01)
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- Synthesis of benzyl substituted naphthalenes from benzylidene tetralones
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A convenient and efficient synthesis of novel highly substituted dimethoxybenzylnaphthalenes, which are precursors to several dihydroxynaphthoic acids, is described. The approach involves the use of aldol chemistry to provide a number of benzylidene tetra
- Deck, Lorraine M.,Mgani, Quintino,Martinez, Andrea,Martinic, Alice,Whalen, Lisa J.,Vander Jagt, David L.,Royer, Robert E.
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scheme or table
p. 373 - 376
(2012/01/31)
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- Friedel-crafts acylation reactions using esters
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Intermolecular and intramolecular Friedel-Crafts acylation reactions of various aliphatic and aromatic esters at room temperature with the use of very simple reagents and activating groups in are described. The products were obtained in good yield (60-85 %). The detailed mechanistic pathway was studied by DFT calculations and supported by experimental evidence. Copyright
- Chavan, Subhash P.,Garai, Sumanta,Dutta, Achintya Kumar,Pal, Sourav
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p. 6841 - 6845
(2013/02/22)
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- Synthesis and deprotection of 1,3-Dithianes and 1,3-Dithiolanes by polyphosphoric acid
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A simply, mild and efficient method for the deprotection of 1,3-dithianes and 1,3-dithiolanes to their corresponding carbonyl compounds using a mixture of polyphosphoric acid and acetic acid at 20-45 °C is reported.
- Jin, Yong-Sheng,Zhang, Wei,Zhang, Da-Zhi,Qiao, Li-Ming,Wu, Qiu-Ye,Chen, Hai-Sheng
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experimental part
p. 1117 - 1119
(2011/12/16)
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- Solvent-free friedel-crafts cyclization with trichloroacetic anhydride
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Friedel-Crafts cyclization products were obtained using 1.1 equivalents of environmentally benign trichloroacetic anhydride as sole reagent and solvent. The resulting ketones included benzothiepins, benzothiopyrans, benzoxepins, dibenzothiepins, dibenzoxepins, and tetralones.
- Andrews, Ben,Bullock, Kae,Condon, Shannon,Corona, John,Davis, Roman,Grimes, John,Hazelwood, Andrew,Tabet, Elie
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experimental part
p. 2664 - 2673
(2009/12/04)
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- MoO2Cl2 as a novel catalyst for Friedel-Crafts acylation and sulfonylation
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The use of MoO2Cl2 as a novel catalyst for Friedel-Crafts acylation and sulfonylation is described. A series of aromatic ketones and sulfones were prepared in moderate to good yields using acyl chloride or sulfonyl chloride in the presence of MoO2Cl2 (20 mol %), under solvent-free conditions.
- de Noronha, Rita G.,Fernandes, Ana C.,Rom?o, Carlos C.
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body text
p. 1407 - 1410
(2009/06/18)
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- Meldrum's acids as acylating agents in the catalytic intramolecular Friedel-Crafts reaction
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(Chemical Equation Presented) The intramolecular Friedel-Crafts acylation of aromatics with Meldrum's acid derivatives catalyzed by metal trifluoromethanesulfonates is reported. Meldrum's acids are easily prepared, functionalized, handled, and purified. The synthesis of polysubstituted 1-indanones from benzyl Meldrum's acids was investigated thoroughly, and it was shown that a variety of catalysts were effective, while accommodating a diversity of functional groups under mild conditions. The scope, limitations, and functional group tolerance (terminal alkene and alkyne, ketal, dialkyl ether, dialkyl thioether, aryl methyl ether, aryl TIPS and TBDPS ethers, nitrile- and nitro-substituted aryls, alkyl and aryl halides) for a variety of 5-benzyl (enolizable Meldrum's acids) and 5-benzyl-5-substituted Meldrum's acids (quaternized Meldrum's acids), forming 1-indanones and 2-substituted-1- indanones, respectively, are delineated. This method was further applied to the synthesis of 1-tetralones, 1-benzosuberones, and the potent acetylcholinesterase inhibitor donepezil. Rate of cyclization as a function of ring size was established for various benzocyclic ketones via competition experiments: 1-tetralones form faster than both 1-indanones and 1-benzosuberones, and 1-benzosuberones cyclize faster than 1-indanones.
- Fillion, Eric,Fishlock, Dan,Wilsily, Ashraf,Goll, Julie M.
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p. 1316 - 1327
(2007/10/03)
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- Synthesis of 1-tetralones by intramolecular Friedel-Crafts reaction of 4-arylbutyric acids using Lewis acid catalysts
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Intramolecular Friedel-Crafts reaction of 4-arylbutyric acids efficiently proceeded in the presence of catalytic amounts of Lewis acids such as Bi(NTf2)3 and M(OTf)3 (M=Bi, Ga, In and rare-earth metals) to form 1-tetralones. Chroman-4-one and thiochroman-4-one were also obtained in good yields from 3-phenoxypropionic acid and 3-phenylthiopropionic acid, respectively.
- Cui, Dong-Mei,Kawamura, Masato,Shimada, Shigeru,Hayashi, Teruyuki,Tanaka, Masato
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p. 4007 - 4010
(2007/10/03)
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- Synthesis and in vitro antibacterial activities of novel conformationally restricted hygromycin A analogues
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The preparation of semisynthetic conformationally restricted hygromycin A analogues are described. Antibacterial results from these compounds suggest active conformations for this class of agents.
- Cooper, Christopher B.,Blair, Kyle T.,Jones, Christopher S.,Minich, Martha L.
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p. 1747 - 1752
(2007/10/03)
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- 1,3-Benzodithiolium Cation Mediated Cyclization Reactions
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General protocols for the construction of various ring systems employing cation olefin cyclizations initiated by the readily accessible 1,3-benzodithiolium ion are described.Several substituted tetralones and tetralins can be rapidly assembled by this methodology as can a variety of substituted bicyclooctane and tricyclic ring systems.The products of these transformations are amenable to interconversion into a range of functionalized species.
- Rigby, James H.,Kotnis, Atul,Kramer, James
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p. 5078 - 5088
(2007/10/02)
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- Total synthesis of (+/-)-nimbidiol dimethyl ether and (+/-)-nimbiol methyl ether
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Steeocontrolled total syntheses of (+/-)-nimbidiol dimethyl ether (4) and (+/-)-nimbiol methyl ether (2) have been accomplished involving reductive methylation of the tricyclic aromatic ketones 11 and 12 respectively as the key steps.
- Karpha, Tapan Kumar,Ghosal, Manuka,Mukherjee, Debabrata
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p. 301 - 303
(2007/10/02)
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- Direct Synthesis of Benzophenanthridines and Benzophenanthridones via SRN1 Reactions
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A straightforward and high-yield route to the 11,12-dihydrobenzophenanthridine (3) and 11,12-dihydrobenzophenanthridone (14) ring systems is based upon an SRN1 reaction between 2-halobenzylamines 1 or 2-halobenzoic acids 11 and enolates derived from tetralones 2.The efficient dehydrogenation of 3 or 14 gives the benzophenthridines 4 or benzophenanthridones 15.Use of properly substituted reactants leads to nitidine, avicine, and fagaronine and to analogues of those natural products.
- Beugelmans, Rene,Chastanet, Jacqueline,Ginsburg, Helene,Quintero-Cortes, Leticia,Roussi, Georges
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p. 4933 - 4938
(2007/10/02)
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- Dopaminergic Agonists: Comparative Actions of Amine and Sulfonium Analogues of Dopamine
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We have investigated the possibility that structural modifications of the sulfonium analogue of dopamine (4) would produce the same pattern of biological activity as structural modifications of dopamine.A series of methyl- tetralinyl-, and naphthalenylsul
- Hamada, Akihiko,Chang, Yu An,Uretsky, Norman,Miller, Duane D.
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p. 675 - 680
(2007/10/02)
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- 1,3-BENZODITHIOLIUM ION MEDIATED ANNULATIONS
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A mild and selective method for cyclizations onto aromatic systems using 1,3-benzodithiolium ions is described.
- Rigby, James H.,Kotnis, Atul,Kramer, James
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p. 2939 - 2940
(2007/10/02)
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- Anomalous Acetoxylation of Aromatic Nuclei: Some Structural Requirements in the Substrate
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For certain aromatic nuclei, bromination in acetic acid in the presence of pyridine is accompanied by nuclear acetoxylation.As first observed with galbulin, when two alkoxyl groups, one meta and one para to a benzylic centre of the substrate are present, acetoxylation occurs at the intervening ortho position.Under the given conditions, acetoxylation occurs at position 8 of 6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydronaphthalene, and at position 2 of 3,4-dimethoxy diphenyl and triphenyl-methanes.Acetoxylation does not occur in the absence of either of the alkoxy groups or in the absence of pyridine, not does it occur in the pendant ring of 1-(3',4'-dimethoxyphenyl)-1,2,3,4-tetrahydronaphthalene.These results are consistent with the earlier suggestion that the reaction occurs by way of initial oxidative formation of a doubly benzylic cation
- Bandaranayake, Wickramasinghe M.,Riggs, Noel V.
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p. 115 - 129
(2007/10/02)
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- 2-Aminomethyl-3,4-dihydronaphthalenes
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Compounds of the formula STR1 and pharmaceutically acceptable salts thereof, wherein X and Y are independently H, F, Cl, Br, alkyl having up to four carbons, or alkoxy having up to four carbons, but X and Y are not both H, and Z is a secondary or tertiary amino group, are useful as analgesics and tranquillizing agents for mammals.
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- Synthesis and antiallergic activity of 2 hydroxy 3 nitro 1,4 naphthoquinones
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A selection of novel 2-hydroxy-3-nitro-1,4-naphthoquinones are shown to be potent inhibitors of rat passive cutaneous anaphylaxis (PCA) and to have highest potency with alkyl substitution at both C-6 and C-7. The most potent compounds were 7c and 7e which produced a 50% inhibition in the rat PCA test at doses of about 10 μM/kg following subcutaneous administration and showed activity after oral administration. Related 4-hydroxy-3-nitro-2(1H)-naphthalenones had no effect on rat PCA in doses up to 500 μM/kg.
- Buckle,Cantello,Smith,Spicer
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p. 1059 - 1064
(2007/10/06)
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