- 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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- 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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- 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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- Pd-Catalyzed Regioselective Branched Hydrocarboxylation of Terminal Olefins with Formic Acid
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A regioselective Pd-catalyzed hydrocarboxylation of terminal olefins with HCOOH is described. A wide variety of branched carboxylic acids can readily be obtained with high regioselectivities under mild reaction conditions. The reaction is operationally simple and requires no handling of toxic CO. The ligand and LiCl are important factors for reaction reactivity and selectivity.
- Chu, Jianxiao,Guo, Jianqiong,Ren, Wenlong,Shi, Yian,Shi, Yuan,Wang, Mingzhou,Zhou, Jintao
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supporting information
p. 886 - 891
(2022/02/07)
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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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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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supporting information
p. 5484 - 5487
(2015/11/18)
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- Synthesis of rigidified eIF4E/eIF4G inhibitor-1 (4EGI-1) mimetic and their in vitro characterization as inhibitors of protein-protein interaction
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The 4EGI-1 is the prototypic inhibitor of eIF4E/eIF4G interaction, a potent inhibitor of translation initiation in vitro and in vivo and an efficacious anticancer agent in animal models of human cancers. We report on the design, synthesis, and in vitro ch
- Mahalingam, Poornachandran,Takrouri, Khuloud,Chen, Ting,Sahoo, Rupam,Papadopoulos, Evangelos,Chen, Limo,Wagner, Gerhard,Aktas, Bertal H.,Halperin, Jose A.,Chorev, Michael
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p. 5094 - 5111
(2014/07/08)
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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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- 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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- 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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- Copper-catalyzed carboxylation of alkylboranes with carbon dioxide: Formal reductive carboxylation of terminal alkenes
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Carboxylation of alkylboron compounds (alkyl-9-BBN) with CO2 proceeded in the presence of catalytic amounts of CuOAc/1,10-phenanthroline and a stoichiometric amount of KOtBu. The alkylboranes are easily and widely available through the alkene hydroboration, and thus the overall process represents a reductive carboxylation of alkenes with CO2. The broad functional group compatibility and the inexpensiveness of the Cu/1,10-phenathoroline catalyst system are attractive features of this protocol.(Figure Presented)
- Ohmiya, Hirohisa,Tanabe, Masahito,Sawamura, Masaya
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p. 1086 - 1088
(2011/04/23)
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- Ring enlargement of eight- and nine-membered cyclic sulfonamide derivatives in reactions with 3-amino-2H-azirines
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The reactions of 3-dimethylamino-2H-azirines (1) with 3,4,5,6- tetrahydro-8,9-dimethoxy-2H-1,2-benzothiazocin-3-one 1,1-dioxide (6a) in acetonitrile gave the correspondingly substituted 3-dimethylamino- 4,5,6,7,8,9-hexahydrobenzo-1-thia-2,5-diazacyclounde
- Mihova, Tonya R.,Linden, Anthony,Heimgartner, Heinz
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p. 215 - 232
(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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- Total synthesis of homoerythrinan alkaloids, schelhammericine and 3-epischelhammericine
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Total syntheses of two homoerythrinan alkaloids, schelhammericine and 3-epischelhammericine, are described. Photocycloaddition of a dioxopyrrolobenzazepine to 1-methoxy-3-trimethylsilyloxybutadiene afforded, in a regio- and stereo-specific manner, the cyc
- Tsuda, Yoshisuke,Ohshima, Takeshi,Hosoi, Shinzo,Kaneuchi, Satomi,Kiuchi, Fumiyuki,Toda, Jun,Sano, Takehiro
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p. 500 - 508
(2007/10/03)
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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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- 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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