60201-22-1Relevant academic research and scientific papers
Nickel-Catalyzed Amination of α-Aryl Methyl Ethers
Patel, Purvish,Rousseaux, Sophie A. L.
supporting information, p. 492 - 496 (2020/03/13)
α-Aryl amines are prevalent in pharmaceutically active compounds and natural products. Herein, we describe a Ni-catalyzed protocol for their synthesis from readily available α-aryl ethers. While α-aryl ethers have been used as electrophiles in Ni-catalyzed C-C bond formations, their use in C-heteroatom bond formation is much less prevalent. Preliminary mechanistic insight suggests that oxidative addition is facilitated by an anionic ligand and that reductive elimination is a reversible process.
Novel BQCA- and TBPB-Derived M1 Receptor Hybrid Ligands: Orthosteric Carbachol Differentially Regulates Partial Agonism
Schramm, Simon,Agnetta, Luca,Bermudez, Marcel,Gerwe, Hubert,Irmen, Matthias,Holze, Janine,Littmann, Timo,Wolber, Gerhard,Tr?nkle, Christian,Decker, Michael
, p. 1349 - 1358 (2019/07/12)
Recently, investigations of the complex mechanisms of allostery have led to a deeper understanding of G protein-coupled receptor (GPCR) activation and signaling processes. In this context, muscarinic acetylcholine receptors (mAChRs) are highly relevant due to their exemplary role in the study of allosteric modulation. In this work, we compare and discuss two sets of putatively dualsteric ligands, which were designed to connect carbachol to different types of allosteric ligands. We chose derivatives of TBPB [1-(1′-(2-tolyl)-1,4′-bipiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one] as M1-selective putative bitopic ligands, and derivatives of benzyl quinolone carboxylic acid (BQCA) as an M1 positive allosteric modulator, varying the distance between the allosteric and orthosteric building blocks. Luciferase protein complementation assays demonstrated that linker length must be carefully chosen to yield either agonist or antagonist behavior. These findings may help to design biased signaling and/or different extents of efficacy.
Gold(i)-catalyzed Nicholas reaction with aromatic molecules utilizing a bifunctional propargyl dicobalt hexacarbonyl complex
Okamura, Toshitaka,Fujiki, Shogo,Iwabuchi, Yoshiharu,Kanoh, Naoki
supporting information, p. 8522 - 8526 (2019/10/02)
A benchtop-stable reagent for the catalytic Nicholas reaction was developed. By combining a propargyl dicobalt hexacarbonyl cluster with an ortho-alkynylbenzoate unit and a fluorous tag, introduction of a propargyl hexacarbonyl complex on various aromatic compounds having acid- or base-sensitive functional groups becomes possible by using a gold(i) catalyst. In addition, the presence of a fluorous tag facilitates convenient separation of the target products from byproducts.
Nickel-Catalyzed Cyanation of Benzylic and Allylic Pivalate Esters
Michel, Nicholas W. M.,Jeanneret, Alexandria D. M.,Kim, Hyehwang,Rousseaux, Sophie A. L.
, p. 11860 - 11872 (2018/10/02)
A nickel-catalyzed cyanation reaction of benzylic and allylic pivalate esters is reported using an air-stable Ni(II) precatalyst and substoichiometric quantities of Zn(CN)2. Alkene additives were found to inhibit catalysis, suggesting that avoiding β-hydride elimination side reactions is essential for productive catalysis. An enantioenriched allylic ester undergoes enantiospecific cross-coupling to produce an enantioenriched allylic nitrile. This method was applied to an efficient synthesis of (±)-naproxen from commercially available starting materials.
Selective acetylation of primary alcohols by ethyl acetate
Singha, Raju,Ray, Jayanta K.
supporting information, p. 5395 - 5398 (2016/11/11)
A KOtBu and ethyl acetate mediated efficient methodology has been developed for the acetylation of primary and secondary alcohols where ethyl acetate is the source of acetyl group. The reaction is fast, mild, efficient, and highly selective towards the primary alcohols.
Rational design of partial agonists for the muscarinic M1 acetylcholine receptor
Chen, Xinyu,Kl?ckner, Jessika,Holze, Janine,Zimmermann, Cornelia,Seemann, Wiebke K.,Schrage, Ramona,Bock, Andreas,Mohr, Klaus,Tr?nkle, Christian,Holzgrabe, Ulrike,Decker, Michael
, p. 560 - 576 (2015/01/30)
Aiming to design partial agonists for a G-protein-coupled receptor based on dynamic ligand binding, we synthesized three different series of bipharmacophoric ligands composed of the orthosteric building blocks iperoxo and 1 linked to allosteric modulators (BQCA-derived compounds, BQCAd; TBPB-derived compound, TBPBd). Their interactions were studied with the human muscarinic acetylcholine M1-receptor (hM1) with respect to receptor binding and Gq-protein signaling. Results demonstrate that iperoxo/BQCAd (2, 3) and 1/BQCAd hybrids (4) act as M1 partial agonists, whereas 1/TBPBd hybrids (5) did not activate M1-receptors. Among the iperoxo/BQCAd-hybrids, spacer length in conjunction with the pattern of substitution tuned efficacy. Most interestingly, a model of dynamic ligand binding revealed that the spacer length of 2a and 3a controlled the probability of switch between the inactive purely allosteric and the active bitopic orthosteric/allosteric binding pose. In summary, dynamic ligand binding can be exploited in M1 receptors to design partial agonists with graded efficacy.
Synthesis and cycloxygenase inhibitory properties of new naphthalene-methylsulfonamido, naphthalene-methylsulfonyl and tetrahydronaphthalen-methylsulfonamido compounds
Nencetti, Susanna,Ciccone, Lidia,Rossello, Armando,Nuti, Elisa,Milanese, Claudio,Orlandini, Elisabetta
, p. 406 - 412 (2015/07/27)
We synthesized a series of new naphthalene derivatives: naproxen- and 6-methoxy naphthalene acetic acid-like 1-5. In these compounds the carboxylic function, typical of the classical NSAIDs, was replaced by a methylsulfonamido (1, 2 and 6a-c) or methylsulfonyl (3-5) group present in some selective COX-2 inhibitors. We also synthesized compounds 7 and 8 in which the naphthalene portion was substituted by tetrahydronaphthalene ring. Some of the new compounds were assayed for their enzymatic inhibitory activity towards cycloxygenase enzymes. Compounds 4 and 6b, at a concentration of 10 μM exhibit percentage inhibition values of 65%, 50% and 29%, 87% towards COX-2 and COX-1, respectively. The substitution of carboxylic group with a mehylsulfonamido or a methylsulfonyl groups does not allow to direct the selectivity versus to cycloxygenase enzymes.
Development of new LXR modulators that regulate LXR target genes and reduce lipogenesis in human cell models
H?gmoen ?strand, Ove Alexander,Gikling, Ingvei,Sylte, Ingebrigt,Rustan, Arild Christian,Thoresen, G. Hege,Rongved, P?l,Kase, Eili Tranheim
supporting information, p. 258 - 263 (2014/02/14)
Four new mimics of 22-S-hydroxycholesterol (22SHC) were synthesized and evaluated using molecular modeling and tested in human muscle cells (primary myotubes) and hepatocytes (HepG2 cells). The new compounds (9, 12, 15a and 15b) showed good interrelationship between docking scores, to both LXRα and LXRβ, and in vitro results. The LXR agonist T0901317 increased the expressions of genes involved in lipogenesis (SCD1, FAS) and cholesterol efflux (ABCA1), but only 22SHC counteracted the up-regulation of SCD1 and FAS by T0901317. Compound 9 and 12 decreased the expression of SCD1, while 9 also decreased the expression of FAS. Compounds 15a showed a significant antagonistic effect on ABCA1 expression, but neither 15a nor 15b were able to counteract the effect of T0901317 on all genes examined. Lipogenesis was increased after T0901317 treatment and only 22SHC significantly counteracted this effect. Treatment with 22SHC and compound 12 reduced lipogenesis compared to control. An increased glucose uptake was observed for all compounds, except for 15b. In summary, the new synthetic 22SHC mimics showed antagonistic effects similar to that of 22SHC, but the new substances were less potent. The sulfonamide 12 showed similar effects to 22SHC and the best effect on gene expression of the new mimics, however, it was not able to reduce the effect of T0901317 as observed for 22SHC.
CATECHOL O-METHYLTRANSFERASE ACTIVITY INHIBITING COMPOUNDS
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Page/Page column 125, (2014/01/07)
Compounds of formula (I), wherein R1 is as defined in the claims, exhibit COMT enzyme inhibiting activity and are thus useful as COMT inhibitors.
Design, synthesis, and antitumor activity of new bis-aminomethylnaphthalenes
Bollini, Mariela,Casal, Juan Jose,Bruno, Ana Maria
, p. 8003 - 8010 (2008/12/23)
A new series of bis-aminomethylnaphthalenes were synthesized in satisfactory overall yield, through a simple synthetic strategy using reductive amination. The DNA binding properties of these compounds have been examined and compared to those of reference drugs using an UV spectroscopy method. The compounds were evaluated for their in vitro anticancer activity and some of them were studied in vivo. Compound 15 exhibited remarkable antitumor activity and represents a novel template for anticancer chemotherapy and can serve as a new lead compound.
