- Nickel-Catalyzed Amination of α-Aryl Methyl Ethers
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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.
- Patel, Purvish,Rousseaux, Sophie A. L.
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supporting information
p. 492 - 496
(2020/03/13)
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- Novel BQCA- and TBPB-Derived M1 Receptor Hybrid Ligands: Orthosteric Carbachol Differentially Regulates Partial Agonism
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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.
- Schramm, Simon,Agnetta, Luca,Bermudez, Marcel,Gerwe, Hubert,Irmen, Matthias,Holze, Janine,Littmann, Timo,Wolber, Gerhard,Tr?nkle, Christian,Decker, Michael
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p. 1349 - 1358
(2019/07/12)
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- Gold(i)-catalyzed Nicholas reaction with aromatic molecules utilizing a bifunctional propargyl dicobalt hexacarbonyl complex
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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.
- Okamura, Toshitaka,Fujiki, Shogo,Iwabuchi, Yoshiharu,Kanoh, Naoki
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supporting information
p. 8522 - 8526
(2019/10/02)
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- Nickel-Catalyzed Cyanation of Benzylic and Allylic Pivalate Esters
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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.
- Michel, Nicholas W. M.,Jeanneret, Alexandria D. M.,Kim, Hyehwang,Rousseaux, Sophie A. L.
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p. 11860 - 11872
(2018/10/02)
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- Selective acetylation of primary alcohols by ethyl acetate
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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.
- Singha, Raju,Ray, Jayanta K.
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supporting information
p. 5395 - 5398
(2016/11/11)
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- Rational design of partial agonists for the muscarinic M1 acetylcholine receptor
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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.
- 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
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p. 560 - 576
(2015/01/30)
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- Synthesis and cycloxygenase inhibitory properties of new naphthalene-methylsulfonamido, naphthalene-methylsulfonyl and tetrahydronaphthalen-methylsulfonamido compounds
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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.
- Nencetti, Susanna,Ciccone, Lidia,Rossello, Armando,Nuti, Elisa,Milanese, Claudio,Orlandini, Elisabetta
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p. 406 - 412
(2015/07/27)
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- Development of new LXR modulators that regulate LXR target genes and reduce lipogenesis in human cell models
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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.
- H?gmoen ?strand, Ove Alexander,Gikling, Ingvei,Sylte, Ingebrigt,Rustan, Arild Christian,Thoresen, G. Hege,Rongved, P?l,Kase, Eili Tranheim
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supporting information
p. 258 - 263
(2014/02/14)
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- CATECHOL O-METHYLTRANSFERASE ACTIVITY INHIBITING COMPOUNDS
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Compounds of formula (I), wherein R1 is as defined in the claims, exhibit COMT enzyme inhibiting activity and are thus useful as COMT inhibitors.
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- Design, synthesis, and antitumor activity of new bis-aminomethylnaphthalenes
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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.
- Bollini, Mariela,Casal, Juan Jose,Bruno, Ana Maria
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p. 8003 - 8010
(2008/12/23)
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- C17,20-lyase inhibitors. Part 2: Design, synthesis and structure-activity relationships of (2-naphthylmethyl)-1H-imidazoles as novel C17,20-lyase inhibitors
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A series of 1- and 4-(2-naphthylmethyl)-1H-imidazoles (3 and 4) has been synthesized and evaluated as C17,20-lyase inhibitors. Several 6-methoxynaphthyl derivatives showed potent C17,20-lyase inhibition, suppression of testosterone biosynthesis in rats and reduction in the weight of prostate and seminal vesicles in rats, whereas most of these compounds increased the liver weight after consecutive administrations. The effect on the liver weight was removed by incorporation of a hydroxy group and an isopropyl group at the methylene bridge, as seen in (S)-28d and (S)-42. Selectivity for C 17,20-lyase over 11β-hydroxylase is also discussed, and (S)-42 was found to be a more than 260-fold selective inhibitor. Furthermore, (S)-42 showed a potent suppression of testosterone biosynthesis after a single oral administration in monkeys. These data suggest that (S)-42 may be a promising agent for the treatment of androgen-dependent prostate cancer.
- Matsunaga, Nobuyuki,Kaku, Tomohiro,Ojida, Akio,Tanaka, Toshimasa,Hara, Takahito,Yamaoka, Masuo,Kusaka, Masami,Tasaka, Akihiro
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p. 4313 - 4336
(2007/10/03)
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- NAPTHTHALENE DERIVATIVES WHICH INHIBIT THE CYTOKINE OR BIOLOGICAL ACTIVITY OF MACROPHAGE MIGRATION INHIBITORY FACTOR (MIF)
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Where Y, R1-R8 and R101-R108 are as defined in the specification. Compounds of formula (II) and methods of inhibiting the cytokine or biological activity of Macrophage Migrating Inhibitory Factor (MIF) comprising contacting MIF with a compound of formula (I) are provided. The invention also relates to methods of treating diseases or conditions where MIF cytokine or biological activity is implicated comprising administration of compounds of formula (I), either alone or as part of a combination therapy.
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- Enantioselective hydrolysis of naproxen ethyl ester catalyzed by monoclonal antibodies
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This report described that a hapten of racemic phosphonate 3 designed as the mimic of the transition state of hydrolysis of naproxen ethyl ester was successfully synthesized from easily available 2-acetyl-6-methoxy-naphthalene 5. Then BALB/C mice were immunized and one of the monoclonal catalytic antibodies, N116-27, which enantioselectively accelerated the hydrolysis of the R-(-)-naproxen ethyl ester was given. The Michaelis-Menton parameter for the catalyzed reaction was KM=6.67 mM and kcat/kuncat=5.8×104. This enantioselective result was explained by the fact that the R-isomer of rac-hapten was more immunogenic than the S-isomer.
- Shi, Zhen-Dan,Yang, Bing-Hui,Zhao, Jing-Jing,Wu, Yu-Lin,Ji, Yong-Yong,Yeh, Ming
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p. 2171 - 2175
(2007/10/03)
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- A photophysical and photochemical study of 6-methoxy-2-naphthylacetic acid, the major metabolite of the phototoxic nonsteroidal antiinflammatory drug nabumetone
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Nabumetone is a phototoxic nonsteroidal antiinflammatory drug used for the treatment of osteoarthritis. However, nabumetone is considered a prodrug with its metabolite 6-methoxy-2-naphthylacetic acid the active form. Photophysical and photochemical studies on this metabolite have been undertaken. It undergoes photodecarboxylation in aerated aqueous and organic solvents. In addition to the accepted photodegradation pathway for related molecules, a new mechanism that implies generation of the naphthalene radical cation from the excited singlet and addition of O2 prior to the decarboxylation process has been demonstrated. Evidence for the involvement of the excited singlet state in this mechanism have been obtained by steady-state and time-resolved fluorescence experiments. The fluorescence quenching by O2 and the shorter singlet lifetime in aerated solvents support this assignment. Laser flash photolysis also supports this mechanism by showing the noninvolvement of the triplet in the formation of the naphthalene radical cation. Finally, the well-known electron acceptor CCl4 acts as an efficient singlet quencher, enhancing the route leading to the radical cation, preventing intersystem crossing to the triplet and thus resulting in a dramatic increase in the yield of 6-methoxy-2-naphthaldehyde, the major oxidative decarboxylation product; this constitutes unambiguous proof in favor of the new mechanistic proposals.
- Bosca,Canudas,Marin,Miranda
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p. 173 - 177
(2007/10/03)
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- Syntheses and biological evaluation of two new naproxen analogs
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Reported herein are the syntheses and biological activities of two structural analogues (2 and 3) of naproxen (1).
- Jung, Kyung Woon,Janda, Kim D.,Sanfilippo, Pauline J.,Wachter, Michael
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p. 2281 - 2282
(2007/10/03)
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- Antihyperglycemic Activity of Novel Naphthalenyl 3H-1,2,3,5-Oxathiadiazole 2-Oxides
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A series of naphthalenyl 3H-1,2,3,5-oxathiadiazole 2-oxides was prepared and tested for antihyperglycemic activity in the db/db mouse, a model for type 2 (non-insulin dependent) diabetes mellitus.Substitution at the 1-,5-, or 8-positions of the naphthalene ring with a halogen was found to be beneficial to antihyperglycemic activity. 4--3H-1,2,3,5-oxathiadiazole 2-oxide (45), one of the most potent compounds in this series, was selected for further pharmacological evaluation.
- Ellingboe, John W.,Lombardo, Louis J.,Alessi, Thomas R.,Nguyen, Thomas T.,Guzzo, Frieda,et al.
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p. 2485 - 2493
(2007/10/02)
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- Synthesis of Naphthoquinolizidines - Analogs of Cryptopleurine
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Condensation of the appropriate bromomethylnaphthalene (I) with 2-(1,3-dioxa-2-cyclopentyl)pyridine followed by treatment with 48percent HBr affords 3-methoxynaphthoquinolizinium bromide (8), 3-methoxy-(9)-, 2-methoxy-(10)- and 2,3-dimethoxy-(11)-naphthoquinolizinium bromides.The compounds (8-11) on catalytic hydrogenation over PtO2 give the corresponding naphthoquinolizidines (12-15).None of these compounds show any significant anticancer activity.
- Mukerjee, Y. N.,Gaur, S. P.,Jain, P. C.,Anand, Nitya
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p. 985 - 987
(2007/10/02)
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- Analogues of clofibrate and clobuzarit containing fluorine in the side chains
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A series of analogues of clofibrate and 2-[4-(4-chlorophenyl)phenylmethoxy]-2-methylpropionic acid (clobuzarit) has been prepared by replacing the methyl groups by trifluoromethyl groups and changing the aromatic moiety. The activity of these compounds has been assayed on the plasma levels of cholesterol, Total Esterified Fatty Acids (T.E.F.A.) and fibrinogen in rats. It appears that derivatives of the first series which contain only one trifluoromethyl group are hypocholesterolaemic and that many mono- of bis- trifluoromethyl derivatives of the second series lower the levels of both cholesterol and T.E.F.A. in contrast to clobuzarit.
- Haydock,Mulholland,Telford,et al.
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p. 205 - 214
(2007/10/02)
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- Synthesis and biological activities of 3-aminomethyl-1,2-dihydronaphthalene derivatives
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A series of 3-aminomethyl-1,2-dihydronaphthalene derivatives was prepared from the corresponding 3,4-dihydro-1(2H)-naphthalenone derivatives in three steps, namely the Mannich reaction, reduction of the carbonyl group with sodium borohydride, and dehydrat
- Itoh,Miyake,Tanabe,Hirata,Oka
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p. 2006 - 2015
(2007/10/02)
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- Fluorinated compounds as therapeutics
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Derivatives of 2-hydroxy-3,3,3-trifluoro-2-(alkyl or trifluoromethyl)propionic acid bearing a phenyl or naphthyl group linked to the 2-hydroxy group either directly or via an intermediate methylene group. The compounds reduce the concentrations of cholesterol, total esterified fatty acids or fibrinogen in the blood plasma of test animals and some compounds show anti-arthritic properties.
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- Substituted aryloxy-3,3,3-trifluoro-2-propionic acids, esters and salts thereof
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Derivatives of 2-hydroxy-3,3,3-trifluoro-2-(alkyl or trifluoromethyl)propionic acid bearing a phenyl or naphthyl group linked to the 2-hydroxy group either directly or via an intermediate methylene group. The compounds reduce the concentrations of cholesterol, total esterified fatty acids or fibrinogen in the blood plasma of test animals and some compounds show anti-arthritic properties.
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