- Design and synthesis of potent dual inhibitors of JAK2 and HDAC based on fusing the pharmacophores of XL019 and vorinostat
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Specifically blocking more than one oncogenic pathway simultaneously in a cancer cell with a combination of different drugs is the mainstay of the majority of cancer treatments. Being able to do this via two targeted pathways without inducing side effects through a general mechanism, such as chemotherapy, could bring benefit to patients. In this work we describe a new dual inhibitor of the JAK-STAT and HDAC pathways through designing and developing two types of molecule based on the JAK2 selective inhibitor XL019 and the pan-HDAC inhibitor, vorinostat. Both series of compounds had examples with low nanomolar JAK2 and HDAC1/6 inhibition. In some cases good HDAC1 selectivity was achieved while retaining HDAC6 activity. The observed potency is explained through molecular docking studies of all three enzymes. One example, 69c had 16–25 fold selectivity against the three other JAK-family proteins JAK1, JAK3 and TYK2. A number of compounds had sub-micromolar potencies against a panel of 4 solid tumor cell lines and 4 hematological cell lines with the most potent compound, 45h, having a cellular IC50 of 70 nM against the multiple myeloma cell line KMS-12-BM. Evidence of both JAK and HDAC pathway inhibition is presented in Hela cells showing that both pathways are modulated. Evidence of apoptosis with two compounds in 4 sold tumor cell lines is also presented.
- Chu-Farseeva, Yu-yi,Mustafa, Nurulhuda,Poulsen, Anders,Tan, Eng Chong,Yen, Jeffrey J.Y.,Chng, Wee Joo,Dymock, Brian W.
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supporting information
p. 593 - 619
(2018/10/02)
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- DIARYLUREAS AS CB1 ALLOSTERIC MODULATORS
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The present invention provides novel diarylurea derivatives (compounds of formula (I)) and their uses. The compounds of the present invention are demonstrated to be allosteric modulators of the CB1 receptor, and therefore useful for the treatment of diseases and conditions mediated by CB1.
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Paragraph 71; 113; 114
(2018/12/02)
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- A fragment merging approach towards the development of small molecule inhibitors of Mycobacterium tuberculosis EthR for use as ethionamide boosters
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With the ever-increasing instances of resistance to frontline TB drugs there is the need to develop novel strategies to fight the worldwide TB epidemic. Boosting the effect of the existing second-line antibiotic ethionamide by inhibiting the mycobacterial
- Nikiforov, Petar O.,Surade, Sachin,Blaszczyk, Michal,Delorme, Vincent,Brodin, Priscille,Baulard, Alain R.,Blundell, Tom L.,Abell, Chris
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supporting information
p. 2318 - 2326
(2016/03/01)
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- Metal-free Synthesis of Aryl Amines: Beyond Nucleophilic Aromatic Substitution
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A mild and metal-free approach to C?N coupling is described that employs diaryliodonium salt electrophiles and secondary aliphatic amine nucleophiles. This reaction results in direct ipso-substitution of the iodonium moiety and unsymmetrical aryl(TMP)iodonium salts are primarily employed. Moreover, arene substituents and substitution patterns that currently pose a challenge to classical metal-free methods are accommodated and the alicyclic amine nucleophiles used here are unprecedented in other contemporary metal-free C?N coupling reactions.
- Sandtorv, Alexander H.,Stuart, David R.
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p. 15812 - 15815
(2016/12/16)
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- Magnetic silica supported copper: A modular approach to aqueous Ullmann-type amination of aryl halides
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One-pot synthesis of a magnetic silica supported copper catalyst has been described via in situ generated magnetic silica (Fe3O 4@SiO2); the catalyst can be used for the efficacious amination of aryl halides in aqueous medium under microwave irradiation.
- Nasir Baig,Varma, Rajender S.
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p. 6568 - 6572
(2014/02/14)
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- Antiprion activity of functionalized 9-aminoacridines related to quinacrine
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A library of functionalized 6-chloro-2-methoxy-(N9-substituted)acridin-9-amines structurally related to quinacrine were synthesized and evaluated for antiprion activity on four different cell models persistently infected with scrapie prion strains (ScN2a, N167, Ch2) or a human disease prion strain (F3). Most of the compounds were distinguished by the side chain attached to 9-amino of the acridine ring. These were dialkylaminoalkyl and phenyl with basic groups on the phenyl ring. The most promising compound was 6-chloro-2-methoxy-N-(4-(4-methylpiperazin-1-yl)phenyl)acridin-9-amine (15) which had submicromolar EC50 values (0.1-0.7 μM) on all cell models, was able to clear PrPSc at non-toxic concentrations of 1.2-2.5 μM, and was more active than quinacrine in terms of EC50 values. Other promising compounds were 14 (a regioisomer of 15) and 17 which had a 1-benzylpiperidin-4-yl substituent attached to the 9-amino function. Activity was strongly dependent on the presence of a substituted acridine ring, which in this library comprised 6-chloro-2-methoxy substituents on the acridine ring. The side chains of 14, 15, and 17 have not been previously associated with antiprion activity and are interesting leads for further optimization of antiprion activity.
- Nguyen Thi, Hanh Thuy,Lee, Chong-Yew,Teruya, Kenta,Ong, Wei-Yi,Doh-ura, Katsumi,Go, Mei-Lin
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p. 6737 - 6746
(2008/12/21)
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- Potent and selective cathepsin K inhibitors
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A novel series of cathepsin K inhibitors derived from Novartis compound I is described. Optimization of the P1, P3, and P1′ units led to the identification of 4-aminophenoxyacetic acid 24b with an IC50 value of 4.8 nM, which possessed an excell
- Shinozuka, Tsuyoshi,Shimada, Kousei,Matsui, Satoshi,Yamane, Takahiro,Ama, Mayumi,Fukuda, Takeshi,Taki, Motohiko,Takeda, Yuko,Otsuka, Eri,Yamato, Michiko,Mochizuki, Shin-ichi,Ohhata, Keiko,Naito, Satoru
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p. 6789 - 6806
(2007/10/03)
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- Mild and efficient copper-catalyzed N-arylation of alkylamines and N-H heterocycles using an oxime-phosphine oxide ligand
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A mild and efficient copper-catalyzed system for N-arylation of alkylamines and N-H heterocycles with aryl iodides using a novel, readily prepared and highly stable oxime-functionalized phosphine oxide ligand was developed. The coupling reactions could even be performed in solvent-free conditions with moderate to good yields.
- Xu, Lei,Zhu, Di,Wu, Fan,Wang, Rongliang,Wan, Boshun
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p. 6553 - 6560
(2007/10/03)
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- HAIR DYES COMPRISING M-PHENYLENEDIAMINE DERIVATIVES AS COUPLING COMPONENTS
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The invention relates to agents for dyeing keratin fibers, especially human hair, containing at least one m-phenylenediamine derivative of formula (I) or one of the physiologically acceptable salts thereof as a coupling component in a cosmetically accepta
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Page/Page column 42
(2010/02/06)
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- Amination of aryl bromides catalysed by supported palladium
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Palladium particles immobilised onto a metal oxide support or Pd(0), Pd(II) and [Pd(NH3)4]2+ in NaY zeolite have been prepared and characterised. They exhibit a good activity towards the amination of aryl bromides using secondary amines such as piperidine and diethyl amine with a good regio-selectivity for these reactions. Low Pd concentrations (1 mol%) are required to observe a reasonable regio-selectivity. The catalysts can easily be separated from the reaction mixture (filtration) and reused without loss of activity and selectivity. The electronic nature of the aryl halides plays an important role for both the reaction yields and the regio-control of the reaction. It depends on the relation of the direct amination via a benzyne intermediate versus the Pd-catalysed route.
- Djakovitch, Laurent,Wagner, Michael,Koehler, Klaus
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p. 225 - 234
(2007/10/03)
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- Cupric acetate mediated N-arylation by arylboronic acids: A preliminary investigation into the scope of application
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A range of NH substrates of varying nucleophilicity were reacted with a selection of electronically diverse aryl boronic acids in the presence of cupric acetate in order to evaluate the generality of a previously described N-arylation procedure. The results of that investigation are discussed.
- Cundy, Darren J.,Forsyth, Stewart A.
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p. 7979 - 7982
(2007/10/03)
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- Aminobenzene compounds to prevent nerve cell degradation
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A compound useful for central antioxidant having inhibitory activity of degeneration and necrocytosis of cerebral cells of the formula (I): STR1 wherein A and B are independently (1) a group of the formula: STR2 wherein R1 and R2 are independently hydrogen atom, an optionally substituted hydrocarbon residue or an optionally substituted heterocyclic group, or R1 together with R2 and the nitrogen atom to which they are bound may form a cyclic amino group, provided that both R1 and R2 are not hydrogen atom at the same time, or (2) a group of the formula: STR3 wherein D is O or S, R3 is hydrogen atom, an optionally substituted hydrocarbon residue or an optionally substituted acyl group, m is 1, 2, or 3 and n is 0, 1, 2, 3 or 4; p is 1 or 2, provided that both A may be the same or different when p is 2; and R4, R5 and R6 are independently hydrogen atom, a lower alkyl or a lower alkoxy, or R5 and R6 may bond together to form --CH=CH--CH=CH--, or a salt thereof.
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- Reductive one batch synthesis of N-arylpiperidines from primary amines and glutaraldehyde
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The construction of the piperidine ring about an aromatic nitrogen atom, by a 5C + N reductiye condensation reaction, using glutaraldehyde (pentanedial) and sodium borohydride in acidic water/methanol medium is described. The reaction is fast, affords good to excellent yields and appears insensitive to electronic effects and severe steric hindrance; it is found to be compatible with a large variety of aryl substituents, including nitro and oxo groups.
- Verardo,Giumanini,Favret,Strazzolini
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p. 447 - 450
(2007/10/02)
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- High pressure organic chemistry; XII. A convenient synthesis of aromatic amines from activated aromatic fluorides
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Aromatic fluorides containing electron-withdrawing substituents are cleanly reacted with amines at 10 kbar pressure to give various aromatic amines.
- Kotsuki,Kobayashi,Matsumoto,Suenaga,Nishizawa
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p. 1147 - 1148
(2007/10/02)
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