- Small-molecule intervention at the dimerization interface of survivin by novel rigidized scaffolds
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Introduction: Survivin is a nodal protein involved in several cellular pathways. It is a member of the IAP family and an integral component of the chromosomal passenger complex, where it binds to borealin and INCENP through its dimerization interface. By targeting survivin with a small molecule at its dimerization interface, inhibition of the proliferation of cancer cells has been suggested. With Abbott 8, a small-molecul e dimerization inhibitor has been recently reported. The structure–activity relationship of this series of inhibitors implied that the middle pyridin-2(1H)-one ring did not tolerate modifications of any kind. Methods: Based on the synthetic strategy of Abbott 8 using multicomponent reactions, we synthesized a series of small molecules bearing a novel rigidized core scaffold. This rigidization strategy was accomplished by integrating the pyridin-2(1H)-one and its 6-phenyl substituent into a tricyclic structure, linking position 5 of pyridin-2(1H)-one to the phenyl substituent by rings of different sizes. The new scaffolds were designed based on in silico molecular dynamics of survivin. Results: Binding of these rigidized scaffolds to the recombinant L54M mutant of survivin was evaluated, revealing affinities in the low micromolar range. Conclusion: This easily accessible, new class of survivin-dimerization modulators is an interesting starting point for further lead optimization.
- Boeckler, Frank M.,Ernst, Christoph,Hennig, Susanne,Ibrahim, Tamer M.,Lange, Andreas
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p. 4247 - 4263
(2020/01/08)
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- Diverse modifications of the 4-methylphenyl moiety of TAK-779 by late-stage Suzuki-Miyaura cross-coupling
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Chemokine receptor 5 (CCR5) antagonists provide a new therapeutic approach in the treatment of HIV-1 (AIDS). TAK-779 displays high affinity and selectivity for the CCR5 receptor and serves as a lead compound for the development of further antagonists. In
- Junker, Anna,Schepmann, Dirk,Yamaguchi, Junichiro,Itami, Kenichiro,Faust, Andreas,Kopka, Klaus,Wagner, Stefan,Wuensch, Bernhard
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p. 177 - 186
(2014/01/06)
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- AMINO-PYRIDINE-CONTAINING SPLEEN TYROSINE KINASE (SYK) INHIBITORS
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The invention provides certain amino-pyridine-containing compounds of the Formula (I) or pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, and n are as defined herein. The invention also provides pharmaceutical compositions comprising such compounds, and methods of using the compounds for treating diseases or conditions mediated by Spleen Tyrosine Kinase (Syk) kinase.
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Page/Page column 55
(2012/11/14)
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- BENZOCYCLOHEPTENE ACETIC ACIDS
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Provided herein are compounds of the formula (I): as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of inflammatory diseases and disorders such as, for example, asthma and COPD.
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Page/Page column 23-24
(2012/12/14)
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- TRICYCLIC COMPOUNDS AS INHIBITORS FOR THE PRODUCTION OF BETA-AMYLOID
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Compounds of formula (I), including pharmaceutically acceptable salts thereof, are set forth herein: formula (I), wherein X is selected from the group of CH2, O, and NR2; m = 0 or 1; R1 at each instance is selected from th
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Page/Page column 24
(2012/12/13)
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- SPIROAMINOOXAZOLINE ANALOGUES AS ALPHA2C ADRENERGIC RECEPTOR MODULATORS
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In its many embodiments, the present invention provides a novel class of spiroaminooxazoline analogues as modulators of α2C adrenergic receptor, methods of preparing such compounds, pharmaceutical compositions containing one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition, or amelioration of one or more conditions associated with the α2C adrenergic receptors using such compounds or pharmaceutical compositions.
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Page/Page column 92
(2010/04/28)
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- ANTIBACTERIAL AGENTS
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Compounds of formula I and methods for their preparation are disclosed. Further disclosed are methods of making biologically active compounds of formula I as well as pharmaceutically acceptable compositions comprising compounds of formula I. Compounds of formula I as disclosed herein can be used in a variety of applications including use as antibacterial agents.
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- OXAZOLIDINONE DERIVATIVES N-SUBSTITUTED BY A BICYCLIC RING, FOR USE AS ANTIBACTERIAL AGENTS
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Compounds of formula (I) and methods for their preparation are disclosed. Further disclosed are methods of making biologically active compounds of formula (I) as well as pharmaceutically acceptable compositions comprising compounds of formula (I). Compoun
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Page/Page column 70; 71
(2010/02/08)
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- Discovery of novel, potent, and selective small-molecule CCR5 antagonists as anti-HIV-1 agents: Synthesis and biological evaluation of anilide derivatives with a quaternary ammonium moiety
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The search for new small-molecule CCR5 antagonists by high-throughput screening (HTS) of the Takeda chemical library using [125I]RANTES and CHO/CCR5 cells led to the discovery of lead compounds (A, B) with a quaternary ammonium or phosphonium m
- Shiraishi, Mitsuru,Aramaki, Yoshio,Seto, Masaki,Imoto, Hiroshi,Nishikawa, Youichi,Kanzaki, Naoyuki,Okamoto, Mika,Sawada, Hidekazu,Nishimura, Osamu,Baba, Masanori,Fujino, Masahiko
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p. 2049 - 2063
(2007/10/03)
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- A convenient synthesis of mono- and polyhalogenated benzocyclanones
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Benzocyclanones were mono- or dihalogenated on the aromatic ring with elemental halogen or N-halosuccinimide without solvent in an aluminum chloride slurry in good yield. This process is the most direct method for the synthesis of 5- or 7-halo, or 5,7-dihalotetralones and can be extended to indan-1-ones and benzocycloheptan-1-ones as well as to trihalogenated and to mixed halogenated products.
- Cornelius,Combs
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p. 2777 - 2788
(2007/10/02)
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- Hydrocarbures arylaliphatiques. Partie VII. Orientation dans la reaction de bromation de benzocyclenes bi- et tricycliques superieurs
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The bromination of 1,2,3-trimethylbenzene, and bi- and tricyclic fused ring systems (i.e. indan, tetralin, benzosuberan, 2a,3,4,5-tetrahydroacenaphthen and higher homologues) is described in this paper.This work is part of a research project studying the ring size influence of peri-fused semi-aromatic ring system on benzene reactivity.This study was started in a first step on acetylation and was continued on bromination.Forthcoming studies (now underway) concern the kinetic measurement of protodesilylation of univocal silyl derivatives.The synthesis of the starting bromo derivatives used for this latter study is described here.These bromides were used for the attribution via NMR spectroscopy of the electrophile reaction site in the direct bromination of the fused ring unsymmetrical systems (the reactive sites are obvious in symmetrical molecules). Thus, meta substitution is predominant in the case of tetraline and benzosuberan, but ortho substitution is relatively more important in tetralin.In 1,2,3-trimethylbenzene and the fused tricyclic compounds, substitution takes place in an ortho position respective to the substituent or the ring system, the meta position being totally deactivated.In the special case of a five-membered ring, the ortho position this ring is always non reactive.The reactivity differences between these compounds are explained by hyper conjugation and the stabilities of the transition states.
- Gruber, Rene,Cagniant, Denise,Cagniant, Paul
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