- Exploration of N-(2-aminoethyl)piperidine-4-carboxamide as a potential scaffold for development of VEGFR-2, ERK-2 and Abl-1 multikinase inhibitor
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VEGFR, ERK and Abl had been respectively identified as good drug targets, and their crosstalk also had been well elaborated. Multitarget drugs were more advantageous for cancer treatment, however, no inhibitors simultaneously acting on the three proteins were developed due to their structural diversities. Herein, N-(4-((2-(2-(naphthaen-1-yl)acetamido)ethyl)carbamoyl)piperidin-4-yl)-6- (trifluoromethyl)nicotinamide (NEPT, 6a) was discovered as an active scaffold against VEGFR-2, ERK-2 and Abl-1 kinases through the combination of support vector machine, similarity searching and molecular docking. NEPT and its derivatives were synthesized by convenient routine, their in vitro anti-proliferative abilities against human liver cancer cell line HepG2 were preliminarily evaluated. A representative compound 6b showed an IC50 value of 11.3 μM and induced significant HepG2 cells apoptosis. Besides, these compounds displayed better anti-proliferative abilities against K562 cells (a cell line with typical hyperactivity of the above multikinases), for example compound 6b exhibited an IC50 value of 4.5 μM. Based on hepatotoxicity case reports of Abl inhibitors, cytotoxicity of synthetic compounds against normal liver cell lines (QSG7701 and HL7702) was studied, 6b had a similar toxic effect with positive control imatinib, and most compounds showed less than 35% inhibition activities at 100 μM. Molecular docking study disclosed interactions of 6b with VEGFR-2, ERK-2 and Abl-1 kinases, respectively. Our data suggested the biological activities of 6b may derived from collaborative effects of VEGFR-2, ERK-2 and Abl-1 inhibition.
- Jin, Feng,Gao, Dan,Wu, Qin,Liu, Feng,Chen, Yuzong,Tan, Chunyan,Jiang, Yuyang
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p. 5694 - 5706
(2013/09/12)
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- PEPTIDYL NITRILCOMPOUNDS AS PEPTIDASE INHIBITORS
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The invention relates to compounds of Formula (II) and their use in theraphy as peptidase inhibitors.
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Page/Page column 110
(2012/09/22)
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- Solid-phase synthesis and utilization of side-chain reactive unnatural amino acids
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Alkylation of the benzophenone imine of glycine Wang resin with α,ω-dihaloalkanes yielded valuable reactive intermediates. These racemic ω-chloro or ω-bromo intermediates were converted to α-amino acids containing diverse side-chain functionalities (e.g.
- O'Donnell, Martin J.,Alsina, Jordi,Scott, William L.
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p. 8403 - 8406
(2007/10/03)
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- Novel selective inhibitors of the interaction of individual nuclear hormone receptors with a mutually shared steroid receptor coactivator 2
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Nuclear hormone receptor (NR) signaling, currently a therapeutic target in multiple diseases, involves an ordered series of protein interactions to regulate transcription in response to changing hormone levels. Later steps in the process of ligand-dependent signaling are driven by a highly conserved interaction between the NRs and the steroid receptor coactivators (SRCs) that is effected by a conserved interaction motif (L1XXL2L3), known as an NR box. Using computational design and combinatorial chemistry, we have produced novel ∞-helical proteomimetics of the second NR box of SRC2 that exploit structural differences between human estrogen receptor ∞ (hER∞), human estrogen receptor β (hERβ), and human thyroid hormone receptor β (hTRβ). The resulting library sequentially replaced each leucine with non-natural side chains. Screening this library using a quantitative competition assay revealed compounds that selectively inhibit the interaction of SRC2-2 with each individual NR in preference to its interaction with the other NR. This approach generated highly selective compounds from one that had no specificity for a particular family member. These compounds represent the first family-member-selective competitive inhibitors of the protein interactions of transcription factors. Copyright
- Geistlinger, Timothy R.,Guy, R. Kiplin
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p. 6852 - 6853
(2007/10/03)
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- Zinc promoted rapid and efficient synthesis of Fmoc- and Z-α,α-dialkylamino acids under neutral conditions
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The introduction of Nα-9-fluorenylmethyloxycarbonyl (Fmoc) and benzyloxycarbonyl (Z) groups into α,α-dialkylamino acids is described at neutral pH using Fmoc-Cl or Z-Cl as an acylating agent respectively in the presence of activated zing powder. The reaction is simple, fast and clean. It also permits the scale up with high yields. It is completely free from protected oligomer formation, which is a known side-reaction when Schotten-Baumann procedure is followed. All the Fmoc- and Z-amino acids prepared have been fully characterized.
- Babu, Vommina V. Suresh,Ananda, Kuppanna
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- Synthesis and conformational characterization of tethered, self-complexing 1,5-dialkoxynaphthalene/1,4,5,8-naphthalenetetracarboxylic diimide systems
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Chemists are beginning to explore the abiotic folding of synthetic chains, and the term "foldamers" has been used to characterize oligomers with a strong inclination to adopt specific, compact conformations. The characterization of folded structure in solution is one of the difficult challenges facing the foldamer field. Aedamers were the first foldamers to make use of aromatic-aromatic interactions in water to direct folding and were designed to have several spectroscopic handles with which to probe folding conformations in solution. Herein is reported the synthesis and spectroscopic characterization of eleven aedamer dimers, with linkers chosen to provide a spectrum of lengths and flexibilities. The dimers, composed of one electron rich (1,5-dialkoxynaphthalene) and one electron deficient (1,4,5,8-naphthalenetetracarboxylic diimide) aromatic group tethered by a linker, are the smallest aedamer folding unit. The powerful spectroscopic handles associated with the stacked aedamer groups were exploited in a comprehensive spectroscopic analysis of conformation that included UV-vis absorption spectroscopy, fluorescence measurements (including time-resolved studies), as well as detailed NMR studies. The spectra were interpreted in the context of molecular modeling/spectral prediction and structural models were developed for the different dimers in aqueous solution. In most instances, the observed data was best described by an ensemble of predicted structures as opposed to one or few conformers. Thus, in the case of these aedamer dimers, "folding" does not appear to imply a two-state model with a rigid, unique conformation. Rather, the reported analysis indicates the data can best be described by a more dynamic model in which a given molecule spends its time in different folded conformations that are related by having a characteristic face-to-face stacking arrangement of the aromatic units.
- Zych, Andrew J.,Iverson, Brent L.
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p. 8898 - 8909
(2007/10/03)
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- Gem-distributed esters of rapamycin
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Compounds of the structure STR1 R and R1 are each, independently, hydrogen, or STR2 R2 and R3 are each, independently, alkyl, arylalkyl, or may be taken together to form a cycloalkyl ring; R4 and R5 are each, independently, hydrogen, alkyl, arylalkyl, or may be taken together to form a saturated heterocycle wherein the heterocyclic ring may be optionally mono-, di-, or tri-substituted; m=0-1; and n=0-6; with the proviso that R and R1 are not both hydrogen, or a pharmaceutically acceptable salt thereof, and STR3 R1 is STR4 R2 and R3 are each, independently, hydrogen, alkyl, arylalkyl, or may be taken together to form a cycloalkyl ring; R4 and R5 are each, independently, hydrogen, alkyl, arylalkyl, or may be taken together to form a saturated heterocycle wherein the heterocyclic ring may be optionally mono-, di-, or tri-substituted; m=0-1; and n=0-6; or a pharmaceutically acceptable salt thereof which are useful as immunosuppressive, antiinflammatory, antifungal, antiproliferative, and antitumor agents.
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