10355-13-2Relevant articles and documents
Photogeneration of Quinone Methides as Latent Electrophiles for Lysine Targeting
Pérez-Ruiz, Raúl,Molins-Molina, Oscar,Lence, Emilio,González-Bello, Concepción,Miranda, Miguel A.,Jiménez, M. Consuelo
, p. 13019 - 13029 (2018)
Latent electrophiles are nowadays very attractive chemical entities for drug discovery, as they are unreactive unless activated upon binding with the specific target. In this work, the utility of 4-trifluoromethyl phenols as precursors of latent electrophiles, quinone methides (QM), for lysine-targeting is demonstrated. These Michael acceptors were photogenerated for specific covalent modification of lysine residues using human serum albumin (HSA) as a model target. The reactive QM-type intermediates I or II, generated upon irradiation of 4-trifluoromethyl-1-naphthol (1)@HSA or 4-(4-trifluorometylphenyl)phenol (2)@HSA complexes, exhibited chemoselective reactivity toward lysine residues leading to amide adducts, which was confirmed by proteomic analysis. For ligand 1, the covalent modification of residues Lys106 and Lys414 (located in subdomains IA and IIIA, respectively) was observed, whereas for ligand 2, the modification of Lys195 (in subdomain IIA) took place. Docking and molecular dynamics simulation studies provided an insight into the molecular basis of the selectivity of 1 and 2 for these HSA subdomains and the covalent modification mechanism. These studies open the opportunity of performing protein silencing by generating reactive ligands under very mild conditions (irradiation) for specific covalent modification of hidden lysine residues.
Ligand-free, recyclable palladium-functionalized magnetite nanoparticles as a catalyst in the Suzuki-, Sonogashira, and Stille reaction
De Cattelle, Amaury,Billen, Arne,O'Rourke, Galahad,Brullot, Ward,Verbiest, Thierry,Koeckelberghs, Guy
, (2019)
A magnetically reusable ligand-free Fe3O4 palladium functionalized catalyst system was successfully prepared without the use of reducing agents, but by making use of the reduction potential of magnetite. The stabilizer was variated depending on the investigated reaction, whereby poly(ethylene glycol) (PEG) stabilized nanoparticles were used for the Suzuki reaction, as it requires protic conditions, while oleic acid stabilized nanoparticles were used for the Sonogashira and Stille reaction. It was found that it was possible to perform the Suzuki reaction and the Sonogashira reaction resulting in good to excellent conversions under air. Despite the good results for the Suzuki and the Sonogashira reaction it was not possible to perform the Stille reaction using this easily synthesized catalyst system due to the poisoning of the reusable catalyst by the tin-compound. Furthermore, the reusable catalyst system was recycled and reused for five times, resulting in a separable, straightforward and less time-consuming catalyst system.
3-Hydroxypyrimidine-2,4-diones as Selective Active Site Inhibitors of HIV Reverse Transcriptase-Associated RNase H: Design, Synthesis, and Biochemical Evaluations
Tang, Jing,Liu, Feng,Nagy, Eva,Miller, Lena,Kirby, Karen A.,Wilson, Daniel J.,Wu, Bulan,Sarafianos, Stefan G.,Parniak, Michael A.,Wang, Zhengqiang
, p. 2648 - 2659 (2016)
Human immunodeficiency virus (HIV) reverse transcriptase (RT) associated ribonuclease H (RNase H) remains an unvalidated antiviral target. A major challenge of specifically targeting HIV RNase H arises from the general lack of selectivity over RT polymerase (pol) and integrase (IN) strand transfer (ST) inhibitions. We report herein the synthesis and biochemical evaluations of three novel 3-hydroxypyrimidine-2,4-dione (HPD) subtypes carefully designed to achieve selective RNase H inhibition. Biochemical studies showed the two subtypes with an N-1 methyl group (9 and 10) inhibited RNase H in low micromolar range without siginificantly inhibiting RT polymerase, whereas the N-1 unsubstituted subtype 11 inhibited RNase H in submicromolar range and RT polymerase in low micromolar range. Subtype 11 also exhibited substantially reduced inhibition in the HIV-1 INST assay and no significant cytotoxicity in the cell viability assay, suggesting that it may be amenable to further structure-activity relationship (SAR) for identifying RNase H inhibitors with antiviral activity.
Structural modification of honokiol, a biphenyl occurring in magnolia officinalis: The evaluation of honokiol analogues as inhibitors of angiogenesis and for their cytotoxicity and structure-activity relationship
Ma, Liang,Chen, Jinying,Wang, Xuewei,Liang, Xiaolin,Luo, Youfu,Zhu, Wei,Wang, Tianen,Peng, Ming,Li, Shucai,Jie, Shi,Peng, Aihua,Wei, Yuquan,Chen, Lijuan
, p. 6469 - 6481 (2011)
Honokiol, widely known as an antitumor agent, has been used as an antiangiogenesis drug lead. In this paper, 47 honokiol analogues and derivatives were investigated for their antiangiogenic activity by application of the transgenic zebrafish screening model, antiproliferative and cytotoxic activity against HUVECs, and three tumor cell lines by MTT assay. 3′,5-Diallyl-2, 4′-dihydroxy-[1,1′-biphen-yl]-3,5′-dicarbaldehyde (8c) was found to suppress the newly grown segmental vessels from the dorsal aorta of zebrafish and prevent inappropriate vascularization as well as exhibit more potent inhibitory effects on the proliferation of HUVECs, A549, HepG2, and LL/2 cells (IC50 = 15.1, 30.2, 10.7, and 21.7 μM, respectively) than honokiol (IC50 = 52.6, 35.0, 16.5, and 65.4 μM, respectively). Analogue 8c also effectively inhibited the migration and capillary-like tube formation of HUVECs in vitro. The antiangiogenic effect and antiproliferative activity of these structurally modified honokiol analogues and derivatives have led to the establishment of a structure-activity relationship.
Experimental evidence for the formation of cationic intermediates during iodine(iii)-mediated oxidative dearomatization of phenols
Tang, Ting,Harned, Andrew M.
, p. 6871 - 6874 (2018)
Iodine(iii)-based oxidants are commonly used reagents for the oxidative dearomatization of phenols. Having a better understanding of the mechanism through which these reactions proceed is important for designing new iodine(iii)-based reagents, catalysts, and reactions. We have performed a Hammett analysis of the oxidative dearomatization of substituted 4-phenylphenols. This study confirms that iodine(iii)-mediated oxidative dearomatizations likely proceed through cationic phenoxenium ions and not the direct addition of a nucleophile to an iodine-bound phenol intermediate.
Magnetically induced Suzuki and Sonogashira reaction performed using recyclable, palladium-functionalized magnetite nanoparticles
De Cattelle, Amaury,Billen, Arne,Brullot, Ward,Verbiest, Thierry,Koeckelberghs, Guy
, (2019)
A magnetically reusable, ligand-free palladium functionalized Fe3O4 catalyst system was successfully prepared. To overcome current problems such as the recyclability of the nanoparticle and the control and safety of the reaction, full advantage of the magnetite support was used. The palladium functionalized magnetite nanoparticle was removed by precipitation using a permanent magnet, while local heating, around the catalytic site, was induced using an external magnetic field. It was found that it was possible to perform the Suzuki reaction resulting in good to excellent conversions under air, with a magnetic field strength of 210 G and a frequency of 160 kHz. Despite the good results for the Suzuki reaction, it was not possible to perform the Sonogashira reaction magnetically due to an insufficient heat generation around the catalytic site. Further, the reusable catalyst system was recycled and reused for five times, resulting in a separable and straightforward catalyst system with the advantage of having full control of the reaction.
Catalyst shuttling enabled by a thermoresponsive polymeric ligand: Facilitating efficient cross-couplings with continuously recyclable ppm levels of palladium
Wang, Erfei,Chen, Mao
, p. 8331 - 8337 (2019/09/30)
A polymeric monophosphine ligand WePhos has been synthesized and complexed with palladium(ii) acetate [Pd(OAc)2] to generate a thermoresponsive pre-catalyst that can shuttle between water and organic phases, with the change being regulated by temperature. The structure of the polymeric ligand was confirmed with matrix-assisted laser desorption/ionization-time-of-flight (MALDI-TOF) mass spectrometry and size-exclusion chromatography (SEC) analysis, as well as nuclear magnetic resonance (NMR) measurements. This polymeric metal complex enables highly efficient Pd-catalyzed cross-couplings and tandem reactions using 50 to 500 ppm palladium, and this can facilitate reactions that are tolerant to a broad spectrum of (hetero)aryl substrates and functional groups, as demonstrated with 73 examples with up to 99% isolated yields. Notably, 97% Pd remained in the aqueous phase after 10 runs of catalyst recycling experiments, as determined via inductively coupled plasma-atomic emission spectrometry (ICP-AES) measurements, indicating highly efficient catalyst transfer. Furthermore, a continuous catalyst recycling approach has been successfully developed based on flow chemistry in combination with the catalyst shuttling behavior, allowing Suzuki-Miyaura couplings to be conducted at gram-scales with as little as 10 ppm Pd loading. Given the significance of transition-metal catalyzed cross-coupling and increasing interest in sustainable chemistry, this work is an important step towards the development of a responsive catalyst, in addition to having high activity, by tuning the structures of the ligands using polymer science.
NOVEL NUCLEOSIDE PHOSPHORAMIDATE COMPOUND AND USE THEREOF
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Paragraph 0155, (2015/11/24)
The present invention provides a novel nucleoside phosphoramidate compound, or a stereoisomer, salt, hydrate, solvate or crystal thereof for the treatment of Flaviviridae family viral infection, especially hepatitis C viral infection. The present invention also provides the pharmaceutical composition comprising a compound of the present invention, or a stereoisomer, salt, hydrate, solvate or crystal thereof and a use of the compound or the composition of the present invention in the treatment of Flaviviridae family viral infection, especially hepatitis C viral infection. The compound of the present invention has a good anti-HCV effect.
Design, synthesis, and anti-proliferative evaluation of [1,1′-biphenyl]-4-ols as inhibitor of HUVEC migration and tube formation
Ran, Yan,Ma, Liang,Wang, Xuewei,Chen, Jinying,Wang, Guangcheng,Peng, Aihua,Chen, Lijuan
, p. 8091 - 8104 (2012/10/07)
Allylated biphenol neolignans contain a variety of chemopreventive entities that have been used as anti-tumor drug leads. Herein, 37 allylated biphenols were evaluated for anti-proliferative activity by the MTT assay and inhibitory effect on the migration and tube formation of HUVECs featuring anti-angiogenic properties. 3-(2-Methylbut-3-en-2-yl)-3′,5′-bis(trifluoromethyl)-[1, 1′-biphenyl]-4-ol (5c) exerted an inhibitory effect on HUVECs compared to honokiol (IC50 = 47.0 vs. 52.6 μM) and showed significant blocking effects on the proliferation of C26, Hela, K562, A549, and HepG2 (IC 50 = 15.0, 25.0, 21.2, 29.5, and 13.0 μM, respectively), superior to those of honokiol (IC50 = 65.1, 62.0, 42.0, 75.0, and 55.4 μM, respectively). Importantly, compound 5c inhibited the migration and capillary-like tube formation of HUVECs in vitro.
Glucagon Receptor Modulators
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Page/Page column 48, (2012/07/13)
The present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof wherein R1, R2, R3, A1, A2, A3, A4, L, B1, B2, B3 and B4 are as defined herein. The compounds of Formula I have been found to act as glucagon antagonists or inverse agonists. Consequently, the compounds of Formula I and the pharmaceutical compositions thereof are useful for the treatment of diseases, disorders, or conditions mediated by glucagon.
