134363-45-4Relevant articles and documents
Novel methyllycaconitine analogues selective for the α4β2 over α7 nicotinic acetylcholine receptors
Gallagher, Ryan,Qudah, Taima,Balle, Thomas,Chebib, Mary,McLeod, Malcolm D.
, (2021/11/27)
Analogues of methyllycaconitine (MLA) based on a (3-ethyl-9-methylidene-3-azabicyclo[3.3.1]nonan-1-yl)methanol template have been designed and synthesised that incorporate the modified ester sidechains distinct from that present in the natural product. Electrophysiology experiments using Xenopus oocytes expressing nicotinic acetylcholine receptors (nAChRs) revealed selected analogues served as non-competitive inhibitors that showed selectivity for the α4β2α7 nAChR subtypes, and selectivity for the (α4)3(β2)2(α4)2(β2)3 stoichiometry. This study more clearly defines the biological effects of MLA analogues and identifies strategies for the development of MLA analogues as selective ligands for the α4β2 nAChR subtype.
Design, synthesis, and biological evaluation of tetrahydroquinolin derivatives as potent inhibitors of CBP bromodomain
Bi, Xiaoyang,Chen, Kaixian,Chen, Yu,Ding, Hong,Jiang, Hao,Jiang, Hualiang,Lu, Tian,Lu, Wenchao,Luo, Cheng,Sun, Zhongya,Xu, Pan,Zhang, Fengcai,Zhang, Naixia,Zhou, Bing
supporting information, (2020/06/21)
CREB-binding protein (CBP) is a large multi-domain protein containing a HAT domain catalyzing transacetylation and a bromodomain responsible for acetylated lysine recognition. CBPs could act as transcription co-activators to regulate gene expression and have been shown to play a significant role in the development and progression of many cancers. Herein, through in silico screening two hit compounds with tetrahydroquinolin methyl carbamate scaffold were discovered, among which DC-CPin7 showed an in vitro inhibitory activity with the TR-FRET IC50 value of 2.5 ± 0.3 μM. We obtained a high-resolution co-crystal structure of the CBP bromodomain in complex with DC-CPin7 to guide following structure-based rational drug design, which yielded over ten DC-CPin7 derivatives with much higher potency, among which DC-CPin711 showed approximately 40-fold potency compared with hit compound DC-CPin7 with an in vitro TR-FRET IC50 value of 63.3 ± 4.0 nM. Notably, DC-CPin711 showed over 150-fold selectivity against BRD4 bromodomains. Moreover, DC-CPin711 showed micromolar level of anti-leukemia proliferation through G1 phase cell cycle arrest and cell apoptosis. In summary, through a combination of computational and crystal-based structure optimization, DC-CPin711 showed potent in vitro inhibitory activities to CBP bromodomain with a decent selectivity towards BRD4 bromodomains and good cellular activity to leukemia cells, which could further be applied to related biological and translational studies as well as serve as a lead compound for future development of potent and selective CBP bromodomain inhibitors.
Vitamin Catalysis: Direct, Photocatalytic Synthesis of Benzocoumarins via (-)-Riboflavin-Mediated Electron Transfer
Morack, Tobias,Metternich, Jan B.,Gilmour, Ryan
supporting information, p. 1316 - 1319 (2018/03/09)
An operationally simple protocol is disclosed to facilitate entry to benzo-3,4-coumarins directly from biaryl carboxylic acids without the need for substrate prefunctionalization. Complementary to classic lactonization strategies, this disconnection relies on the oxidation competence of photoactivated (-)-riboflavin (vitamin B2) to generate the heterocyclic core via photoinduced single electron transfer. Collectively, the inexpensive nature of the catalyst, ease of execution, and absence of external metal additives are a convincing endorsement for the incorporation of simple vitamins in contemporary catalysis.
Photocatalytic Dehydrogenative Lactonization of 2-Arylbenzoic Acids
Ramirez, Nieves P.,Bosque, Irene,Gonzalez-Gomez, Jose C.
supporting information, p. 4550 - 4553 (2015/09/28)
A metal-free dehydrogenative lactonization of 2-arylbenzoic acids at room temperature was developed. This work illustrates the first application of visible-light photoredox catalysis in the preparation of benzo-3,4-coumarins, an important structural motif in bioactive molecules. The combination of photocatalyst [Acr+-Mes] with (NH4)2S2O8 as a terminal oxidant provides an economical and environmentally benign entry to different substituted benzocoumarins. Preliminary mechanistic studies suggest that this reaction most likely occurs through a homolytic aromatic substitution pathway.
1-HYDROXY NAPHTHYRIDINE COMPOUNDS AS ANTI-HIV AGENTS
-
, (2008/06/13)
1-Hydroxy naphthyridine compounds (e.g., 1-hydroxy naphthyridin-2(1H)-one compounds of Formula I are inhibitors of HIV integrase and/or HIV RNase H and inhibitors of HIV replication: (I) wherein X and R1-R6 are as defined herein. The compounds are useful in the prophylaxis and treatment of infection by HIV and in the prophylaxis, delay in the onset, and treatment of AIDS. The compounds are employed against HIV infection and AIDS as compounds per se or in the form of pharmaceutically acceptable salts. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other anti-HIV agents such as HIV antivirals, immunomodulators, antibiotics and vaccines.
Design and synthesis of 6-fluoro-2-naphthyl derivatives as novel CCR3 antagonists with reduced CYP2D6 inhibition
Sato, Ippei,Morihira, Koichiro,Inami, Hiroshi,Kubota, Hirokazu,Morokata, Tatsuaki,Suzuki, Keiko,Iura, Yosuke,Nitta, Aiko,Imaoka, Takayuki,Takahashi, Toshiya,Takeuchi, Makoto,Ohta, Mitsuaki,Tsukamoto, Shin-ichi
, p. 8607 - 8618 (2008/12/23)
In our previous study on discovering novel types of CCR3 antagonists, we found a fluoronaphthalene derivative (1) that exhibited potent CCR3 inhibitory activity with an IC50 value of 20 nM. However, compound 1 also inhibited human cytochrome P450 2D6 (CYP2D6) with an IC50 value of 400 nM. In order to reduce its CYP2D6 inhibitory activity, we performed further systematic structural modifications on 1. In particular, we focused on reducing the number of lipophilic moieties in the biphenyl part of 1, using C log D7.4 values as the reference index of lipophilicity. This research led to the identification of N-{(3-exo)-8-[(6-fluoro-2-naphthyl)methyl]-8-azabicyclo[3.2.1]oct-3-yl}-3-(piperidin-1-ylcarbonyl)isonicotinamide 1-oxide (30) which showed comparable CCR3 inhibitory activity (IC50 = 23 nM) with much reduced CYP2D6 inhibitory activity (IC50 = 29,000 nM) compared with 1.
Synthesis and metallation of 2-(pyridyl)benzoic acids and ethyl 2-(pyridyl)benzoates: A new route to azafluorenones
Rebstock, Anne-Sophie,Mongin, Florence,Trécourt, Fran?ois,Quéguiner, Guy
, p. 4973 - 4977 (2007/10/03)
The ring deprotonation of 2-(2- and 4-pyridyl)benzoic acids using lithium dialkylamides in THF at rt, and the in situ cyclization afforded 4- and 2-azafluorenones, respectively. 1-Azafluorenone was obtained from ethyl 2-(3-pyridyl)benzoate using a similar protocol.
A convenient synthesis of heteroaryl benzoic acids via Suzuki reaction
Gong, Yong,Pauls, Henry W.
, p. 829 - 831 (2007/10/03)
An one step approach to heteroaryl benzoic acids from readily accessible heteroaryl halides and carboxybenzene boronic acids is described. The Suzuki coupling is carried out in the presence of Pd(PPh3)4 and sodium carbonate in aqueous acetonitrile. The scope and limitations of the reaction are discussed.
Inhibition of Myeloperoxidase Release from Rat Polymprphonuclear Leukocytes by a Series of Azachalcone Derivatives
Edwards, Michael L.,Stemerick, David M.,Sabol, Jeffrey S.,Diekema, Keith A.,Dinerstein, Robert J.
, p. 4357 - 4362 (2007/10/02)
A series of azachalcones was evaluated for ability to affect secretion of myeloperoxidase by rat polymorphonuclear leukocytes by fMLP.The compounds were found to interfere with cellular uptake of extracellular calcium.Structure-activity relationships are
