180635-74-9Relevant articles and documents
DITERPENOID COMPOUNDS THAT ACT ON PROTEIN KINASE C (PKC)
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Paragraph 0565-0567, (2021/04/02)
This present disclosure relates to protein kinase C (PKC) modulating compounds, methods of treating a subject with cancer using the compounds, and combination treatments with a second therapeutic agent.
Design, synthesis, and evaluation of dihydropyranopyrazole derivatives as novel pde2 inhibitors for the treatment of alzheimer’s disease
Huang, Ling,Huang, Yi-You,Huang, Yue,Li, Jinjian,Li, Zhe,Luo, Hai-Bin,Su, Rui,Wu, Yinuo,Yuan, Han,Zhang, Chen,Zhou, Yan
, (2021/06/03)
Phosphodiesterase 2 (PDE2) has been regarded as a novel target for the treatment of Alz-heimer’s disease (AD). In this study, we obtained (R)‐LZ77 as a hit compound with moderate PDE2 inhibitory activity (IC50 = 261.3 nM) using a high‐throughput virtual screening method based on molecular dynamics. Then, we designed and synthesized 28 dihydropyranopyrazole derivatives as PDE2 inhibitors. Among them, compound (+)‐11h was the most potent PDE2 inhibitor, with an IC50 value of 41.5 nM. The molecular docking of PDE2‐(+)‐11h reveals that the 4‐(trifluoromethyl)ben-zyl)oxyl side chain of the compound enters the H‐pocket and forms strong hydrophobic interactions with L770/L809/F862, which improves inhibitory activity. The above results may provide insight for further structural optimization of highly potent PDE2 inhibitors and may lay the foundation for their use in the treatment of AD.
Access to Trisubstituted Fluoroalkenes by Ruthenium-Catalyzed Cross-Metathesis
Nouaille, Augustin,Pannecoucke, Xavier,Poisson, Thomas,Couve-Bonnaire, Samuel
supporting information, p. 2140 - 2147 (2021/03/06)
Although the olefin metathesis reaction is a well-known and powerful strategy to get alkenes, this reaction remained highly challenging with fluororalkenes, especially the Cross-Metathesis (CM) process. Our thought was to find an easy accessible, convenient, reactive and post-functionalizable source of fluoroalkene, that we found as the methyl 2-fluoroacrylate. We reported herein the efficient ruthenium-catalyzed CM reaction of various terminal and internal alkenes with methyl 2-fluoroacrylate giving access, for the first time, to trisubstituted fluoroalkenes stereoselectively. Unprecedent TON for CM involving fluoroalkene, up to 175, have been obtained and the reaction proved to be tolerant and effective with a large range of olefin partners giving fair to high yields in metathesis products. (Figure presented.).
Iridium Complex-Catalyzed C2-Extension of Primary Alcohols with Ethanol via a Hydrogen Autotransfer Reaction
Kobayashi, Masaki,Itoh, Satoshi,Yoshimura, Keisuke,Tsukamoto, Yuya,Obora, Yasushi
, p. 11952 - 11958 (2020/10/23)
The development of a C2-extension of primary alcohols with ethanol as the C2 source and catalysis by [Cp*IrCl2]2 (where Cp? = pentamethylcyclopentadiene) is described. This new extension system was used for a range of benzylic alcohol substrates and for aliphatic alcohols with ethanol as an alkyl reagent to generate the corresponding C2-extended linear alcohols. Mechanistic studies of the reaction by means of intermediates and deuterium labeling experiments suggest the reaction is based on hydrogen autotransfer.
Synthesis and inhibitory studies of phosphonic acid analogues of homophenylalanine and phenylalanine towards alanyl aminopeptidases
Wanat, Weronika,Talma, Micha?,Dziuk, B?a?ej,Kafarski, Pawe?
, p. 1 - 22 (2020/09/18)
A library of novel phosphonic acid analogues of homophenylalanine and phenylalanine, containing fluorine and bromine atoms in the phenyl ring, have been synthesized. Their inhibitory properties against two important alanine aminopeptidases, of human (hAPN, CD13) and porcine (pAPN) origin, were evaluated. Enzymatic studies and comparison with literature data indicated the higher inhibitory potential of the homophenylalanine over phenylalanine derivatives towards both enzymes. Their inhibition constants were in the submicromolar range for hAPN and the micromolar range for pAPN, with 1-amino-3-(3-fluorophenyl) propylphosphonic acid (compound 15c) being one of the best low-molecular inhibitors of both enzymes. To the best of our knowledge, P1 homophenylalanine analogues are the most active inhibitors of the APN among phosphonic and phosphinic derivatives described in the literature. Therefore, they constitute interesting building blocks for the further design of chemically more complex inhibitors. Based on molecular modeling simulations and SAR (structure-activity relationship) analysis, the optimal architecture of enzyme-inhibitor complexes for hAPN and pAPN were determined.
4“-O-Alkylated α-Galactosylceramide Analogues as iNKT-Cell Antigens: Synthetic, Biological, and Structural Studies
Janssens, Jonas,Bitra, Aruna,Wang, Jing,Decruy, Tine,Venken, Koen,van der Eycken, Johan,Elewaut, Dirk,Zajonc, Dirk M.,van Calenbergh, Serge
, p. 147 - 168 (2019/01/04)
Invariant natural killer T-cells (iNKT) are a glycolipid-responsive subset of T-lymphocytes that fulfill a pivotal role in the immune system. The archetypical synthetic glycolipid, α-galactosylceramide (α-GalCer), whose molecular framework is inspired by
Chemical modification-mediated optimisation of bronchodilatory activity of mepenzolate, a muscarinic receptor antagonist with anti-inflammatory activity
Yamashita, Yasunobu,Tanaka, Ken-ichiro,Yamakawa,Asano,Kanda, Yuki,Takafuji,Kawahara, Masahiro,Takenaga, Mitsuko,Fukunishi, Yoshifumi,Mizushima
supporting information, p. 3339 - 3346 (2019/06/18)
The treatment for patients with chronic obstructive pulmonary disease (COPD) usually involves a combination of anti-inflammatory and bronchodilatory drugs. We recently found that mepenzolate bromide (1) and its derivative, 3-(2-hydroxy-2, 2-diphenylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (5), have both anti-inflammatory and bronchodilatory activities. We chemically modified 5 with a view to obtain derivatives with both anti-inflammatory and longer-lasting bronchodilatory activities. Among the synthesized compounds, (R)-(–)-12 ((R)-3-(2-hydroxy-2,2-diphenylacetoxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane bromide) showed the highest affinity in vitro for the human muscarinic M3 receptor (hM3R). Compared to 1 and 5, (R)-(–)-12 exhibited longer-lasting bronchodilatory activity and equivalent anti-inflammatory effect in mice. The long-term intratracheal administration of (R)-(–)-12 suppressed porcine pancreatic elastase-induced pulmonary emphysema in mice, whereas the same procedure with a long-acting muscarinic antagonist used clinically (tiotropium bromide) did not. These results suggest that (R)-(–)-12 might be therapeutically beneficial for use with COPD patients given the improved effects seen against both inflammatory pulmonary emphysema and airflow limitation in this animal model.
Practical Intermolecular Hydroarylation of Diverse Alkenes via Reductive Heck Coupling
Gurak, John A.,Engle, Keary M.
, p. 8987 - 8992 (2018/09/11)
The hydroarylation of alkenes is an attractive approach to construct carbon-carbon (C-C) bonds from abundant and structurally diverse starting materials. Herein we report a palladium-catalyzed reductive Heck hydroarylation of aliphatic and heteroatom-substituted terminal alkenes and select internal alkenes with an array of (hetero)aryl iodides. The reaction is anti-Markovnikov selective with terminal alkenes and tolerates a wide variety of functional groups on both the alkene and (hetero)aryl coupling partners. Additionally, applications of this method to complex molecule diversifications are demonstrated. Mechanistic experiments are consistent with a mechanism in which the key alkylpalladium(II) intermediate is intercepted with formate and undergoes a decarboxylation/C-H reductive elimination cascade to afford the saturated product and turn over the cycle.
Salt-Free Strategy for the Insertion of CO2 into C?H Bonds: Catalytic Hydroxymethylation of Alkynes
Wendling, Timo,Risto, Eugen,Krause, Thilo,Goo?en, Lukas J.
supporting information, p. 6019 - 6024 (2018/03/27)
A copper(I) catalyst enables the insertion of carbon dioxide into alkyne C?H bonds by using a suitable organic base with which hydrogenation of the resulting carboxylate salt with regeneration of the base becomes thermodynamically feasible. In the presence of catalytic copper(I) chloride/4,7-diphenyl-1,10-phenanthroline, polymer-bound triphenylphosphine, and 2,2,6,6-tetramethylpiperidine as the base, terminal alkynes undergo carboxylation at 15 bar CO2 and room temperature. After filtration, the ammonium alkynecarboxylate can be hydrogenated to the primary alcohol and water at a rhodium/molybdenum catalyst, regenerating the amine base. This demonstrates the feasibility of a salt-free overall process, in which carbon dioxide serves as a C1 building block in a C?H functionalization.
Inexpensive Ruthenium NNS-Complexes as Efficient Ester Hydrogenation Catalysts with High C=O vs. C=C Selectivities
Stadler, Bernhard M.,Puylaert, Pim,Diekamp, Justus,van Heck, Richard,Fan, Yuting,Spannenberg, Anke,Hinze, Sandra,de Vries, Johannes G.
supporting information, p. 1151 - 1158 (2018/02/06)
Ru(NNS)(PPh3)Cl2 (NNS=2-(methylthio)-N-(pyridin-2-yl-methyl)ethan-1-amine) was employed in the hydrogenation of α,β-unsaturated esters, reaching selectivities for the allylic alcohol up to 95% in the hydrogenation of iso-butylcinnamate. In addition, several ester substrates were hydrogenated with catalyst loadings as low as 0.05?mol%. Surprisingly, selectivity of the hydrogenation of the C=O vs the C=C bonds strongly depends on the solvent. (Figure presented.).
