Enantioselective Synthesis of 5‑Alkylated Thiazolidinones via Palladium-Catalyzed Asymmetric Allylic C–H Alkylations of 1,4-Pentadienes with 5<i>H</i>‑Thiazol-4-ones

A palladium-catalyzed, enantioselective allylic C–H alkylation of 1,4-pentadienes with 5<i>H</i>-thiazol-4-ones has been developed. Under the cooperative catalysis of a palladium complex of chiral phosphoramidite ligand and an achiral Brønsted acid, a broad range of substituted 5<i>H</i>-thiazol-4-ones bearing sulfur-containing tertiary chiral centers were accessed from the allylic C–H alkylation in high levels of yields and enantioselectivities. Alkyl and aryl 1,4-pentadienes led to linear and branched allylation products, respectively

Facile Construction of Inorganic Phosphorus/Boron-Layered Double Hydroxide Complexes for Highly Efficient Fire-Safety Epoxy Resin

For inorganic flame retardants, facile fabrication and high-efficiency fire safety without compromising the mechanical property of the matrix are still significant challenges. Here, nanolayered double hydroxide containing boron constructed on the surface of ammonium polyphosphate (APP) complexes (B-LDH@APP) is prepared by a simple in situ coprecipitation technology to reduce the fire hazard and improves the mechanical performances of epoxy resin (EP). The as-obtained 4B-LDH@APP/EP achieves the UL-94 V-0 rating and presents superior flame-safety performance. With respect to the 4APP/EP, the fire growth rate (FIGRA), the peak heat release rate (pHRR), and the peak smoke production rate (pSPR) of 4B-LDH@APP/EP decrease by 77.8, 57.3, and 52.6%, respectively. This is mainly attributed to the excellent synergistic flame-retardant effect among boron, LDH, and APP, which can accelerate the generation of compact charring residual with a good microstructure during combustion of B-LDH@APP/EP composites. Furthermore, B-LDH@APP slightly affects the mechanical performances of the EP matrix due to the upgraded interfacial interaction

Discovery of Novel Pyrazole-Based KDM5B Inhibitor <b>TK</b>-<b>129</b> and Its Protective Effects on Myocardial Remodeling and Fibrosis

Lysine-specific demethylase 5B (KDM5B) has been recognized as a potential drug target for cardiovascular diseases. In this work, we first found that the KDM5B level was increased in mouse hearts after transverse aortic constriction (TAC) and in Ang II-induced activated cardiac fibroblasts. Structure-based design and further optimizations led to the discovery of highly potent pyrazole-based KDM5B inhibitor TK-129 (IC50 = 0.044 μM). TK-129 reduced Ang II-induced activation of cardiac fibroblasts in vitro, exhibited good PK profile (F = 42.37%), and reduced isoprenaline-induced myocardial remodeling and fibrosis in vivo. Mechanistically, we found that KDM5B up-regulation in cardiac fibroblast activation was associated with the activation of Wnt-related pathway. The protective effects of TK-129 were associated with its KDM5B inhibition and blocking KDM5B-related Wnt pathway activation. Taken together, TK-129 may represent a novel KDM5-targeting lead compound for cardiac remodeling and fibrosis

Discovery of Novel Pyrazole-Based KDM5B Inhibitor <b>TK</b>-<b>129</b> and Its Protective Effects on Myocardial Remodeling and Fibrosis

Lysine-specific demethylase 5B (KDM5B) has been recognized as a potential drug target for cardiovascular diseases. In this work, we first found that the KDM5B level was increased in mouse hearts after transverse aortic constriction (TAC) and in Ang II-induced activated cardiac fibroblasts. Structure-based design and further optimizations led to the discovery of highly potent pyrazole-based KDM5B inhibitor TK-129 (IC50 = 0.044 μM). TK-129 reduced Ang II-induced activation of cardiac fibroblasts in vitro, exhibited good PK profile (F = 42.37%), and reduced isoprenaline-induced myocardial remodeling and fibrosis in vivo. Mechanistically, we found that KDM5B up-regulation in cardiac fibroblast activation was associated with the activation of Wnt-related pathway. The protective effects of TK-129 were associated with its KDM5B inhibition and blocking KDM5B-related Wnt pathway activation. Taken together, TK-129 may represent a novel KDM5-targeting lead compound for cardiac remodeling and fibrosis

Discovery of Novel Pyrazole-Based KDM5B Inhibitor <b>TK</b>-<b>129</b> and Its Protective Effects on Myocardial Remodeling and Fibrosis

Lysine-specific demethylase 5B (KDM5B) has been recognized as a potential drug target for cardiovascular diseases. In this work, we first found that the KDM5B level was increased in mouse hearts after transverse aortic constriction (TAC) and in Ang II-induced activated cardiac fibroblasts. Structure-based design and further optimizations led to the discovery of highly potent pyrazole-based KDM5B inhibitor TK-129 (IC50 = 0.044 μM). TK-129 reduced Ang II-induced activation of cardiac fibroblasts in vitro, exhibited good PK profile (F = 42.37%), and reduced isoprenaline-induced myocardial remodeling and fibrosis in vivo. Mechanistically, we found that KDM5B up-regulation in cardiac fibroblast activation was associated with the activation of Wnt-related pathway. The protective effects of TK-129 were associated with its KDM5B inhibition and blocking KDM5B-related Wnt pathway activation. Taken together, TK-129 may represent a novel KDM5-targeting lead compound for cardiac remodeling and fibrosis