Phosphine-Catalyzed Domino Annulation of γ-Vinyl Allenoates: Synthesis of Tetrahydrofuro[3,2-c]quinoline Derivatives.

A novel phosphine-catalyzed domino annulation reaction of γ-vinyl allenoates and o-aminotrifluoacetophenones for the construction of terahydrofuro[3,2-c]quinoline derivatives has been developed. In this domino reaction, two kinds of terahydrofuro[3,2-c]quinoline compounds containing CF3 groups were obtained with good yields under mild conditions, three new C-N, C-C, and C-O bonds can be built in one step, and the reaction selectivity is achieved by adjusting the reaction conditions. Furthermore, preliminary studies on an asymmetric variant of this reaction proceeded with moderate enantioselectivity.

Cardiac Metabolism, Reprogramming, and Diseases.

Cardiovascular diseases (CVD) account for the largest bulk of deaths worldwide, posing a massive burden on societies and the global healthcare system. Besides, the incidence and prevalence of these diseases are on the rise, demanding imminent action to revert this trend. Cardiovascular pathogenesis harbors a variety of molecular and cellular mechanisms among which dysregulated metabolism is of significant importance and may even proceed other mechanisms. The healthy heart metabolism primarily relies on fatty acids for the ultimate production of energy through oxidative phosphorylation in mitochondria. Other metabolites such as glucose, amino acids, and ketone bodies come next. Under pathological conditions, there is a shift in metabolic pathways and the preference of metabolites, termed metabolic remodeling or reprogramming. In this review, we aim to summarize cardiovascular metabolism and remodeling in different subsets of CVD to come up with a new paradigm for understanding and treatment of these diseases.

Rnd3 suppresses endothelial cell pyroptosis in atherosclerosis through regulation of ubiquitination of TRAF6.

BACKGROUND: As the main pathological basis for various cardiovascular and cerebrovascular diseases, atherosclerosis has become one of the leading causes of death and disability worldwide. Emerging evidence has suggested that Rho GTPase Rnd3 plays an indisputable role in cardiovascular diseases, although its function in atherosclerosis remains unclear. Here, we found a significant correlation between Rnd3 and pyroptosis of aortic endothelial cells (ECs). METHODS: ApoeKO mice were utilized as a model for atherosclerosis. Endothelium-specific transgenic mice were employed to disrupt the expression level of Rnd3 in vivo. Mechanistic investigation of the impact of Rnd3 on endothelial cell pyroptosis was carried out using liquid chromatography tandem mass spectrometry (LC-MS/MS), co-immunoprecipitation (Co-IP) assays, and molecular docking. RESULTS: Evidence from gain-of-function and loss-of-function studies denoted a protective role for Rnd3 against ECs pyroptosis. Downregulation of Rnd3 sensitized ECs to pyroptosis under oxidized low density lipoprotein (oxLDL) challenge and exacerbated atherosclerosis, while overexpression of Rnd3 effectively prevented these effects. LC-MS/MS, Co-IP assay, and molecular docking revealed that Rnd3 negatively regulated pyroptosis signaling by direct interaction with the ring finger domain of tumor necrosis factor receptor-associated factor 6 (TRAF6). This leads to the suppression of K63-linked TRAF6 ubiquitination and the promotion of K48-linked TRAF6 ubiquitination, inhibiting the activation of NF-κB and promoting the degradation of TRAF6. Moreover, TRAF6 knockdown countered Rnd3 knockout-evoked exacerbation of EC pyroptosis in vivo and vitro. CONCLUSIONS: These findings establish a critical functional connection between Rnd3 and the TRAF6/NF-κB/NLRP3 signaling pathway in ECs, indicating the essential role of Rnd3 in preventing pyroptosis of ECs.

Photoinduced Three-Component Difluoroalkylation of Quinoxalinones with Alkenes via Difluoroiodane(III) Reagents.

An environmentally friendly strategy for the photocatalyzed three-component reaction between quinoxalinones, alkenes, and hypervalent iodine(III) reagents is disclosed. The new designed difluoroiodane(III) reagent shows excellent reactivity, providing a wide range of difluoroalkyl-substituted quinoxaline-2(1H)-ones in moderate to excellent yields under mild conditions. Experimental studies demonstrated that a difluoroalkyl radical intermediate was involved in this reaction.

Phosphine-Catalyzed (3 + 2)/(3 + 2) Sequential Annulation of γ-Vinyl Allenoates: Access to Fused Carbocycles.

The first (3 + 2)/(3 + 2) sequential annulation of γ-vinyl allenoates with alkylidenemalononitriles enabled by phosphine catalysis has been reported. A broad range of structurally dense tetra- and penta-substituted bicyclic[3,3,0]octene derivatives, containing a quaternary center and three sequential stereogenic center, were synthesized in good to excellent yields. In this approach, three new C-C bonds are formed in one pot, and εC and αC of γ-vinyl allenoate are two electrophilic centers, whereas its γC exhibits nucleophilic reactivity.

Phosphine-catalyzed (3+2)/(2+3) sequential annulation involving a triple nucleophilic addition reaction of γ-vinyl allenoates.

A phosphine-catalyzed (3+2)/(2+3) sequential annulation involving a triple nucleophilic addition reaction of γ-vinyl allenoates was successfully developed. The reaction provided efficient and more practical access to functionalized hydropyrroloimidazolones with good to excellent yields under mild reaction conditions. Notably, γ-vinyl allenoate served as a triple-electrophilic intermediate in this protocol.

Sequential Phosphine-Catalyzed [4 + 2] Annulation of ß'-Acetoxy Allenoates: Enantioselective Synthesis of 3-Ethynyl-Substituted Tetrahydroquinolines.

The first enantioselective sequential phosphine-catalyzed (SPC as abbreviation) mode for the formation of tetrahydroquinolines with an ethynyl-substituted all-carbon quaternary stereogenic center is reported. In this SPC process, a novel [4 + 2] annulation process was devised employing α-substituted allenoates as C2 synthons (α-ß', 1,2-dipole) for the first time. 3-Ethynyl-substituted tetrahydroquinolines were readily prepared in good yields and high enantioselectivities.

Mst1 inhibits CMECs autophagy and participates in the development of diabetic coronary microvascular dysfunction.

Cardiovascular complications account for a substantial proportion of morbidity and mortality in diabetic patients. Abnormalities of cardiac microvascular endothelial cells (CMECs) lead to impaired cardiac microvascular vessel integrity and subsequent cardiac dysfunction, underlining the importance of coronary microvascular dysfunction. In this study, experimental diabetes models were constructed using Mst1 transgenic, Mst1 knockout and sirt1 knockout mice. Diabetic Mst1 transgenic mice exhibited impaired cardiac microvessel integrity and decreased cardiac function. Mst1 overexpression deceased CMECs autophagy as evidenced by decreased LC3 expression and enhanced protein aggregation when subjected to high glucose culture. Mst1 knockout improved cardiac microvessel integrity and enhanced cardiac functions in diabetic mice. Mst1 knockdown up-regulated autophagy as indicated by more typical autophagosomes and increased LC3 expression in CMECs subjected to high glucose cultures. Mst1 knockdown also promoted autophagic flux in the presence of bafilomycin A1. Mst1 overexpression increased CMECs apoptosis, whereas Mst1 knockout decreased CMECs apoptosis. Sirt1 knockout abolished the effects of Mst1 overexpression in cardiac microvascular injury and cardiac dysfunction. In conclusion, Mst1 knockout preserved cardiac microvessel integrity and improved cardiac functions in diabetic mice. Mst1 decreased sirt1 activity, inhibited autophagy and enhanced apoptosis in CMECs, thus participating in the pathogenesis of diabetic coronary microvascular dysfunction.

MST1 coordinately regulates autophagy and apoptosis in diabetic cardiomyopathy in mice.

AIMS/HYPOTHESIS: Diabetic cardiomyopathy (DCM) is associated with suppressed autophagy and augmented apoptosis in the heart although the interplay between the two remains elusive. The ability of mammalian sterile 20-like kinase 1 to regulate both autophagy and apoptosis prompted us to investigate it as a possible candidate in the progression of DCM. METHODS: Wild-type, Mst1 (also known as Stk4) transgenic and Mst1-knockout mice were challenged with streptozotocin to induce experimental diabetes. In addition, cultured neonatal mouse cardiomyocytes were subjected to simulated diabetes to probe mechanisms. RESULTS: Mst1 knockout alleviated while Mst1 overexpression aggravated cardiac dysfunction in diabetes. Diabetic Mst1 transgenic mice exhibited decreased LC3 expression and enhanced protein aggregation. In contrast, typical autophagosomes were observed in diabetic Mst1-knockout mice with increased LC3 expression and reduced protein aggregation. Mst1 downregulation promoted autophagic flux as demonstrated by increased LC3-II and decreased p62 expression in the presence of bafilomycin A1. Furthermore, Mst1 overexpression increased, while Mst1 knockout decreased, cardiomyocyte apoptosis both in vivo and in vitro. Co-immunoprecipitation assays showed that Mst1 overexpression promoted Beclin1 binding to B cell lymphoma 2 (Bcl-2) and induced dissociation of Bcl-2 from Bax in diabetic mice. Conversely, Mst1 knockout disrupted the Beclin1-Bcl-2 complex and enhanced the interaction between Bcl-2 and Bax. CONCLUSIONS/INTERPRETATION: Mst1 knockout restores autophagy and protects against apoptosis in cardiomyocytes, en route to the rescue against DCM.