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Cardiac metabolic dysfunction is a hallmark of heart failure. Estrogen related receptors ERRα and ERRγ are essential regulators for cardiac metabolism. Therefore, activation of ERR could be a potential therapeutic intervention for heart failure. However, no natural or synthetic ERR agonist is available to demonstrate their pharmacological effectin vivo. Using a structure-based design approach, we designed and synthesized two structurally distinct pan-ERR agonists, SLU-PP-332 (332) and SLU-PP-915 (915), which significantly improved ejection fraction and ameliorated fibrosis against pressure overload-induced heart failure without affecting cardiac hypertrophy. Mechanistically, a broad-spectrum of metabolic genes were transcriptionally activated by ERR agonists, particularly genes involved in fatty acid metabolism and mitochondrial function, which were mainly mediated by ERRγ. Metabolomics analysis showed significant normalization of metabolic profiles in fatty acid/lipid and TCA/OXPHOS metabolites by 915 in the mouse heart with 6-week pressure overload. Autophagy was also induced by ERR agonists in cardiomycoyte. On the other hand, ERR agonism led to downregulation of cell cycle and development pathways, which was partially mediated by E2F1 in cardiomyocyte. In summary, ERR agonists maintain oxidative metabolism, which confers cardiac protection against pressure overload-induced heart failurein vivo. Our results provided direct pharmacological evidence supporting the further development of ERR agonists as novel heart failure therapeuticsin vivo.

Sucrose transporter (SUT) proteins translocate sucrose across cell membranes; however, mechanistic aspects of sucrose binding by SUTs are not well resolved. Specific hydroxyl groups in sucrose participate in hydrogen bonding with SUT proteins. We previously reported that substituting a radioactive fluorine-18 [18F] at the C-6' position within the fructosyl moiety of sucrose did not affect sucrose transport by the maize (Zea mays) ZmSUT1 protein. To determine how 18F substitution of hydroxyl groups at two other positions within sucrose, the C-1' in the fructosyl moiety or the C-6 in the glucosyl moiety, impact sucrose transport, we synthesized 1'-[F18]fluoro-1'-deoxysucrose and 6-[F18]fluoro-6-deoxysucrose ([18F]FDS) analogs. Each [18F]FDS derivative was independently introduced into wild-type or sut1 mutant plants, which are defective in sucrose phloem loading. All three (1'-, 6'-, and 6-) [18F]FDS derivatives were efficiently and equally translocated, similarly to carbon-14 [14C]-labeled sucrose. Hence, individually replacing the hydroxyl groups at these positions within sucrose does not interfere with substrate recognition, binding, or membrane transport processes, and hydroxyl groups at these three positions are not essential for hydrogen bonding between sucrose and ZmSUT1. [18F]FDS imaging afforded several advantages compared to [14C]-sucrose detection. We calculated that 1'-[18F]FDS was transported at approximately a rate of 0.90 ± 0.15 m.h-1 in wild-type leaves, and at 0.68 ± 0.25 m.h-1 in sut1 mutant leaves. Collectively, our data indicated that [18F]FDS analogs are valuable tools to probe sucrose-SUT interactions and to monitor sucrose transport in plants.

The scope of the [2,3]-sigmatropic rearrangement of propargylic sulfinates to allenic sulfones by silver catalysis was expanded. A series of new propargylic sulfinate esters was generated from a variety of aromatic and heteroaromatic sulfonyl chlorides and their rearrangement to allenic sulfones is reported. In addition, the synthesis of propargylic sulfinate esters containing electron-withdrawing benzenesulfonyl chlorides is reported.

A cyclic diamine ligand whose core structure was derived from Troger's base, and included additional pendant arms containing ancillary donor coordination sites was prepared and coordination with transition metals attempted.

1-Arylsulfonyl-1,3-dienes may be deprotonated in the presence of a strong base and subsequently trapped by several different electrophilic functional groups.

In the course of a study of the alkoxyallylation of allenic sulfones through the use of π-allylpalladium chemistry, we discovered an isomerization of allenic sulfones to arylsulfonyl 1,3-dienes. Under conditions of palladium catalysis in the presence of acids such as acetic acid, allenic sulfones are converted to 1-arylsulfonyl 1,3-dienes. On the other hand, nucleophilic catalysis using triphenylphosphine in the presence of a proton shuttle yields 2-arylsulfonyl 1,3-dienes. Thus, either regioisomer of the arylsulfonyl diene can be prepared at will based on changes in reaction conditions.

Sucrose transporter (SUT) proteins translocate sucrose across cell membranes; however, mechanistic aspects of sucrose binding by SUTs are not well resolved. Specific hydroxyl groups in sucrose participate in hydrogen bonding with SUT proteins. We previously reported that substituting a radioactive fluorine-18 [

The sigmatropic rearrangement of propargylic sulfinates to allenic sulfones is catalyzed by the copper cation. The Pale Cu 1 -USY zeolite, as well as copper salts, lead to essentially quantitative yield of the corresponding allenic sulfones.

When an allenic sulfone is treated under palladium catalysis in the presence of a weak acid, isomerization to a 1-arylsulfonyl 1,3-diene occurs. Investigations of the mechanistic aspects of this isomerization were performed, leading to the mechanism proposed herein. Some further studies of reaction parameters are reported.

When an allenic sulfone is treated with a phosphine nucleophile and a proton shuttle, an isomerization to a 2-arylsulfonyl 1,3-diene occurs. Mechanistic aspects of the process were investigated leading to the formulation of a mechanism for the reaction. Some further optimization studies of this process are reported.

Trogers bases (TBs) react with dimethyldioxirane to produce the corresponding N-oxides in excellent yields. Upon treatment with acetic anhydride, these N-oxides undergo a Polonovski-type reaction that involves fragmentation and ultimate nitrogen–nitrogen bond formation to form hydrazines. Steric effects are evident in both the oxidation step and in the step involving the activation of the N-oxide, such that certain TBs are not amenable to the process.

When an allenic sulfone is treated with a phosphine nucleophile and a proton shuttle, an isomerization to a 2-arylsulfonyl 1,3-diene occurs. Mechanistic aspects of the process were investigated leading to the formulation of a mechanism for the reaction. Some further optimization studies of this process are reported.

The applied catalyst (zeolite Ag-USY) can be recycled several times and therefore this reaction becomes “greener”.

Oxidation of readily prepared allenols with PCC affords α′-hydroxydienones rather than simple oxidation products.

In the course of a study of the alkoxyallylation of allenic sulfones through the use of π-allylpalladium chemistry, we discovered an isomerization of allenic sulfones to arylsulfonyl 1,3-dienes. Under conditions of palladium catalysis in the presence of acids such as acetic acid, allenic sulfones are converted to 1-arylsulfonyl 1,3-dienes. On the other hand, nucleophilic catalysis using triphenylphosphine in the presence of a proton shuttle yields 2-arylsulfonyl 1,3-dienes. Thus, either regioisomer of the arylsulfonyl diene can be prepared at will based on changes in reaction conditions.