Catalytic Regio- and Enantioselective Boracarboxylation of Arylalkenes with CO2 and Diboron.

Catalytic asymmetric carboxylation of readily available alkenes with CO2, an abundant and sustainable one-carbon building block, that gives access to value-added α-stereogenic carboxylic acids in an atom- and step-economic manner is highly attractive. However, it has remained a formidable challenge for the synthetic community. Here, the first example of Cu-catalyzed highly regio- and enantioselective boracarboxylation reaction on various arylalkenes with diboron under an atmospheric pressure of CO2 is described, which afforded a variety of chiral ß-boron-functionalized α-aryl carboxylic acids with up to 87% yield and 97% ee under mild conditions. Importantly, α-substituted arylalkenes could also be subject to this protocol with excellent enantiopurities, thereby rendering an efficient approach for the generation of enantioenriched carboxylic acids with an α-chiral all-carbon quaternary center. Moreover, high functional group tolerance, scalable synthesis, and facile access to bioactive compounds, like (-)-scopolamine, (-)-anisodamine, and (-)-tropicamide, further demonstrated the synthetic utility of this strategy.

TRIM37 promotes the aggressiveness of ovarian cancer cells and increases c-Myc expression by binding to HUWE1.

Tripartite motif containing 37 (TRIM37) was reported to function as a tumor promoter in the development of various cancers. However, the biological role of TRIM37 in ovarian cancer (OC) was still unclear. Expressions of TRIM37 and HUWE1 were detected by qRT-PCR and western blotting in OC cells. Cell proliferation was evaluated by CCK-8 assay and colony formation assay. Cell migration and invasion capabilities were examined by wound healing and transwell assay. Flow cytometry and western blotting were performed to measure cell apoptosis. Wnt/ß-catenin pathway and the expression of c-Myc were identified by qRT-PCR and western blotting. The binding of TRIM37 and HUWE1 was predicted by STRING database and verified by co-immunoprecipitation. In addition, a xenograft mouse model was established to evaluate the effects of TRIM37 and HUWE1 on tumor growth and c-MYC expression in vivo. The present study revealed that TRIM37 expression was upregulated in OC tissues and cells. TRIM37 silencing inhibited OC cell migration and invasion, promoted OC cell apoptosis, and blocked Wnt/ß-catenin signaling pathway, as well as suppressing c-MYC protein expression. Mechanistic studies suggested that TRIM37 binds to HUWE1. HUWE1 was upregulated in OC cells and TRIM37 promoted the c-MYC expression through targeting HUWE1. Animal experiments showed that TRIM37 silencing significantly repressed the tumor growth and c-MYC protein level, but HUWE1 overexpression reversed the effects of TRIM37 knockdown on mice with OC. Our findings revealed that TRIM37 accelerated the progression of OC and promoted c-MYC expression by binding to HUWE1, which provides therapeutic targets for OC treatment.

Significance of glutathione peroxidase 4 and intracellular iron level in ovarian cancer cells-"utilization" of ferroptosis mechanism.

OBJECTIVE AND DESIGN: Ovarian cancer is the major cause of death in gynecologic diseases worldwide. Ferroptosis, a nonapoptotic form of cell death, is featured by accumulation of iron-based lipid peroxidation. The elevated iron level and malondialdehyde (MDA) in ovarian cancer cells suggest more vulnerable to ferroptosis, nevertheless, ferroptosis is not observed in ovarian cancer cells. Glutathione peroxidase 4 (GPX4) is a critical regulator of ferroptosis. METHODS: We determined whether GPX4 knockdown could induce ferroptosis to prevent cell proliferation in ovarian cancer. Human ovarian cancer cells and normal human ovarian epithelial cell line IOSE-80 were cultured and administrated with deferoxamine (DFO) or ferric ammonium citrate (FAC). GPX4 knockdown was established for investigating the functions of GPX4 in ovarian cancer cells and in tumor xenograft mice. RESULTS: A positively correlation was showed among the levels of GPX4, iron and cell proliferation. Chelation of intracellular iron by DFO disrupted intracellular iron level and was detrimental to ovarian cancer cell survival. FAC-induced elevation of intracellular iron inhibited proliferation, aggravated apoptosis, boosted inflammation and suppressed lipid peroxide reducibility in ovarian cancer cells. Knockdown of GPX4 had similar effects with FAC in ovarian cancer cells. Inhibition of GPX4 suppressed tumor growth, induced ferroptosis, accelerated cell apoptosis, reduced Fe3+ accumulation and suppressed lipid peroxide reducibility in tumor bearing mice. CONCLUSION: We demonstrate the significance of GPX4 and intracellular iron level in ovarian cancer cells. Importantly, inhibition of GPX4 interferes with both intracellular iron homeostasis and lipid peroxide reducibility, inducing ferroptosis and exerting anti-cancer effect, which can be a potential effective strategy for ovarian cancer therapy.

Asymmetric Synthesis of 1-Benzazepine Derivatives via Copper-Catalyzed Intramolecular Reductive Cyclization.

An asymmetric construction of enantioenriched 2,3-substituted-1-benzazepine derivatives containing a cyclic tertiary amine moiety was developed by copper-catalyzed reductive intramolecular cyclization of (E)-dienyl arenes with a tethered ketimine. This protocol involves tandem chemo-, regio-, and enantioselective hydrocupration and asymmetric cyclization in the presence of a chiral bisphosphine-copper catalyst. Under mild conditions, a broad range of 1-benzazepine derivatives was obtained in good to high yields with high degrees of diastereoselectivity and enantioselectivity.

Copper-Catalyzed Regioselective and Diastereoselective Synthesis of Borylated 1-Benzo[ b]azepines.

A practical regioselective and diastereoselective synthesis of functionalized 1-benzo[ b]azepines by copper-catalyzed intramolecular cyclization has been developed. The reaction involves borylcupration of a mixture of ( E/ Z)-1,3-dienes, followed by capture of the generated ( Z)-allylcopper species with an imine to produce 7-membered N-heterocycles as single diastereomers. The reaction is applicable to various ( E/ Z)-dienyl arenes with an imine moiety at the ortho-position, including aryl, alkyl, and heterocyclic aldimines, and ketimines, affording borylated 2,3- cis-substituted 1-benzo[ b]azepines in good yields.

Copper-Catalyzed Asymmetric Synthesis of Borylated cis-Disubstituted Indolines.

A copper-catalyzed, intramolecular borylative cyclization of vinyl arenes with imines is reported, which affords enantio-enriched indolines as a single diastereomer under mild conditions. A benzylcopper species is generated by Cu-Bpin addition to the alkene, which then acts as a nucleophile for intramolecular imine addition. The reaction is applicable to various vinyl arenes with an imine moiety at the ortho-position, including heterocycles, for formation of borylated indolines in good yields and ee values up to 90 %.

Highly regio- and stereoselective synthesis of boron-substituted enynes via copper-catalyzed borylation of conjugated diynes.

A mild copper-catalyzed regio- and stereoselective monoborylation of conjugated diynes with bis(pinacolato)diboron that affords enynylboronates is reported. The reaction is efficient for different types of conjugated diynes including unsymmetrical diynes and produces enynylboron compounds with high and complementary regioselectivity compared with classical hydrometalation reactions. In particular, the reactions of internal conjugated diynes with a silyl substitution produced highly functionalized enynes with high regio- and stereoselectivity, which can be used in further transformations.

Regioselective synthesis of highly functionalized alkenylboronates by Cu-catalyzed borylation of propargylic silylalkynes.

High regioselectivity was achieved in the Cu(i)-catalyzed borylation of internal propargylic alkynes with a silyl substituent to afford multifunctionalized alkenylboron compounds. While both the silyl and propargylic substituents are known to act as directing groups, a N-heterocyclic carbene (NHC)-Cu complex furnished ß-vinylboronate products (relative to Si) with high selectivity.

Copper-catalyzed synthesis of 1,1-diborylalkanes through regioselective dihydroboration of terminal alkynes.

The copper-catalyzed sequential hydroboration of terminal alkynes with pinacolborane to prepare 1,1-diborylalkanes directly from alkynes was studied. Protected propargyl amines, propargyl alcohol derivatives, and simple alkynes regioselectively produced the desired 1,1-diborylalkanes in good yields with a copper/xantphos catalyst.