Electrochemical Radical Retro-Allylation of Homoallylic Alcohols with Sulfonyl Hydrazides.

We report herein the first examples of electrochemical radical retro-allylation of homoallylic alcohols via the cleavage of the C(sp3)-C(sp3) bond. In this reaction, a variety of sulfonyl hydrazides were employed as the environmentally friendly radical sources via an electrochemical dehydrazination with the release of N2 and H2 as the byproducts, leading to sulfonyl allylic compounds in moderate to good yields. The reaction features metal- and base-free reaction conditions, broad functional group tolerance, and a broad substrate scope.

Design, synthesis and antitumor activity of novel 4-oxobutanamide derivatives.

To find highly effective and low-toxicity antitumor drugs to overcome the challenge of cancer, we designed and synthesized a series of novel 4-oxobutanamide derivatives using the principle of molecular hybridization and tested the antiproliferative ability of the title compounds against human cervical carcinoma cells (HeLa), human breast carcinoma cells (MDA-MB-231) and human kidney carcinoma cells (A498). Among them, N1-(4-methoxybenzyl)-N4-(4-methoxyphenyl)-N1-(3,4,5-trimethoxyphenyl) succinimide DN4 (IC50 = 1.94 µM) showed the best proliferation activity on A498, superior to the positive control paclitaxel (IC50 = 8.81 µM) and colchicine (IC50 = 7.17 µM). Compound DN4 not only inhibited the proliferation, adhesion and invasion of A498, but also inhibited angiogenesis and tumor growth in a dose-dependent manner in the xenograft model of A498 cells. In addition, we also predicted the physicochemical properties and toxicity (ADMET) of these derivatives, and the results suggested that these derivatives may have the absorption, distribution, metabolism, excretion, and toxicity properties of drug candidates. Thus, compound DN4 may be a promising drug candidate for the treatment of cancer.

Access to Saturated Oxygen Heterocycles and Lactones via Electrochemical Sulfonylative Oxycyclization of Alkenes with Sulfonyl Hydrazides.

A facile electrochemical sulfonylative cycloetherification of linear unsaturated alcohols with sulfonyl hydrazides under mild conditions has been accomplished. This catalyst- and oxidant-free protocol proceeds via electro-oxidation, followed by radical addition, as well as an intramolecular oxygen nucleophilic process. This methodology is compatible with a broad substrate scope and good functional group compatibility, which provides a valuable and convenient synthetic tool for the synthesis of saturated five-, six-, seven-, and eight-membered ring oxygen heterocycles. Furthermore, sulfonylative cycloesterification of linear unsaturated acids toward the lactone products has also been established under this electrochemical system. In addition, control experiments indicated that the N-H bonds of the sulfonyl hydrazide molecule are non-essential.

Palladium-Catalyzed Oxidative Nonclassical Heck Reaction of Arylhydrazines with Allylic Alcohols via C-N Bond Cleavage: Access to ß-Arylated Carbonyl Compounds.

An efficient palladium-catalyzed oxidative nonclassical Heck reaction of arylhydrazines with allylic alcohols via C-N bond cleavage has been successfully developed. This method provides a series of ß-arylated carbonyl compounds with broad functional group tolerance under base-free, simple, and mild open air reaction conditions. In the reaction, arylhydrazines with the smaller molecular weight of the leaving group were employed as the "green" arylation reagent, which released N2 and water as the byproducts under air. Mechanistic studies suggested that an aryl radical process and Pd-H complex migration reinsertion were involved. Moreover, the synthesis of the antiarrhythmic drug propafenone was completed with this transformation as the key step.

Synthesis of (Z)-ß-Chloro-enamides via a Base-Promoted trans-Hydroamidation of Alkynyl Chlorides Using 1,1-Dichloroalkenes as Precursor.

An efficient and general base-promoted reaction of 1,1-dichloroalkenes with secondary sulfonamides and amides for the synthesis of (Z)-ß-chloro-enamides has been described. This reaction exhibits functional group tolerance under simple and mild conditions. Mechanistic study indicated that a stereoselective trans-hydroamidation of alkynyl chlorides generated in situ from 1,1-dichloroalkenes was the key step.

Identification of DNA methylation regulated novel host genes relevant to inhibition of virus replication in porcine PK15 cell using double stranded RNA mimics and DNA methyltransferase inhibitor.

During RNA viruses's replication, double-stranded RNA (dsRNA) is normally produced and induce host innate immune response. Most of gene activation due cytokine mediated but which are due to methylation mediated is still unknown. In the study, DNA methylome was integrated with our previous transcriptome data to investigate the differentially methylated regions and genes using MeDIP-chip technology. We found that the transcriptional expressions of 15, 37 and 18 genes were negatively related with their promoter DNA methylation levels in the cells treated by PolyI:C, Aza-CdR, as well as PolyI:C plus Aza-CdR, respectively, compared with the untreated cells. GO analysis revealed hypo-methylated genes (BNIP3L and CDK9) and a hyper-methylated gene (ZC3HAV1) involved in the host response to viral replication. Our results suggest that these novel genes targeted by DNA methylation can be potential markers relevant to virus replication and host innate immune response to set up a medical model of infectious diseases.

Genome-wide effects of DNA methyltransferase inhibitor on gene expression in double-stranded RNA transfected porcine PK15 cells.

Double-stranded RNA (dsRNA) is produced in host cells during viral replication. The effects of DNA demethylation on gene expression in dsRNA transfected swine cells are unclear. The study aims to profile the transcriptome changes which are induced by DNA methyltransferase inhibitor (Aza-CdR) in porcine PK15 cells transfected with viral-like dsRNA (Poly(I:C)). A total of 44, 76 and 952 differentially expressed genes (DEGs) were detected in the cells treated by Poly(I:C) plus Aza-CdR (P+A), Poly(I:C) (P) or Aza-CdR (A) alone compared to the controls (C). Immune response-related pathways are observed in the comparison of A vs. C and P vs. C, and the genes in the pathways were recovered in the comparison of (P+A) vs. C. GO analysis indicated that Aza-CdR has negative regulatory effects on viral reproduction. The results suggest that the stimulant of Poly(I:C) could be regressed by Aza-CdR. These observations provide new insights into the epigenetic regulatory effects on viral replication.

CENPK orchestrates ovarian cancer progression via GOLPH3-Mediated activation of mTOR signaling.

Ovarian cancer stands as a formidable clinical challenge, with limited therapeutic options. This investigation delves into the intricate molecular mechanisms governing ovarian cancer progression and uncovers Centromere Protein K (CENPK) as a central figure in disease pathogenesis. Elevated CENPK levels within ovarian cancer tissues conspicuously align with adverse clinical outcomes, positioning CENPK as a promising prognostic biomarker. Deeper exploration reveals a direct transcriptional connection between CENPK and the E2F1 transcription factor and clearly establishes E2F1's role as the master regulator of CENPK expression in ovarian cancer. Our inquiry revealing a suppression of tumor-promoting signaling pathways, most notably the mTOR pathway, upon CENPK silencing. Intriguingly, CENPK renders ovarian cancer cells more responsive to the mTOR inhibitor rapamycin, introducing a promising avenue for therapeutic intervention. In summation, our study unravels the multifaceted role of CENPK in ovarian cancer progression. It emerges as a prognostic indicator, a pivotal mediator of cell proliferation and tumorigenicity, and a regulator of the mTOR pathway, shedding light on potential therapeutic avenues for this formidable disease.

Design, synthesis and biological evaluation of piperine derivatives as potent antitumor agents.

A series of piperine derivatives were designed and successfully synthesized. The antitumor activities of these compounds against 293 T human normal cells, as well as MDA-MB-231 (breast) and Hela (cervical) cancer cell lines, were assessed through the MTT assay. Notably, compound H7 exhibited moderate activity, displaying reduced toxicity towards non-tumor 293 T cells while potently enhancing the antiproliferative effects in Hela and MDA-MB-231 cells. The IC50 values were determined to be 147.45 ± 6.05 µM, 11.86 ± 0.32 µM, and 10.50 ± 3.74 µM for the respective cell lines. In subsequent mechanistic investigations, compound H7 demonstrated a dose-dependent inhibition of clone formation, migration, and adhesion in Hela cells. At a concentration of 15 µM, its inhibitory effect on Hela cell function surpassed that of both piperine and 5-Fu. Furthermore, compound H7 exhibited promising antitumor activity in vivo, as evidenced by significant inhibition of tumor angiogenesis and reduction in tumor weight in a chicken embryo model. These findings provide a valuable scientific foundation for the development of novel and efficacious antitumor agents, particularly highlighting the potential of compound H7 as a therapeutic candidate for cervical cancer and breast cancer.

JHD205, A Novel Abemaciclib Derivative, Exerts Antitumor Effects on Breast Cancer by CDK4/6.

BACKGROUND: Efficient targeted molecular therapeutics are needed for the treatment of triple-negative breast cancer (TNBC), a highly invasive and difficult-to-treat form of breast cancer associated with a poor prognosis. OBJECTIVES: This study aims to evaluate the potential of selective CDK4/6 inhibitors as a therapeutic option for TNBC by impairing the cell cycle G1 phase through the inhibition of retinoblastoma protein (Rb) phosphorylation. METHODS: In this study, we synthesized a compound called JHD205, derived from the chemical structure of Abemaciclib, and examined its inhibitory effects on the malignant characteristics of TNBC cells. RESULTS: Our results demonstrated that JHD205 exhibited superior tumor growth inhibition compared to Abemaciclib in breast cancer xenograft chicken embryo models. Western blot analysis revealed that JHD205 could dosedependently degrade CDK4 and CDK6 while also causing abnormal changes in other proteins associated with CDK4/6, such as p-Rb, Rb, and E2F1. Moreover, JHD205 induced apoptosis and DNA damage and inhibited DNA repair by upregulating Caspase3 and p-H2AX protein levels. CONCLUSION: Collectively, our findings suggest that JHD205 holds promise as a potential treatment for breast carcinoma.

N1-Allylation of Arylhydrazines via a Palladium-Catalyzed Allylic Substitution.

A direct and efficient method for constructing N,N-disubstituted hydrazines via a palladium-catalyzed allylic substitution of allyl acetates with arylhydrazines as nucleophiles has been developed. This method is highly selective in terms of both chemo- and regio-selectivity and is carried out under an open-air system with the use of the DPPPy phosphine ligand. Additionally, this reaction is compatible with a wide variety of substrates, including those bearing reactive groups such as Cl, Br, and I, to afford various N1-allylation products in moderate to good yields under simple and mild reaction conditions.

[Regulation mechanisms of epigenetics on inflammation and its perspective on breeding for mastitis resistance in dairy cattle].

Inflammation is controlled by genetic and non-genetic factors (environment and epigenetics), within non-genetic factors, epigenetics play important roles in the development of inflammation. Epigenetic modifications, referring to changes in phenotype or gene expression caused by mechanisms other than changes in the underlying DNA sequence, mainly include DNA methylation and histone modification. Epigenetic study builds up the relationships between microorganism and inflammation. In inflammation responses, differentiation of T helper cells and gene expression of cytokine and chemokine are all regulated by epigenetics. Here, we reviewed the regulation mechanisms of DNA methylation and histone modifications on inflammation, especially on cow mastitis. The progress and application trends of epigenetics on treatment of mastitis and breeding for mastitis resistance in dairy cattle are also discussed.