A regio- and stereoselective Heck-Matsuda process for construction of γ-aryl allylsulfonyl fluorides.

A highly efficient regio- and stereoselective Heck-Matsuda method was developed employing aryl diazoniums and allylsulfonyl fluorides for the construction of a class of novel γ-aryl allylsulfonyl fluorides in the presence of Pd(OAc)2 and PPh3. The method features excellent regio- and stereoselectivity (up to 100% E-selectivity), broad substrate scope and mild reaction conditions. Further application of γ-aryl allylsulfonyl fluoride in SuFEx reactions was achieved to provide their corresponding sulfonates and sulfonamides in excellent yields.

Structure-activity relationship, in vitro and in vivo evaluation of novel dienyl sulphonyl fluorides as selective BuChE inhibitors for the treatment of Alzheimer's disease.

To discover novel scaffolds as leads against dementia, a series of δ-aryl-1,3-dienesulfonyl fluorides with α-halo, α-aryl and α-alkynyl were assayed for ChE inhibitory activity, in which compound A10 was identified as a selective BuChE inhibitor (IC50 = 0.021 µM for eqBChE, 3.62 µM for hBuChE). SAR of BuChE inhibition showed: (i) o- > m- > p-; -OCH3 > -CH3 > -Cl (-Br) for δ-aryl; (ii) α-Br > α-Cl, α-I. Compound A10 exhibited neuroprotective, BBB penetration, mixed competitive inhibitory effect on BuChE (Ki = 29 nM), and benign neural and hepatic safety. Treatment with A10 could almost entirely recover the Aß1-42-induced cognitive dysfunction to the normal level, and the assessment of total amount of Aß1-42 confirmed its anti-amyloidogenic profile. Therefore, the potential BuChE inhibitor A10 is a promising effective lead for the treatment of AD.

A general approach to nitrile- and sulfonyl fluoride-substituted cyclopropanes.

Both cis and trans relative configurations of functionalized cyano cyclopropane bearing sulfonyl fluoride moiety were accessed by Corey-Chaykovsky cyclopropanation reactions. This protocol used mild conditions, and obtained good yields with excellent functional group compatibility. Further application of this class of compounds in SuFEx reactions and cyano reductions were also successfully achieved in good yields.

Clickable Transformation of Nitriles (RCN) to Oxazolyl Sulfonyl Fluoride Warheads.

The protocol for simple, efficient, and mild synthesis of oxazolyl sulfonyl fluorides was developed through Rh2(OAc)4-catalyzed annulation of methyl-2-diazo-2-(fluorosulfonyl)acetate (MDF) or its ethyl ester derivative with nitriles. This practical method provides a general and direct route to a unique class of highly functionalized oxazolyl-decorated sulfonyl fluoride warheads with great potential in medicinal chemistry, chemical biology, and drug discovery.

Antibacterial activities with the structure-activity relationship of coumarin derivatives.

The development of drug-resistant bacteria, as well as multidrug-resistant pathogens related to substantial mortality, is an important global health threat. The wide range of biological activities and the wealthy use of coumarin-containing drugs in the clinic have encouraged more and more interest in this class of heterocycles. Various coumarin-based antibiotic hybrids have been developed in the last decade and most of them exhibited potential antibacterial potency. This present review summarizes the current innovations of coumarin-based derivatives with potential antibacterial activities against a variety of Gram-negative and Gram-positive bacteria discussing various aspects of structure-activity relationship (SAR). The improved SAR will provide further insight into the rational improvement of coumarin hybrids with astounding strength against multidrug-resistant bacteria.

Protocol for Stereoselective Construction of Highly Functionalized Dienyl Sulfonyl Fluoride Warheads.

A pyrrolidine-mediated Knoevenagel-type reaction for highly stereoselective construction of novel α-halo-1,3-dienylsulfonyl fluorides was achieved in up to 100% Z-selectivity and high yields at room temperature from condensation of the readily available aldehydes and halomethanesulfonyl fluorides. This protocol provided a class of unique α-halo-1,3-dienylsulfonyl fluorides with wide scope and excellent functional group compatibility. The α-halo-1,3-dienylsulfonyl fluorides were used as versatile building blocks in sulfur fluoride exchange click chemistry, Suzuki reaction, and Sonogashira reaction for the assembly of highly functionalized dienyl sulfonyl fluoride derivatives to be applied as covalent warheads for the discovery of new drugs.

MFGE8, ALB, APOB, APOE, SAA1, A2M, and C3 as Novel Biomarkers for Stress Cardiomyopathy.

BACKGROUND: Stress cardiomyopathy (SCM) is a transient reversible left ventricular dysfunction that more often occurs in women. Symptoms of SCM patients are similar to those of acute coronary syndrome (ACS), but little is known about biomarkers. The goals of this study were to identify the potentially crucial genes and pathways associated with SCM. METHODS: We analyzed microarray datasets GSE95368 derived from the Gene Expression Omnibus (GEO) database. Firstly, identify the differentially expressed genes (DEGs) between SCM patients in normal patients. Then, the DEGs were used for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Finally, the protein-protein interaction (PPI) network was constructed and Cytoscape was used to find the key genes. RESULTS: In total, 25 DEGs were identified, including 10 upregulated genes and 15 downregulated genes. These DEGs were mainly enriched in ECM-receptor interaction, dilated cardiomyopathy (DCM), human papillomavirus infection, and focal adhesion, whereas in GO function classification, they were mainly enriched in the extracellular region, positive regulation of the multicellular organismal process, establishment of localization, and intracellular vesicle. CONCLUSION: Seven hub genes contained APOE, MFGE8, ALB, APOB, SAA1, A2M, and C3 identified as hub genes of SCM, which might be used as diagnostic biomarkers or molecular targets for the treatment of SCM.

Chalcone hybrids as privileged scaffolds in antimalarial drug discovery: A key review.

Malaria remains a serious worldwide health danger and massive economic trouble to disease-endemic nations. Presently, 250 million of malarial cases are expected worldwide. The emergence of fighting of the Plasmodium parasite against the first-line antimalarial drugs has fueled research attention in the way of designing new scaffolds as well as strategies to counter the drug resistance. Chalcones are simple and well-known analogs, which were found in a huge number of natural compounds and also been prepared according to their suitable synthetic approaches. This review illustrates the current progresses on structure-activity relationship (SAR) and mechanism of diverse types of chalcone derivatives that play a significant role for the development of novel safe, less toxic and highly active antimalarials. This present mini-review will be useful to scientists in research fields of medicinal chemistry, organic synthesis, and also various biological applications particularly for the development of novel antiplasmodial and antimalarial agents.

miR-140-5p aggravates hypoxia-induced cell injury via regulating MLK3 in H9c2 cells.

Myocardial infarction (MI) is an important cause of cardiovascular disease. microRNAs (miRNAs) have been indicated as pivotal regulators in the physiological and pathological processes of heart diseases. The purpose of this study was to investigate the role of miR-140-5p in hypoxia-induced cell injury in H9c2 cells and its underlying mechanism. H9c2 cells were subjected to hypoxia, before which the expression levels of miR-140-5p and MLK3 were overexpressed or knocked down through transient transfection. The efficiency of transfection was verified by qRT-PCR and Western blotting. Cell viability, apoptotic cell rate, and the expression changes of apoptosis-related proteins were determined by trypan blue exclusion, flow cytometry, and Western blotting, respectively. Furthermore, Western blotting was performed to assess the expression levels of core factors related with p38MAPK and JNK signaling pathways. As a result, hypoxia significantly reduced cell viability and increased cell apoptosis in H9c2 cells. miR-140-5p inhibition attenuated cell injury induced by hypoxia in H9c2 cells, while miR-140-5p overexpression expedited the cell injury, as evidenced by the decreased cell viability and enhanced cell apoptosis. Moreover, miR-140-5p promoted the activation of p38MAPK and JNK pathways. miR-140-5p positively modulated the expression of MLK3. ML3 overexpression reversed the regulatory effects of miR-140-5p inhibition on hypoxia-injured H9c2 cells. In conclusion, this study demonstrated that miR-140-5p aggravated hypoxia-induced cell injury partially through up-regulation of MLK3.

[Studies on the nucleotides sequences of extended-spectrum-beta-lactamases encoding genes of Escherichia coli and Klebsiella pneumoniae and the related molecular evolution].

OBJECTIVE: To identify TEM-type and SHV-type ESBLs encoding genes of ESBLs-producing Klebsiella pneumoniae and Escherichia coli isolated from clinical species in West China Hospital of Sichuan University and study the molecular evolution of the ESBLs. METHODS: The nucleotide sequences of TEM-type and SHV-type ESBLs encoding genes amplified by PCR were detected by automatic sequencer, and the subtypes of the encoding genes were determined by Blastx searching. The molecular evolution of ESBLs was studied by means of bioinformatics. RESULTS: In this study, the subtypes of ESBLs were SHV-2 and TEM-19, the distribution of silent mutation in ten bla(SHV-2) was identical, and that of two bla(TEM-19) was the same; the distribution of silent mutation of bla(TEM-19) was the same as that of bla(TEM-1). The distribution of silent mutation of bla(SHV-2) observed here was different from that observed in other countries. CONCLUSION: SHV-2 was the main ESBLs in this study. The bla(SHV-2) and bla(TEM-19) in this study originated from the same transferable variants respectively. The prevalent SHV-2 in different countries resulted from convergent evolution. It seems possible that the bla(TEM-19) identified by this study might originate directly from the transferable bla(TEM-1) identified in this study.