Multi‐component carbonylation of olefins, a reaction that installs both a carbon–carbon(heteroatom) bond and a carbonyl group across the double bond, is an attractive strategy for alkene ...functionalization. Herein, we developed a novel nickel‐catalyzed four‐component carbonylation of olefins with ethers under low CO gas pressure. Using alcohols and amines as the reaction partner, diverse γ‐oxy‐substituted esters and amides were produced in good yields with excellent functional group tolerance. Notably, Naftidrofuryl, a medicine for the treatment of cerebrovascular disease (CVD), can be synthesized by this process straightforwardly.
A new nickel‐catalyzed four‐component carbonylation of ethers with olefins to synthesize γ‐substituted carbonyl compounds has been developed. A variety of γ‐substituted carbonyl compounds were produced in excellent yields under 1 atm pressure of CO. Notably, this strategy has been successfully applied to the one‐step synthesis of the drug molecule Naftidrofuryl, which is a medicine for the treatment of cerebrovascular disease (CVD).
Antimicrobial peptides (AMPs) are expressed in various living organisms as first-line host defenses against potential harmful encounters in their surroundings. AMPs are short polycationic peptides ...exhibiting various antimicrobial activities. The principal antibacterial activity is attributed to the membrane-lytic mechanism which directly interferes with the integrity of the bacterial cell membrane and cell wall. In addition, a number of AMPs form a transmembrane channel in the membrane by self-aggregation or polymerization, leading to cytoplasm leakage and cell death. However, an increasing body of evidence has demonstrated that AMPs are able to exert intracellular inhibitory activities as the primary or supportive mechanisms to achieve efficient killing. In this review, we focus on the major intracellular targeting activities reported in AMPs, which include nucleic acids and protein biosynthesis and protein-folding, protease, cell division, cell wall biosynthesis, and lipopolysaccharide inhibition. These multifunctional AMPs could serve as the potential lead peptides for the future development of novel antibacterial agents with improved therapeutic profiles.
A procedure on palladium‐catalyzed carbonylative reaction of trifluoroacetimidoyl chlorides and nitro compounds for the construction of pharmaceutically valuable ...2‐(trifluoromethyl)quinazolin‐4(3H)‐ones has been achieved. In this transformation, Mo(CO)6 has been used both as a convenient CO source and a reducing reagent. This newly developed protocol is compatible with various nitro compounds and can be readily scaled up to 1 mmol scale.
Ethers are of central importance in the fields of biomass, energy, and organic chemistry. Herein, a novel cobalt‐catalyzed carbonylative coupling of ethers with amines to construct α‐carbonylated ...ethers has been achieved. Remarkably, Alfuzosin, a medicine for treatment of benign prostatic hyperplasia (BPH), can be synthesized by this process straightforwardly. Notably, this protocol presents the first example on the direct carbonylative reaction of ethers.
A novel cobalt‐catalyzed carbonylative coupling of ethers with amines to construct α‐carbonylated ethers has been achieved. Alfuzosin, a medicine for treatment of benign prostatic hyperplasia (BPH), can be synthesized by this process straightforwardly.
A low cost FeCl3‐mediated cascade annulation of trifluoroacetimidoyl chlorides and hydrazides for the efficient synthesis of 5‐trifluoromethyl‐1,2,4‐triazoles has been developed. The transformation ...proceeds through a cascade base‐promoted intermolecular C−N bond formation and FeCl3‐mediated intramolecular dehydration sequence under mild conditions. The protocol exhibits many notable features and can be readily scaled up to gram scale.
An FeCl3-mediated cascade coupling/decarbonylative annulation reaction for the efficient construction of 2-(trifluoromethyl)quinazolin-4(3H)-ones has been developed. This transformation employs ...readily available isatins and trifluoroacetimidoyl chlorides as the starting materials, providing a facile and practical route to diverse biologically relevant quinazolin-4(3H)-one derivatives. A plausible reaction pathway has been proposed based on the mechanistic observations.
Abstract
Context
The associations of circulating insulin-like growth factor-1 (IGF-1) levels with bone mineral density and fracture risk are inconclusive in observational studies.
Objective
We ...conducted a mendelian randomization study to assess the associations of serum IGF-1 levels with estimated bone mineral density (eBMD) and fracture.
Methods
Genetic instruments for IGF-1 were selected at the genome-wide significance level (P < 5 × 10–8) from a genome-wide association study including 358 072 individuals of European ancestry. Summary-level data for eBMD (426 824 individuals) and fracture (53 184 fracture cases and 373 611 noncases) were obtained from the UK Biobank study. Univariable and multivariable mendelian randomization analyses methods were used to estimate the associations of IGF-1 with eBMD and fracture. The main outcome measure included the change of eBMD and odds ratio of fracture per genetically predicted 1-SD increase of serum IGF-1 levels.
Results
For 1-SD increase in IGF-1, the change of eBMD levels was 0.04 g/cm2 (95% CI, 0.01-0.07; P = .011) and the odds ratio of fracture was 0.94 (95% CI, 0.91-0.98; P = .003). The associations persisted with similar magnitude after adjustment for height. The association was consistent for fracture but not for eBMD after excluding genetic instruments that might directly influence these outcomes. The association between IGF-1 and fracture was somewhat attenuated after adjustment for eBMD (odds ratio 0.96; 95% CI, 0.92-0.99; P = .012).
Conclusion
The present study supports a role for IGF-1 in preventing fracture, possibly and partly mediated by greater bone mineral density.
Primary liver cancer is a lethal cancer. The phosphatidylinositol 3-kinase (PI3K)–Akt–mammalian target of rapamycin (mTOR) pathway has been implicated in the pathogenesis of liver cancer. Gomisin N ...(GN), a lignan isolated from the dried fruits of Schisandra chinensis (Turca.) Baill., has been reported to reduce viability of, and induce apoptosis in, HepG2 liver cancer cells. In preadipocytes, GN was found to inhibit Akt activity. In the present study, Akt signaling-related anti-liver cancer mechanisms of GN were investigated. We confirmed that GN reduces cell viability of, and triggers apoptosis in, more liver cancer cell lines. Mechanistic studies revealed that GN lowers protein levels of phospho-PI3K (p85 tyrosine (Tyr)458), phospho-Akt (serine (Ser)473), and Akt downstream molecules Mcl-1 in HepG2 and HCCLM3 cells. Meanwhile, GN activates mTOR and inhibits ULK1 (a negative downstream effector of mTOR) activities. Activation of mTOR has been reported to suppress ULK1 activity and repress autophagy. Indeed, we observed that GN inhibits autophagy in liver cancer cells. In summary, we for the first time demonstrated that GN inhibits the PI3K–Akt pathway and regulates the mTOR–ULK1 pathway in liver cancer cells.
Circular RNAs (circRNAs) are 3'-5' head-to-tail covalently closed non-coding RNA that have been proved to play essential roles in many cellular and developmental processes. However, no information ...relate to cucumber circRNAs is available currently, especially under salt stress condition.
In this study, we sequenced circRNAs in cucumber and a total of 2787 were identified, with 1934 in root and 44 in leaf being differentially regulated under salt stress. Characteristics analysis of these circRNAs revealed following features: most of them are exon circRNAs (79.51%) and they prefer to arise from middle exon(s) of parent genes (2035/2516); moreover, most of circularization events (88.3%) use non-canonical-GT/AG splicing signals; last but not least, pairing-driven circularization is not the major way to generate cucumber circRNAs since very few circRNAs (18) contain sufficient flanking complementary sequences. Annotation and enrichment analysis of both parental genes and target mRNAs were launched to uncover the functions of differentially expressed circRNAs induced by salt stress. The results showed that circRNAs may be paly roles in salt stress response by mediating transcription, signal transcription, cell cycle, metabolism adaptation, and ion homeostasis related pathways. Moreover, circRNAs may function to regulate proline metabolisms through regulating associated biosynthesis and degradation genes.
The present study identified large number of cucumber circRNAs and function annotation revealed their possible biological roles in response to salt stress. Our findings will lay a solid foundation for further structure and function studies of cucumber circRNAs.
Abstract
γ-Amino acids and peptides analogues are common constituents of building blocks for numerous biologically active molecules, pharmaceuticals, and natural products. In particular, γ-amino ...acids are providing with better metabolic stability than α-amino acids. Herein we report a multicomponent carbonylation technology that combines readily available amides, alkenes, and the feedstock gas carbon monoxide to build architecturally complex and functionally diverse γ-amino acid derivatives in a single step by the implementation of radical relay catalysis. This transformation can also be used as a late-stage functionalization strategy to deliver complex, advanced γ-amino acid products for pharmaceutical and other areas.
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