Silver-catalyzed cascade cyclization for the synthesis of 4-aminotetrahydrocarbazole.

A silver-catalyzed cascade cyclization strategy has been developed for the synthesis of 4-aminotetrahydrocarbazole, a common core structure found in various alkaloids. This target molecule can be synthesized through a one-step tandem cyclization reaction, thereby eliminating the need for a prior synthesis of tetrahydrocarbazole. Furthermore, the use of chiral tert-butylsulfinamide facilitates in situ chiral resolution of the resulting product.

Iron-Catalyzed Electrophotochemical α-Functionalization of a Silylcyclobutanol.

Four-membered ring structure is important in organic chemistry, and selective cleavage and functionalization of these strained rings are of great interest. However, direct α-functionalization of cyclobutanols is rarely reported because of the high O-H bond dissociation energy and the occurrence of ß-scission of C-C bonds in these alcohols. Recently, transition-metal catalysis has facilitated alkoxy radical generation. Herein, we report a method for electrophotochemical α-functionalization of a silylcyclobutanol via visible-light-induced LMCT reactions of M-alkoxy complexes. Introduction of the silyl group into the cyclobutanol structure favored fast [1,2]-silyl transfer over ring opening, thus allowing the generation of α-functionalized products.

Effects of triclosan on lipid metabolism and underlying mechanisms in the cyprinid fish Squalidus argentatus.

The ubiquitous presence of the disinfectant triclosan (TCS) has raised global concerns regarding its potential threat to aquatic organisms. However, the effects of TCS on lipid metabolism in fish and its underlying mechanisms remain unclear. This study investigated the effect of environmentally relevant levels of TCS on the lipid metabolism in the cyprinid fish Squalidus argentatus. Our results showed that the lipid metabolism in the cyprinid fish S. argentatus was perturbed by 28-day exposure to TCS, as evidenced by higher levels of lipid accumulation in both the liver and blood. To elucidate the mechanisms underlying toxicity, we evaluated oxidative stress, inflammatory status, and lipase activity in the liver. Our findings indicated increased ROS-specific fluorescence intensity, superoxide dismutase (SOD) activity, and malondialdehyde (MDA) content in the livers of S. argentatus exposed to TCS, suggesting oxidative damage. Additionally, TCS treatment induced the production of proinflammatory cytokines in the liver of S. argentatus exposed to TCS, which suppressed hepatic lipase activity. Intestinal tissue morphology, inflammation, and blood lipopolysaccharide (LPS) levels were also examined. Significant increases in goblet cell count and MDA levels were observed in the intestinal tract. After 28 days of TCS exposure, the serum LPS levels were significantly elevated. 16S rRNA sequencing was conducted to analyze the effects of TCS on the diversity and composition of the intestinal microbiota. Transcriptomic analysis was performed to reveal global molecular alterations following TCS exposure. In conclusion, our results indicate that TCS may disrupt the lipid metabolism in S. argentatus by (i) inducing hepatic oxidative stress and inflammation, which suppress lipoprotein lipase activity, (ii) affecting the production of beneficial metabolites and endotoxins by dysregulating gut microbiota composition, and (iii) altering the expression levels of lipid metabolism-related pathways.

Deboronative functionalization of alkylboron species via a radical-transfer strategy.

With advances in organoboron chemistry, boron-centered functional groups have become increasingly attractive. In particular, alkylboron species are highly versatile reagents for organic synthesis, but the direct generation of alkyl radicals from commonly used, bench-stable boron species has not been thoroughly investigated. Herein, we describe a method for activating C-B bonds by nitrogen- or oxygen-radical transfer that is applicable to alkylboronic acids and esters and can be used for both Michael addition reactions and Minisci reactions to generate alkyl or arylated products.

Palladium-Catalyzed Coordination-Induced Remote C-H Aryl Etherification/Amination of 8-Amidoquinolines.

Herein, we report a direct method for palladium-catalyzed coordination-induced oxidative remote C-H aryl etherification of 8-amidoquinolines with p-benzoquinone monoacetal. The method provides access to C5-aryl etherified quinolines and shows site-selectivity different from that of typical palladium-catalyzed C(sp2)-H activation reactions. The p-benzoquinone monoacetals act both as oxidants and as aryl etherification reagents. By using proper substrates, C5-aminated quinolines and C4-etherifed 1-naphthylamine could also be formed.

A Transformable Specific-Responsive Peptide for One-Step Synergistic Therapy of Bladder Cancer.

Synergistic therapy has shown greater advantages compared with monotherapy. However, the complex multiple-administration plan and potential side effects limit its clinical application. A transformable specific-responsive peptide (TSRP) is utilized to one-step achieve synergistic therapy integrating anti-tumor, anti-angiogenesis and immune response. The TSRP is composed of: i) Recognition unit could specifically target and inhibit the biological function of FGFR-1; ii) Transformable unit could self-assembly and trigger nanofibers formation; iii) Reactive unit could specifically cleaved by MMP-2/9 in tumor micro-environment; iv) Immune unit, stimulate the release of immune cells when LTX-315 (Immune-associated oncolytic peptide) exposed. Once its binding to FGFR-1, the TSRP could cleaved by MMP-2/9 to form the nanofibers on the cell membrane, with a retention time of up to 12 h. Through suppressing the phosphorylation levels of ERK 1/2 and PI3K/AKT signaling pathways downstream of FGFR-1, the TSRP significant inhibit the growth of tumor cells and the formation of angioginesis. Furthermore, LTX-315 is exposed after TSRP cleavage, resulting in Calreticulin activation and CD8+ T cells infiltration. All above processes together contribute to the increasing survival rate of tumor-bearing mice by nearly 4-folds. This work presented a unique design for the biological application of one-step synergistic therapy of bladder cancer.

Photoinduced Dehydrogenative Amination of Quinoxalin-2(1H)-ones with Air as an Oxidant.

A facile and eco-friendly photoinduced dehydrogenative amination of quinoxalin-2(1H)-ones with aliphatic amines without any metal, strong oxidant, and photocatalyst has been established for the first time. This reaction proceeding efficiently with air as the sole oxidant at room temperature obtains a wide range of 3-aminoquinoxaline-2(1H)-ones in high yields with excellent functional group tolerance. The mechanistic studies show an interesting involvement of quinoxalin-2(1H)-ones as a photosensitizer, which eliminates the requirement for external photocatalysts.

Intramolecular trapping of an iminium salt: rapid construction of quindoline derivatives.

Construction of the pyridine ring is a practical and streamline way to construct a variety of quindoline derivatives. We have developed a novel method for synthesis of quindoline derivatives by means of intramolecular ring-closure reactions of 3-N-methylphenylindoles via an iminium salt intermediate. This practical method has the advantages of a short reaction time, operational simplicity, and nearly quantitative yields; and it can be used for the rapid synthesis of a variety of valuable quindoline derivatives.

Recent advances in combining photo- and N-heterocyclic carbene catalysis.

N-Heterocyclic carbenes (NHCs) are unique Lewis basic catalysts that mediate various organic transformations by means of polarity reversal. Although the scope of research on two-electron reactions mediated by NHC catalysts has been expanding, the types of these reactions are limited by the inability of NHCs to engage sp3-electrophiles. However, the revival of photocatalysis has accelerated the development of free-radical chemistry, and combining photoredox catalysis and NHC catalysis to achieve NHC-mediated radical reactions under mild conditions could overcome the above-mentioned limitation. This review summarizes recent advances in combining photoredox and NHC catalysis, focusing on elucidation and exploration of mechanisms, with the aim of identifying challenges and opportunities to develop more types of catalytic models.

Design, Synthesis, and Bioactivity of Aldisine Derivatives Containing Oxime and Hydrazine Moieties Based on Hydrogen Bonds.

Marine natural products have attracted more and more attention in drug research and development due to their unique structure, diverse biological activities, and novel mode of action. Using antiviral alkaloid aldisine as the lead compound and drawing on the hydrogen bond effect widely used in drug design, derivatives containing oxime and hydrazone moieties were designed and synthesized by introducing functional groups with hydrogen-bond receptors or donors into molecules. The configuration of derivatives was systematically studied through nuclear Overhauser effect (NOE) spectroscopy and single crystal analysis. The antiviral activity test result showed that most derivatives had antiviral activity against tobacco mosaic virus (TMV), and some compounds had better activity than the commercial antiviral drug ribavirin, especially compounds 2 and 24, which had comparable activity to the most effective commercial antiviral drug ningnanmycin. Preliminary mode of action studies showed that compound 2 could affect the assembly of rod-shaped TMVs by promoting the aggregation and fragmentation of TMV coat proteins. Molecular docking experiments demonstrated that the introduction of oxime and hydrazone moieties could indeed increase the hydrogen bond between molecules and target proteins. In addition, we conducted fungicidal and larvicidal activities study of these derivatives. Most of these derivatives had good larvicidal activities against Mythimna separata and Plutella xylostella and showed broad-spectrum fungicidal activities.

Design, Synthesis and Various Bioactivity of Acylhydrazone-Containing Matrine Analogues.

Compounds with acylhydrazone fragments contain amide and imine groups that can act as electron donors and acceptors, so they are easier to bind to biological targets and thus generally exhibit significant biological activity. In this work, acylhydrazone fragments were introduced to the C-14 or C-11 position of matrine, a natural alkaloid, aiming to enhance their biological activities. The result of this bioassay showed that many synthesized compounds exhibited excellent anti-virus activity against the tobacco mosaic virus (TMV). Seventeen out of 25 14-acylhydrazone matrine derivatives and 17 out of 20 11-butanehydrazone matrine derivatives had a higher inhibitory activity against TMV than the commercial antiviral agent Ribavirin (the in vitro activity, in vivo inactivation, curative and protection activities at 500 µg/mL were 40.9, 36.5 ± 0.9, 38.0 ± 1.6 and 35.1 ± 2.2%, respectively), and four 11-butanehydrazone matrine derivatives even had similar to or higher activity than the most efficient antiviral agent Ningnanmycin (55.4, 57.8 ± 1.4, 55.3 ± 0.5 and 60.3 ± 1.2% at 500 µg/mL for the above four test modes). Among them, the N-benzyl-11-butanehydrazone of matrine formed with 4-bromoindole-3-carboxaldehyde exhibited the best anti-TMV activity (65.8, 71.8 ± 2.8, 66.8 ± 1.3 and 69.5 ± 3.1% at 500 µg/mL; 29, 33.5 ± 0.7, 24.1 ± 0.2 and 30.3 ± 0.6% at 100 µg/mL for the above four test modes), deserving further investigation as an antiviral agent. Other than these, the two series of acylhydrazone-containing matrine derivatives were evaluated for their insecticidal and fungicidal activities. Several compounds were found to have good insecticidal activities against diamondback moth (Plutella xylostella) and mosquito larvae (Culex pipiens pallens), showing broad biological activities.

Direct allylic acylation via cross-coupling involving cooperative N­heterocyclic carbene, hydrogen atom transfer, and photoredox catalysis.

Herein, we report a mild, operationally simple, multicatalytic method for the synthesis of ß,γ-unsaturated ketones via allylic acylation of alkenes. Specifically, the method combines N­heterocyclic carbene catalysis, hydrogen atom transfer catalysis, and photoredox catalysis for cross-coupling reactions between a wide range of feedstock carboxylic acids and readily available olefins to afford structurally diverse ß,γ-unsaturated ketones without olefin transposition. The method could be used to install acyl groups on highly functionalized natural-product-derived compounds with no need for substrate pre-activation, and C-H functionalization proceed with excellent site selectivity. To demonstrate the potential applications of the method, we convert a representative coupling product into various useful olefin synthons.

A Self-Disguised Nanospy for Improving Drug Delivery Efficiency via Decreasing Drug Protonation.

Nanoscale drug carriers play a crucial role in reducing side effects of chemotherapy drugs. However, the mononuclear phagocyte system (MPS) and the drug protonation after nanoparticles (NPs) burst release still limit the drug delivery efficiency. In this work, a self-disguised Nanospy is designed to overcome this problem. The Nanospy is composed of: i) poly (lactic-co-glycolic acid)-polyethylene glycol (PLGA-PEG) loading doxorubicin is the core structure of the Nanospy. ii) CD47 mimic peptides (CD47p) is linked to NPs which conveyed the "don't eat me" signal. iii) 4-(2-aminoethyl) benzenesulfonamide (AEBS) as the inhibitor of Carbonic anhydrase IX (CAIX) linked to NPs. Briefly, when the Nanospy circulates in the bloodstream, CD47p binds to the regulatory protein α (SIRPα) on the surface of macrophages, which causes the Nanospy escapes from phagocytosis. Subsequently, the Nanospy enriches in tumor and the AEBS reverses the acidic microenvironment of tumor. Due to above characteristics, the Nanospy reduces liver macrophage phagocytosis by 25% and increases tumor in situ DOX concentration by 56% compared to PLGA@DOX treatment. In addition, the Nanospy effectively inhibits tumor growth with a 63% volume reduction. This work presents a unique design to evade the capture of MPS and overcomes the influence of acidic tumor microenvironment (TME) on weakly alkaline drugs.

Formation of C-B, C-C, and C-X Bonds from Nonstabilized Aryl Radicals Generated from Diaryl Boryl Radicals.

With the development of organoboron chemistry, boron-centered radicals have become increasingly attractive. However, their synthetic applications remain limited in that they have been used only as substrates for addition reactions or as initiators for catalytic reactions. We have achieved a new reaction pathway in which tetraarylborate salts are used as precursors for aryl radicals via boron radicals, by introducing a simple activation reagent. In addition, we carried out a diverse array of transformations involving these aryl radical precursors, which allowed the construction of new C-B, C-C, and C-X bonds in the presence of visible light.

Alkylboronic acids as alkylating agents: photoredox-catalyzed alkylation reactions assisted by K3PO4.

Despite the ubiquity of alkylboronic acids in organic synthesis, their utility as alkyl radical precursors in visible-light-induced photocatalytic reactions is limited by their high oxidation potentials. In this study, we demonstrated that an inorganophosphorus compound can modulate the oxidation potentials of alkylboronic acids so that they can act as alkyl radical precursors. We propose a mechanism based on the results of fluorescence quenching experiments, electrochemical experiments, 11B and 31P NMR spectroscopy, and other techniques. In addition, we describe a simple and reliable alkylation method that has good functional group tolerance and can be used for direct C-B chlorination, cyanation, vinylation, alkynylation, and allylation, as well as late-stage functionalization of derivatized drug molecules. Notably, alkylboronic acids can be selectively activated in the presence of a boronic pinacol ester.

Synthesis and Evaluation of 11-Butyl Matrine Derivatives as Potential Anti-Virus Agents.

Matrine derivatives were reported to have various biological activities, especially the ester, amide or sulfonamide derivatives of matrine deriving from the hydroxyl or carboxyl group at the end of the branch chain after the D ring of matrine is opened. In this work, to investigate whether moving away all functional groups from the C-11 branch chain could have an impact on the bioactivities, such as anti-tobacco mosaic virus (TMV), insecticidal and fungicidal activities, a variety of N-substituted-11-butyl matrine derivatives were synthesized. The obtained bioassay result showed that most N-substituted-11-butyl matrine derivatives had obviously enhanced anti-TMV activity compared with matrine, especially many compounds had good inhibitory activity close to that of commercialized virucide Ningnanmycin (inhibition rate 55.4, 57.8 ± 1.4, 55.3 ± 0.5 and 60.3 ± 1.2% at 500 µg/mL; 26.1, 29.7 ± 0.2, 24.2 ± 1.0 and 27.0 ± 0.3% at 100 µg/mL, for the in vitro activity, in vivo inactivation, curative and protection activities, respectively). Notably, N-benzoyl (7), N-benzyl (16), and N-cyclohexylmethyl-11-butyl (19) matrine derivatives had higher anti-TMV activity than Ningnanmycin at both 500 and 100 µg/mL for the four test modes, showing high potential as anti-TMV agent. Furthermore, some compounds also showed good fungicidal activity or insecticidal activity.

Achievements and perspectives of synthetic biology in botanical insecticides.

Botanical insecticides are the origin of all insecticidal compounds. They have been widely used to control pests in crops for a long time. Currently, the commercial production of botanical insecticides extracted from plants is limited because of insufficient raw material supply. Synthetic biology is a promising and effective approach for addressing the current problems of the production of botanical insecticides. It is an emerging biological research hotspot in the field of botanical insecticides. However, the biosynthetic pathways of many botanical insecticides are not completely elucidated. On the other hand, the cytotoxicity of botanical pesticides and low efficiency of these biosynthetic enzymes in new hosts make it still challenging for their heterologous production. In the present review, we summarized the recent developments in the heterologous production of botanical insecticides, analyzed the current challenges, and discussed the feasible production strategies, focusing on elucidating biosynthetic pathways, enzyme engineering, host engineering, and cytotoxicity engineering. Looking to the future, synthetic biology promises to further advance heterologous production of more botanical pesticides.

Design, Synthesis, and Bioactivity Study of Novel Tryptophan Derivatives Containing Azepine and Acylhydrazone Moieties.

Based on the scaffolds widely used in drug design, a series of novel tryptophan derivatives containing azepine and acylhydrazone moieties have been designed, synthesized, characterized, and evaluated for their biological activities. The bioassay results showed that the target compounds possessed moderate to good antiviral activities against the tobacco mosaic virus (TMV), among which compounds 5c, 6a, 6h, 6t, 6v, and 6y exhibited higher inactivation, curative, and protection activities in vivo than that of ribavirin (40 ± 1, 37 ± 1, 39 ± 2% at 500 mg/L). Especially, 6y showed comparable activities to that of ningnanmycin (57 ± 2, 55 ± 3, 58 ± 1% at 500 mg/L). Meanwhile, we were pleased to find that almost all these derivatives showed good larvicidal activities against Plutella xylostella. Meanwhile, these derivatives also showed a broad spectrum of fungicidal activities.

Promoting Efficacy and Environmental Safety of Pesticide Synergists via Non-Ionic Gemini Surfactants with Short Fluorocarbon Chains.

Improving the utilization rate of pesticides is key to achieve a reduction and synergism, and adding appropriate surfactant to pesticide preparation is an effective way to improve pesticide utilization. Fluorinated surfactants have excellent surface activity, thermal and chemical stability, but long-chain linear perfluoroalkyl derivatives are highly toxic, obvious persistence and high bioaccumulation in the environment. Therefore, new strategies for designing fluorinated surfactants which combine excellent surface activity and environmental safety would be useful. In this study, four non-ionic gemini surfactants with short fluorocarbon chains were synthesized. The surface activities of the resulting surfactants were assessed on the basis of equilibrium surface tension, dynamic surface tension, and contact angle. Compared with their monomeric counterparts, the gemini surfactants had markedly lower critical micelle concentrations and higher diffusivities, as well as better wetting abilities. We selected a single-chain surfactant and a gemini surfactant with good surface activities as synergists for the glyphosate water agent. Both surfactants clearly improved the efficacy of the herbicide, but the gemini surfactant had a significantly greater effect than the single-chain surfactant. An acute toxicity test indicated that the gemini surfactant showed slight toxicity to rats.