Synthesis of C(3) SCF3-Substituted Pyrrolidinoindoline by PIII/PV Redox Catalysis Using CF3SO2Cl as Electrophilic CF3S Reagent.

This work reports a method for the catalytic synthesis of C(3) SCF3-substituted pyrrolidinindoline using a small-ring organophosphorus-based catalyst and a hydrosilane reductant, with trifluoromethanesulfonyl chloride as the electrophilic SCF3 reagent. This method can drive the conversion of tryptamine to the C(3) SCF3-substituted pyrrolidine indoline. The readily available, inexpensive trifluoromethanesulfonyl chloride could be activated as an electrophilic SCF3 source by PIII/PV redox catalysis and could efficiently participate in the reaction of tryptamines, thus providing various substituted C(3) SCF3-substituted pyrrolidinoindoline in moderate to excellent yields. This presented strategy features a broad substrate scope, and the structure has value for in-depth research.

A Comparative Study of Surfactant Solutions Used for Enhanced Oil Recovery in Shale and Tight Formations: Experimental Evaluation and Numerical Analysis.

Applying chemical enhanced oil recovery (EOR) to shale and tight formations is expected to accelerate China's Shale Revolution as it did in conventional reservoirs. However, its screening and modeling are more complex. EOR operations are faced with choices of chemicals including traditional surfactant solutions, surfactant solutions in the form of micro-emulsions (nano-emulsions), and nano-fluids, which have similar effects to surfactant solutions. This study presents a systematic comparative analysis composed of laboratory screening and numerical modeling. It was conducted on three scales: tests of chemical morphology and properties, analysis of micro-oil-displacing performance, and simulation of macro-oil-increasing effect. The results showed that although all surfactant solutions had the effects of reducing interfacial tension, altering wettability, and enhancing imbibition, the nano-emulsion with the lowest hydrodynamic radius is the optimal selection. This is attributed to the fact that the properties of the nano-emulsion match well with the characteristics of these shale and tight reservoirs. The nano-emulsion is capable of integrating into the tight matrix, interacting with the oil and rock, and supplying the energy for oil to flow out. This study provides a comprehensive understanding of the role that surfactant solutions could play in the EOR of unconventional reservoirs.

Leveraging high-throughput screening technologies in targeted mRNA delivery.

Messenger ribonucleic acid (mRNA) has emerged as a promising molecular preventive and therapeutic approach that opens new avenues for healthcare. Although the use of delivery systems, especially lipid nanoparticles (LNPs), greatly improves the efficiency and stability of mRNA, mRNA tends to accumulate in the liver and hardly penetrates physiological barriers to reach the target site after intravenous injection. Hence, the rational design of targeting strategies aimed at directing mRNA to specific tissues and cells remains an enormous challenge in mRNA therapy. High-throughput screening (HTS) is a cutting-edge targeted technique capable of synthesizing chemical compound libraries for the large-scale experiments to validate the efficiency of mRNA delivery system. In this review, we firstly provide an overview of conventional low-throughput targeting strategies. Then the latest advancements in HTS techniques for mRNA targeted delivery, encompassing optimizing structures of large-scale delivery vehicles and developing large-scale surface ligands, as well as the applications of HTS techniques in extrahepatic systemic diseases are comprehensively summarized. Moreover, we illustrate the selection of administration routes for targeted mRNA delivery. Finally, challenges in the field and potential solutions to tackle them are proposed, offering insights for future development toward mRNA targeted therapy.

PIII/PV-Catalyzed Beckmann Reaction and Sequential [2,3]-Sigmatropic Rearrangement to Construct 2-Amidopyridines.

An organophosphorus catalytic method for the synthesis of substituted 2-amidopyridines is reported. The method employs a small-ring organophosphorus-based catalyst and a hydrosilane reductant to drive the conversion of ketoximes and pyridine-N-oxides into 2-amidopyridines through sequential Beckmann rearrangement followed by [2,3]-sigmatropic rearrangement. The readily available ketoximes could be activated to nitrilium ions in PIII/PV redox catalysis and could efficiently participate in the domino reaction of pyridine-N-oxides, thus providing various substituted 2-amidopyridines in moderate to excellent yields. This presented strategy features excellent functional group tolerance and a broad substrate scope.

Discovery of Novel PD-L1 Small-Molecular Inhibitors with Potent In Vivo Anti-tumor Immune Activity.

Programmed death-ligand 1 (PD-L1) has surfaced as a promising therapeutic target for various cancers due to its pivotal role in facilitating tumor immune evasion. Herein, we report a series of novel small-molecule PD-L1 inhibitors exhibiting remarkable inhibitory activity against the PD-1/PD-L1 interaction (X18: IC50 = 1.3 nM) and reinstating the suppressive effect of PD-L1 on T cells (X18: EC50 = 152.8 nM). Crystallographic studies revealed the binding mode of X18 and PD-L1. Through a rational prodrug design approach, we have successfully optimized the oral pharmacokinetic properties of X22, effectively addressing the poor oral pharmacokinetic profile of PD-L1 small-molecule inhibitors. Notably, X22 demonstrated significant antitumor efficacy in murine models of MC38 and CT26 colon cancer through the upregulation of tumor infiltration and cytotoxicity of CD8+ T cells partially. These findings offer promising prospects for the advancement of PD-L1 inhibitors as innovative agents in cancer immunotherapy.

Organophosphorus-Catalyzed Direct Dehydroxylative Thioetherification of Alcohols with Hypervalent Organosulfur Compounds.

A metal-free and thiol-free organophosphorus-catalyzed method for forming thioethers was disclosed, driven by PIII/PV═O redox cycling. In this work, one-step dehydroxylative thioetherification of alcohols was fulfilled with various hypervalent organosulfur compounds. This established strategy features an excellent functional group tolerance and broad substrate scope, especially inactivated alcohols. The scale-up reaction and further transformation of the product were also successful. Additionally, this method offers a protecting-group-free and step-efficient approach for synthesizing peroxisome proliferator-activated receptor agonists which exhibited promising potential for treating osteoporosis in mammals.

Organophosphorus-Catalyzed "Dual-Substrate Deoxygenation" Strategy for C-S Bond Formation from Sulfonyl Chlorides and Alcohols/Acids.

A green method to construct C-S bonds using sulfonyl chlorides and alcohols/acids via a PIII/PV═O catalytic system is reported. The organophosphorus-catalyzed umpolung reaction promotes us to propose the "dual-substrate deoxygenation" strategy. Herein, we adopt the "dual-substrate deoxygenation" strategy, which achieves the deoxygenation of sulfonyl chlorides and alcohols/acids to synthesize thioethers/thioesters driven by PIII/PV═O redox cycling. The catalytic method represents an operationally simple approach using stable phosphine oxide as a precatalyst and shows broad functional group tolerance. The potential application of this protocol is demonstrated by the late-stage diversification of drug analogues.

Discovery of the First Subnanomolar PPARα/δ Dual Agonist for the Treatment of Cholestatic Liver Diseases.

Peroxisome proliferator-activator receptors α/δ (PPARα/δ) are considered as potential drug targets for cholestatic liver diseases (CLD) via ameliorating hepatic cholestasis, inflammation, and fibrosis. In this work, we developed a series of hydantoin derivatives as potent PPARα/δ dual agonists. Representative compound V1 exhibited PPARα/δ dual agonistic activity at the subnanomolar level (PPARα EC50 = 0.7 nM; PPARδ EC50 = 0.4 nM) and showed excellent selectivity over other related nuclear receptors. The crystal structure revealed the binding mode of V1 and PPARδ at 2.1 Å resolution. Importantly, V1 demonstrated excellent pharmacokinetic (PK) properties and a good safety profile. Notably, V1 showed potent anti-CLD and antifibrotic effects in preclinical models at very low doses (0.03 and 0.1 mg/kg). Collectively, this work provides a promising drug candidate for treating CLD and other hepatic fibrosis diseases.

Synthesis of Functionalized Thiazolidin-2-imine and Oxazolidin-2-one Derivatives from p-Quinamines via [3 + 2] Annulation of Isothiocyanates and CO2.

An efficient and environmentally friendly synthetic approach to prepare thiazolidine-2-imine and oxazolidine-2-one derivatives has been developed. Thiazolidine-2-imines are synthesized in good to excellent yields by [3 + 2] annulation of p-quinamines with isothiocyanates under catalyst- and solvent-free conditions. Oxazolidine-2-ones are produced in good to excellent yields via [3 + 2] annulation of p-quinamines with CO2 using triethylenediamine (DABCO) as an organocatalyst. Furthermore, this strategy can be performed on a gram scale and tolerate a wide range of functional groups.

Discovery of Orally Bioavailable N-Benzylpiperidinol Derivatives as Potent and Selective USP7 Inhibitors with In Vivo Antitumor Immunity Activity against Colon Cancer.

USP7 emerges as a potential therapeutic target for cancers, as it plays an important role in the development of tumorigenesis by stabilizing multiple cancer-relevant proteins. Nevertheless, the discovery of drug-like USP7 inhibitors remains challenging. Herein, we report a series of N-benzylpiperidinol derivatives as potent and selective USP7 inhibitors (e.g., X20 and X26: IC50 = 7.6 and 8.2 nM), whose binding modes were revealed by crystallographic studies to be distinct from the known N-acylpiperidinol USP7 inhibitors. Among them, X36 with good oral PK profiles (rat: F = 40.8% and T1/2 = 3.5 h) exhibited significant antitumor efficacy in the MC38 colon cancer syngeneic mouse model, at least partly through upregulating the tumor infiltration of CD8+ T, NK, and NKT cells and downregulating that of Tregs and MDSCs. These findings may further pave the way for the development of USP7 inhibitors as novel cancer immunotherapy drugs.

Diversity synthesis of indole derivatives via catalyst control cyclization reaction of 2-indolylmethanols and azonaphthalene.

A series of indole-fused scaffolds and derivatives was synthesized via the cyclization reaction of 2-indolylmethanols with azonaphthalene. These reactions were realized under mild reaction conditions through catalyst control, providing structurally diverse indole derivatives with moderate to excellent yields. This protocol also shows good substrate adaptability, especially in six-membered ring products.

Design, Synthesis, and Biological Evaluation of Triazolone Derivatives as Potent PPARα/δ Dual Agonists for the Treatment of Nonalcoholic Steatohepatitis.

Peroxisome proliferator-activator receptors α/δ (PPARα/δ) are regarded as potential therapeutic targets for nonalcoholic steatohepatitis (NASH). However, PPARα/δ dual agonist GFT-505 exhibited poor anti-NASH effects in a phase III clinical trial, probably due to its weak PPARα/δ agonistic activity and poor metabolic stability. Other reported PPARα/δ dual agonists either exhibited limited potency or had unbalanced PPARα/δ agonistic activity. Herein, we report a series of novel triazolone derivatives as PPARα/δ dual agonists. Among them, compound H11 exhibited potent and well-balanced PPARα/δ agonistic activity (PPARα EC50 = 7.0 nM; PPARδ EC50 = 8.4 nM) and a high selectivity over PPARγ (PPARγ EC50 = 1316.1 nM) in PPAR transactivation assays. The crystal structure of PPARδ in complex with H11 revealed a unique PPARδ-agonist interaction. H11, which had excellent PK properties and a good safety profile, showed potent in vivo anti-NASH effects in preclinical models. Together, H11 holds a great promise for treating NASH or other inflammatory and fibrotic diseases.

Comparative Lipid Profile Analysis of Hermetia illucens Larvae Fed Food Waste at Different Days of Age Using an LC-MS-Based Lipidomics Approach.

A lipidomics approach based on liquid chromatography-tandem mass spectrometry (LC-MS) was applied to analyze the molecular-level mechanism of lipid deposition in Hermetia illucens (H. illucens) larvae fed food waste (FW) at different days of age. The H. illucens larvae reared on FW substrates generally became larger, heavier, and fatter at 5-15 d of age. A large amount of glycerolipids (GL) were deposited, while glycerophospholipids (GP), sphingolipids, and derivatized lipids became relatively less abundant during the growth stage of the larvae. Forty-three subclasses of 3,205 lipid molecules were identified in larvae, and 139 lipids (79 upregulated and 60 downregulated during larval growth and development) were identified as potential biomarkers (variable importance in projection > 1; P < 0.05). The differential lipids were mainly enriched in 19 metabolic pathways, of which 9 metabolic pathways related to lipids, including GL and GP metabolisms. The results demonstrate that the lipid composition and mechanisms changed during the growth and development stage of H. illucens larvae. To the best of our knowledge, this is the first work exploring the molecular-level mechanism of lipid deposition during the growth and development stage of H. illucens larvae. The findings provide novel information for determining and utilizing the nutritional value of H. illucens larvae.

Chiral Phosphoric Acid Catalyzed Asymmetric Desymmetrization of para-Quinamines with Isocyanates: Access to Functionalized Imidazolidin-2-one Derivatives.

The development of enantioselective desymmetrization of para-quinamines with isocyanates catalyzed by chiral phosphoric acid is reported. The strategy provides concise access to functionalized imidazolidin-2-one derivatives in high yields and enantioselectivities under mild reaction conditions. Remarkably, this reaction could be performed on a gram scale using 5 mol % catalyst loading and the chiral imidazolidin-2-one derivatives could be easily transformed into valuable scaffolds without disturbing the enantiopurity, demonstrating the synthetic utility of this protocol.

Discovery of Novel Small Molecule Inhibitors Disrupting the PCSK9-LDLR Interaction.

Proprotein convertase subtilisin kexin 9 (PCSK9) has been identified as a reliable therapeutic target for hypercholesterolemia and coronary artery heart diseases since the monoclonal antibodies of PCSK9 have launched. Disrupting the protein-protein interaction (PPI) between PCSK9 and the low-density lipoprotein receptor (LDLR) has been considered as a promising approach for developing PCSK9 inhibitors. However, PPIs have been traditionally considered difficult to target by small molecules since the PPI surface is usually large, flat, featureless, and without a "pocket" or "groove" for ligand binding. The PCSK9-LDLR PPI interface is such a typical case. In this study, a potential binding pocket was generated on the PCSK9-LDLR PPI surface of PCSK9 through induced-fit docking. On the basis of this induced binding pocket, virtual screening, molecular dynamics (MD) simulation, and biological evaluations have been applied for the identification of novel small molecule inhibitors of PCSK9-LDLR PPI. Among the selected compounds, compound 13 exhibited certain PCSK9-LDLR PPI inhibitory activity (IC50: 7.57 ± 1.40 µM). The direct binding affinity between 13 and PCSK9 was determined with a KD value of 2.50 ± 0.73 µM. The LDLR uptake function could be also restored to a certain extent by 13 in HepG2 cells. This well-characterized hit compound will facilitate the further development of novel small molecule inhibitors of PCSK9-LDLR PPI.

Cu-Catalyzed Dimerization of Indole Derived Oxime Acetate for Synthesis of Biimidazo[1,2-a]indoles.

A copper-mediated cyclization and dimerization of indole derived oxime acetate was developed to generate a series of biimidazo[1,2-a]indole scaffolds with two contiguous stereogenic quaternary carbons in one step.

Design, synthesis, and biological evaluation of a novel dual peroxisome proliferator-activated receptor alpha/delta agonist for the treatment of diabetic kidney disease through anti-inflammatory mechanisms.

Diabetic kidney disease (DKD) is a major feature of the final stage of nearly all cause types of diabetes mellitus (DM). To date, few safe and effective drugs are available to treat. Peroxisome proliferator-activated receptors (PPARs), comprised of three members: PPAR-α, PPAR-δ and PPAR-γ, play a protective role in the DKD through glycemic control and lipid metabolism, whereas systemic activation of PPAR-γ causes serious side-effects in clinical trials. GFT505 is a dual PPAR-α/δ agonist, and the selectivity against PPAR-γ is still to be improved. Sulfuretin has been shown to suppress the expression of PPAR-γ and improve the pathogenesis of diabetic complications. In this study, by hybridizing the carboxylic acid of GFT505 and the parent nucleus of sulfuretin, we pioneeringly designed and synthetized a series of novel dual PPAR-α/δ agonists, expecting to provide a better benefit/risk ratio for PPARs. Of all the synthesized compounds, compound 12 was identified with highly activity on PPAR-α/δ and higher selectivity against PPAR-γ than that of GFT505 (EC50: hPPAR-α: 0.26 µM vs.0.76 µM; hPPAR-δ: 0.50 µM vs.0.73 µM; hPPAR-γ: 4.22 µM vs.2.79 µM). The molecular docking studies also depicted good binding affinity of compound 12 for PPAR-α and PPAR-δ compared to GFT505. Furthermore, compound 12 exhibited an evidently renoprotective effect on the DKD through inhibiting inflammatory process, which might at least partly via JNK/NF-κB pathways in vivo and in vitro. Overall, compound 12 hold therapeutic promise for DKD.

Synthesis and anti-inflammatory activity of saponin derivatives of δ-oleanolic acid.

Pentacyclic triterpenes (PTs) are the active ingredients of many medicinal herbs and pharmaceutical formulations, and are well-known for their anti-inflammatory activity. On the other hand, anti-inflammatory effects of AMP-activated protein kinase (AMPK) have recently drawn much attention. In this study, we found that a variety of naturally occurring PTs sapogenins and saponins could stimulate the phosphorylation of AMPK, and identified δ-oleanolic acid (10) as a potent AMPK activator. Based on these findings, 23 saponin derivatives of δ-oleanolic acid were synthesized in order to find more potent anti-inflammatory agents with improved pharmacokinetic properties. The results of cellular assays showed that saponin 29 significantly inhibited LPS-induced secretion of pro-inflammatory factors TNF-α and IL-6 in THP1-derived macrophages. Preliminary mechanistic studies showed that 29 stimulated the phosphorylation of AMPK and acetyl-CoA carboxylase (ACC). The bioavailability of 29 was significantly improved in comparison with its aglycon. More importantly, 29 showed significant anti-inflammatory and liver-protective effects in LPS/D-GalN-induced fulminant hepatic failure mice. Taken together, PTs saponins hold promise as therapeutic agents for inflammatory diseases.

Cobalt doped iron oxychloride as efficient heterogeneous Fenton catalyst for degradation of paracetamol and phenacetin.

Cobalt doped iron oxychloride (Co-FeOCl) was synthesized and employed as catalyst in Fenton degradation of paracetamol (APAP) and phenacetin (PNCT) for the first time. The catalytic performance was evaluated by means of various parameters including catalyst load, hydrogen peroxide (H2O2) dose and pH value. The high removal of APAP (87.5%) and PNCT (76.0%) was obtained under conditions of 0.2 g/L Co-FeOCl and 0.5 mM H2O2 at pH 7.0, with calculated pseudo-first order kinetic constants of 0.031 min-1 for APAP and 0.023 min-1 for PNCT. Particularly, quenching tests and in situ electron spin resonance (ESR) tests were employed for the identification of the reactive oxygen species (ROS) in system. Hydroxyl radical (·OH) and superoxide radical (O2-·) were the primary ROS in Co-FeOCl/H2O2 system. A possible mechanism for H2O2 activation by Co-FeOCl catalyst was proposed as well. Finally, the formation of typical disinfection by-products (DBPs) decreased slightly in Co-FeOCl/H2O2 pre-oxidation. However, stability and reusability of Co-FeOCl were deactivated in the consecutive three cycles.

Reactive oxygen species generation in FeOCl nanosheets activated peroxymonosulfate system: Radicals and non-radical pathways.

Iron oxychloride (FeOCl) is utilized as a activator of peroxymonosulfate (PMS) for the degradation of paracetamol (APAP) and phenacetin (PNCT) in response to the water pollution by persistent pharmaceuticals. The degradation process was well fitted with a pseudo-first order kinetic pattern, and the excellent catalytic performance towards APAP (100 % removal) and PNCT (86.5 % removal) was obtained in the presence of 0.2 g/L FeOCl and 2.0 mM PMS at pH 7.0 in 30 min. In-situ electron spin resonance (ESR) and scavenging tests revealed the generation of a series of ROS (·OH, SO4-, O2-, 1O2), which was highly dependent on pH. Besides, the non-radical pathways process involved 1O2 was dominant in APAP oxidation, while both ·OH and 1O2 are significant in PNCT removal. Furthermore, the formation of disinfection by-products (DBPs) during post-chlorination showed neglectable increment at neutral and alkaline condition with FeOCl/PMS pre-oxidation, and the calculated cytotoxicity would experience a continuous deterioration with pH increase. These results displayed high efficiency of FeOCl/PMS system in micropollutants degradation and a relatively comprehensive activation process of PMS, which may promote practical application in environmental remediation.