Natural Molecules Research Articles

In silico analysis of Cucumis pubescens Willd. fruit extract phytocompounds and its activity against anti-diabetic targets

Diabetes mellitus is a chronic disease which causes complications in a large population worldwide. Traditionally, medicinal plants possess numerous bioactive compounds to treat chronic diseases. In this study, the bioactive compounds in Cucumis pubescens Willd. were screened computationally to treat diabetes. Ten ligand molecules from C. pubescens Willd. plant fruit were selected from GC-MS analysis. The target proteins like Lipase-related Protein 2 (2OXE), α – amylase (2QV4) and β – Glucosidase (2ZOX) were retrieved from the PDB databank. The proteins have been selected based on their role in anti-diabetic activity. All ten ligands were docked with all three proteins to identify the suitable ligand possessing high binding energy. The ligand (4H-Pyran-4-one, 2,3-Dihydro 3,5-Dihydroxy-6-Methyl) had a maximum binding energy of -4.3 kcal/mol and -4.4 kcal/mol with the targets 2OXE and 2ZOX respectively. The ligand molecule 1,4-dimethyl-2,3-diazabicyclo[2.2.1]hept-2-ene produced the highest binding energy of -4.7 kcal/mol with 2QV4. The predicted active phytochemicals can be used as natural drug molecules to treat diabetes mellitus in future.

Stereoselective rhodium-catalyzed reaction of allenes with organoboronic reagents for diversified branched 1,3-alkadienes.

The terminalisoprene unit, as the simplest branched 1,3-diene unit, exists in a wide range of natural products and bioactive molecules. Herein, we report a stereoselective rhodium-catalyzed reaction of allenes with readily available methyl pinacol boronic ester, providing a straightforward approach to isoprene derivatives with a very high E-stereoselectivity. Its synthetic potential has been illustrated by a concise synthesis of natural product schinitrienin. Such a protocol can be easily extended to aryl and alkenyl boronic reagents affording 2-aryl or -alkenyl substituted 1,3-dienes, which are also of high importance in organic synthesis but remain challenging for their selective synthesis, with a remarkable stereoselectivity. A series of deuterium-labeling experiments indicate a unique mechanism, which involves reversible β-H elimination as well as hydrometalation and isomerization of the allylic rhodium species.

Natural Binary Herbal Small Molecules Self-Assembled Nanogel for Synergistic Inhibition of Respiratory Syncytial Virus.

Respiratory syncytial virus (RSV) is one of the most significant pathogenic infections in childhood, associated with high morbidity and mortality rates. Currently, there is no effective and safe drug or vaccine available for RSV. Glycyrrhizic acid (GA), an active compound derived from the natural herb licorice, has been reported to provide protection against influenza and coronaviruses, exhibiting notable antiviral and anti-inflammatory properties. Ephedrine (EPH) is a commonly prescribed medication for the treatment of cough and asthma, and it also demonstrates certain antiviral effects. In this study, EPH and GA were combined to form an efficient nanomaterial (EPH-GA nanogel). The self-assembly of this nanogel is driven by hydrogen bonding and hydrophobic interactions, allowing it to serve as an antiviral nanomedicine without the need for a dual-component carrier, achieving a 100% drug loading efficiency. Oral administration of the EPH-GA nanogel significantly reduced viral load in the lungs of mice and improved lung lesions and tissue infiltration caused by RSV. Notably, we discovered that the assembled drug may create a "physical barrier" that prevents RSV from adsorbing to host cells, while free GA and EPH may compete with RSV for protein binding sites, thereby enhancing cellular uptake of EPH. Consequently, this prevents RSV infection and proliferation within host cells. Furthermore, the EC50 values changed from 310.83 μM for EPH and 262.88 μM for GA to 68.25 μM for the EPH-GA combination, with a combination index of 0.458. In addition, the in vivo biopharmaceutic process of GA and EPH was investigated, revealing that the oral administration of EPH-GA significantly increased the bioavailability of EPH while maintaining its plasma concentration at a relatively stable level. This enhancement may contribute to a synergistic antiviral effect when combined with GA. Furthermore, the in vivo process of EPH-GA demonstrates the advantage of delivering the drug to the lesion at elevated levels, thereby facilitating its antiviral mechanism at the cellular level. In this study, we identified an effective nanomedicine, EPH-GA nanogel, which can inhibit the proliferation of RSV and mitigate lung lesions resulting from viral infection by influencing the biopharmaceutical process in vivo. This research not only offers a novel strategy for the nanomedicine treatment of RSV but also elucidates, to some extent, the compatibility mechanisms of the multicomponents of traditional Chinese medicine.

Identification of a Fomitopsis pinicola from Xiaoxing’an Mountains and Optimization of Cellulase Activity

Brown-rot fungi are large fungi that can decompose the cell walls of wood; they are notable for their secretion of diverse and complex enzymes that synergistically hydrolyze natural wood cellulose molecules. Fomitopsis pinicola (F. pinicola) is a brown-rot fungus of interest for its ability to break down the cellulose in wood efficiently. In this study, through a combination of rDNA-ITS analysis and morphological observation, the wood decay pathogen infecting Korean pine (Pinus koraiensis Siebold and Zucc.) was identified. Endoglucanase (CMCase) and β-glucosidase were quantified using the DNS (3,5-Dinitrosalicylic acid) method, and the cellulase activity was optimized using a single-factor method and orthogonal test. The results revealed that the wood-decaying fungus NE1 identified was Fomitopsis pinicola with the ITS accession number OQ880566.1. The highest cellulase activity of the strain reached 116.94 U/mL under the condition of an initial pH of 6.0, lactose 15 g·L−1, KH2PO4 0.5 g·L−1, NH4NO3 15 g·L−1, MgSO4 0.5 g·L−1, VB1 0.4 g·L−1, inoculated two 5 mm fungal cakes in 80 mL medium volume cultured 28 °C for 5 days. This laid a foundation for improving the degradation rate of cellulose and biotransformation research, as well as exploring the degradation of cellulose by brown rot fungi.

Natural small molecule compounds targeting Wnt signaling pathway inhibit HPV infection

BackgroundHigh-risk human papillomavirus (HPV) infection is a major risk factor of HPV-related tumors, especially cervical cancer. To date, there is no specific drug for the treatment of HPV infection. PurposeTo explore the role of canonical Wnt signaling pathway in HPV16 infection and to screen inhibitors against HPV16 infection from natural small molecule compounds targeting the canonicalWnt pathway. MethodsWnt pathway inhibitor IWP-2 and FH535 were used to inhibit Wnt/β-catenin signaling pathway. HPV16-GFP pseudovirus infectivity were analyzed by fluorescence microscopy and fluorescence activated cell sorting. A small molecule screening of a total of CFDA-approved 29 natural compounds targeting the Wnt pathway was performed. ResultsWnt signaling pathway inhibitor suppressed HPV16-GFP pseudovirus infection in HaCat cells. Natural small molecule compounds screening identified 6-Gingerol, gossypol, tanshinone II2A, and EGCG as inhibitors of HPV16-GFP pseudovirus infection. ConclusionWnt signaling pathway is involved in the process of HPV infection of host cells. 6-Gingerol, gossypol, tanshinone II2A, and EGCG inhibited HPV16-GFP pseudovirus infection and suppressed Wnt/β-catenin pathway in HaCat cells.

A new catalyst derived from the sulfur-doped metal-organic framework for Fenton-like reaction

Fenton-like reaction exhibits considerable advantages in the remediation of pollutants. To fabricate an efficient catalyst becomes an issue concerning the performance enhancement in Fenton-like reaction. Herein, S-Fe-MOF-400 which was derived from a sulfur-doped metal-organic framework (Fe-MOF), was newly prepared and exhibited high ability for H2O2 activation during Fenton-like reaction. The results showed that the sulfurization effectively reduced the charge transfer resistance (Rct) of S-Fe-MOF-400, and facilitated the charge transfer, consequently enhancing the catalytic performance of S-Fe-MOF-400 in the Fenton-like reaction. XRD analysis revealed that FeS2 was the predominant reactive component in S-Fe-MOF-400 with a regular cubic structure and pronounced crystallinity. Additionally, the presence of low-valent sulfur ensured the availability of Fe (II), thereby facilitating the occurrence of the Fenton reaction. Under optimal conditions, the removal efficiency of pollutants reached 86.7 % within 60 min, resulting in total organic carbon (TOC) removal efficiency at 40.6 %. Quenching experiments and electron paramagnetic resonance (EPR) detections revealed that •OH, 1O2, and O2•− synergistically participated in the Fenton-like reaction, with •OH being the primary active species. The activation process of H2O2 induced by S-Fe-MOF-400 mainly yielded hydroxyl radicals and superoxide radicals. The 1O2 was generated through two following pathways: (i) the transformation of superoxide and hydroxyl radicals, and (ii) the conversion of natural oxygen molecules (O2). This current study illustrated the significant potential for the application of sulfur-modified Fe-MOF in the Fenton-like reaction for pollutant removal.

Photocatalytic PPh3-Mediated Synthesis of C3-Functionalized Indoles via Radical Annulation of Nitroarenes and Alkenes.

Oxidatively generated phosphine radical cations are reactive intermediates that can be used for the generation of carbon and heteroatom centered radicals via deoxygenation processes. Such P-radical cations can readily be generated via single electron transfer oxidation using a redox catalyst. Cheap and commercially available nitroarenes are ideal nitrogen sources for the construction of organic amines and N-containing heterocycles. Activation of nitroarenes with phosphines has been achieved in the ionic mode, which requires specially designed P-nucleophiles and high temperatures. Herein, we report an alternative mode of nitro activation that proceeds via a radical process. The radical strategy leads to open shell intermediates that show interesting unexplored reactivity. This is documented by the development of an economic and highly efficient synthesis of valuable indole derivatives through photocatalytic PPh3-mediated annulation of nitroarenes with alkenes showing large functional group tolerance. The method allows room-temperature activation of nitroarenes and a double C-H bond functionalization of alkenes is achieved to provide rapid access to C3-functionalized indoles, which are key structural components of diverse natural and drug molecules. Experimental mechanistic studies that are further supported by DFT calculations indicate that a nitrosoarene radical cation plays a key role in the annulation process.

Antioxidant Activities of Exopolysaccharides Extracts from Two Endemic Fungi from Patagonia.

A great number of free radicals have a negative impact on the human body, and an increased interest in the identification of new natural molecules with antioxidant properties has emerged due to concerns about synthetic antioxidants. Here, the antioxidant effect of four exo-polysaccharides (EPS) extracts obtained from submerged cultivation of Nothophellinus andinopatagonicus and Pseudoinonotus crustosus (N and P, respectively) in two culture media (M1 and M2) at 2 concentrations (100 and 250µg/ml) was studied; then, its relation with the chemical composition of the EPS was evaluated. To assess the antioxidant activities of the extracts, several in vitro assays were performed: DPPH and ABTS radical scavenging, ferric-reducing antioxidant power, chelating ability on ferrous ions, and inhibition of the lipid peroxidation. The concentrations tested here were much lower than those reported in previous works. Despite variations in chemical composition and monosaccharide profiles among the extracts, all demonstrated antioxidant activity, although the type of activity differed; only P-M1 exhibited a good antioxidant activity across all assays. This extract contained the highest proportion of phenolic compounds, and also displayed the highest radical scavenging activity. Although the utilization of polysaccharides as functional food ingredients remains limited, we propose P-M1 as a promising candidate for a nutraceutical product. Additionally, a formulation could be made with a combination of extracts to create an antioxidant-rich supplement. Additional research is needed to confirm our findings in a cellular environment and to elucidate the mechanisms that drive their antioxidant activities, ultimately facilitating their development and utilization as nutraceutical products.

Exploring Chemical Space to Identify Partial Binders Against hMPV Nucleocapsid Protein.

Human metapneumovirus (hMPV) has gained prominence in recent times as the predominant etiological agent of acute respiratory tract infections. This virus targets children, the elderly, and individuals with compromised immune systems. Given the protracted duration of hMPV transmission, it is probable that the majority of children will have acquired the virus by the age of 5. In individuals with compromised immune systems, recurrence of hMPV infection is possible. As hMPV matures, it remains latent from the time of acquisition. The genome of hMPV encompasses a pivotal protein referred to as the nucleocapsid protein (N). This protein assumes the form of a left-handed helical nucleocapsid, enveloping the viral RNA genome. The primary function of this structure is to protect nucleases, rendering it a potentially promising target for therapeutic advancements. The present study employs a methodology that involves structure-based virtual screening, followed by molecular dynamics simulation at a 250-ns time scale, to identify potential natural molecules or their derivatives from the ZINC Database. These molecules are investigated for their binding properties against the hMPV nucleoprotein. Based on an evaluation of the docking score, binding site interaction, and molecular dynamics studies, it has been found that two naturally occurring molecules, namely M1 (ZINC85629735) and M3 (ZINC85569125), have shown notable docking scores of -9.6and -10.7 kcal/mol, acceptable RMSD, RMSF, Rg, and soon calculated from molecular dynamics trajectory associated with MMGBSA binding energy of -81.94 and -99.63 kcal/mol, respectively. These molecules have shown the highest binding affinity towardnucleocapsid protein and demonstrated promising attributes as potential binders against hMPV.

Treatment with Epigallocatechin Gallate, Folic Acid, Vitamin B12, and Hyaluronic Acid Decreases HPV Positivity in Women Attending Regional Screening in Puglia.

Human Papillomavirus (HPV) infection represents a global health concern. HPV infects the mucosa, particularly in the uterine cervix, where it may establish a persistent infection, exposing women to a risk of developing cancer. The available treatments include surgery or topic solutions, while a systemic treatment is still unavailable. In recent years, natural molecules such as epigallocatechin gallate (EGCG), folic acid (FA), vitamin B12, and hyaluronic acid (HA) gained importance as innovative therapies for HPV. We enrolled 163 women with a positive HPV DNA test or previous history of HPV infections, and a PAP test indicating LSIL/AGUS/ASCUS cytology. The patients in the treatment group (n = 86) received an oral combination of EGCG 200 mg, FA 400 µg, vitamin B12 1 mg, and HA 50 mg (1 cps/day) for 3 months (T1), while the control group (n = 77) underwent standard clinical surveillance. Both groups repeated a PAP test and an HPV DNA test after 3 (T1) months, and another PAP test after 6 months (T2) as a follow up. The treatment group experienced a significant reduction in HPV positivity at T1 compared to the control group. Moreover, the treatment group exhibited an improvement in cervical lesions either at T1 (p < 0.0001) or T2 (p < 0.00001).

Structure based exploration of mitochondrial alpha carbonic anhydrase inhibitors as potential leads for anti-obesity drug development.

Obesity has emerged as a major health challenge globally in the last two decades. Dysregulated fatty acid metabolism and de novo lipogenesis are prime causes for obesity development which ultimately trigger other co-morbid pathological conditions thereby risking life longevity. Fatty acid metabolism and de novo lipogenesis involve several biochemical steps both in cytosol and mitochondria. Reportedly, the high catalytically active mitochondrial carbonic anhydrases (CAVA/CAVB) regulate the intercellular depot of bicarbonate ions and catalyze the rapid carboxylation of pyruvate and acetyl-co-A to acetyl-co-A and malonate respectively, which are the precursors of fatty acid synthesis and lipogenesis. Several in vitro and in vivo investigations indicate inhibition of mitochondrial carbonic anhydrase isoforms interfere in the functioning of pyruvate, fatty acid and succinate pathways. Targeting of mitochondrial carbonic anhydrase isoforms (CAVA/CAVB) could thereby modulate gluconeogenetic as well as lipogenetic pathways and pave way for designing of novel leads in the development pipeline of anti-obesity medications. The present review unveils a diverse chemical space including synthetic sulphonamides, sulphamates, sulfamides and many natural bioactive molecules which selectively inhibit the mitochondrial isoform CAVA/CAVB with an emphasis on major state-of-art drug design strategies. More than 60% similarity in the structural framework of the carbonic anhydrase isoforms has converged the drug design methods towards the development of isoform selective chemotypes. While the benzene sulphonamide derivatives selectively inhibit CAVA/CAVB in low nanomolar ranges depending on the substitutions on the phenyl ring, the sulpamates and sulpamides potently inhibit CAVB. The virtual screening and drug repurposing methods have also explored many non-sulphonamide chemical scaffolds which can potently inhibit CAVA. The review could pave way for the development of novel and effective anti-obesity drugs which can modulate the energy metabolism.

TRPML1 gating modulation by allosteric mutations and lipids.

Transient Receptor Potential Mucolipin 1 (TRPML1) is a lysosomal cation channel whose loss-of-function mutations directly cause the lysosomal storage disorder mucolipidosis type IV (MLIV). TRPML1 can be allosterically regulated by various ligands including natural lipids and small synthetic molecules and the channel undergoes a global movement propagated from ligand-induced local conformational changes upon activation. In this study, we identified a functionally critical residue, Tyr404, at the C-terminus of the S4 helix, whose mutations to tryptophan and alanine yield gain- and loss-of-function channels, respectively. These allosteric mutations mimic the ligand activation or inhibition of the TRPML1 channel without interfering with ligand binding and both mutant channels are susceptible to agonist or antagonist modulation, making them better targets for screening potent TRPML1 activators and inhibitors. We also determined the high-resolution structure of TRPML1 in complex with the PI(4,5)P2 inhibitor, revealing the structural basis underlying this lipid inhibition. In addition, an endogenous phospholipid likely from sphingomyelin is identified in the PI(4,5)P2-bound TRPML1 structure at the same hotspot for agonists and antagonists, providing a plausible structural explanation for the inhibitory effect of sphingomyelin on agonist activation.

Synthesis of Non-canonical Tryptophan Variants via Rh-catalyzed C-H Functionalization of Anilines.

Tryptophan and its non-canonical variants play critical roles in pharmaceutical molecules and enzymes. Facile access to this privileged class of amino acids from readily available building blocks remains a long-standing challenge. Here, we report a regioselective synthesis of non-canonical tryptophans bearing C4-C7 substituents via Rh-catalyzed annulation between structurally diverse tert-butyloxycarbonyl (Boc)-protected anilines and alkynyl chlorides readily prepared from amino acid building blocks. This transformation harnesses Boc-directed C-H metalation and demetalation to afford a wide range of C2-unsubstituted indole products in a redox-neutral fashion. This umpolung approach compared to the classic Larock indole synthesis offers a novel mechanism for heteroarene annulation and will be useful for the synthesis of natural products and drug molecules containing non-canonical tryptophan residues in a highly regioselective manner.

Phytic acid-loaded polyvinyl alcohol hydrogel promotes wound healing of injured corneal epithelium through inhibiting ferroptosis

As the important barrier of intraocular tissue, cornea is easy to suffer various kinds of injuries. Among them, acute alkali burn is a thorny ophthalmic emergency event, which can lead to corneal persistent epithelial defects, ulcers, and even perforation. Ferroptosis, a mode of regulatory cell death, has been found to play a key role in the process of corneal alkali burn, of which lipid peroxidation and intracellular iron levels are considered to be the possible therapeutic targets. To seek new effective treatments, the study herein focused on the occurrence of oxidative stress and ferroptosis in corneal alkali burn, exploring the role of phytic acid (PA), a natural small molecule with both antioxidant and iron chelating capacity, in the repair of corneal epithelial injury. The in vivo therapeutic results showed that PA eyedrops treatment promoted the recovery of corneal morphology and function, and in vitro experiments proved that PA prompted the repair of oxidative stress induced-corneal epithelial injury through ferroptosis inhibition. In addition, better drug treatment effect could be achieved through hydrogel delivery and sustained release, and our in vivo experiments showed the superior therapeutic effects of PA delivered by PVA hydrogels with larger molecular weights on corneal injury. In summary, this study demonstrated the excellent effect of natural small molecule PA with antioxidant and high efficiency chelating ferrous ions on ferroptosis inhibition, and showed the outstanding application prospect of PVA/PA hydrogels in the treatment of corneal epithelial injury.

Ellagic acid-enhanced biocompatibility and bioactivity in multilayer core-shell gold nanoparticles for ameliorating myocardial infarction injury

BackgroundMyocardial infarction (MI) is the main contributor to most cardiovascular diseases (CVDs), and the available post-treatment clinical therapeutic options are limited. The development of nanoscale drug delivery systems carrying natural small molecules provides biotherapies that could potentially offer new treatments for reactive oxygen species (ROS)-induced damage in MI. Considering the stability and reduced toxicity of gold-phenolic core-shell nanoparticles, this study aims to develop ellagic acid-functionalized gold nanoparticles (EA-AuNPs) to overcome these limitations.ResultsWe have successfully synthesized EA-AuNPs with enhanced biocompatibility and bioactivity. These core-shell gold nanoparticles exhibit excellent ROS-scavenging activity and high dispersion. The results from a label-free imaging method on optically transparent zebrafish larvae models and micro-CT imaging in mice indicated that EA-AuNPs enable a favorable excretion-based metabolism without overburdening other organs. EA-AuNPs were subsequently applied in cellular oxidative stress models and MI mouse models. We found that they effectively inhibit the expression of apoptosis-related proteins and the elevation of cardiac enzyme activities, thereby ameliorating oxidative stress injuries in MI mice. Further investigations of oxylipin profiles indicated that EA-AuNPs might alleviate myocardial injury by inhibiting ROS-induced oxylipin level alterations, restoring the perturbed anti-inflammatory oxylipins.ConclusionsThese findings collectively emphasized the protective role of EA-AuNPs in myocardial injury, which contributes to the development of innovative gold-phenolic nanoparticles and further advances their potential medical applications.Graphical

Salsoline derivatives, genistein, semisynthetic derivative of kojic acid, and naringenin as inhibitors of A42R profilin-like protein of monkeypox virus: in silico studies.

Monkeypox virus (MPV) infection has developed into a re-emerging disease, and despite the potential of tecovirimat and cidofovir drugs, there is currently no conclusive treatment. The treatment's effectiveness and cost challenges motivate us to use In Silico approaches to seek natural compounds as candidate antiviral inhibitors. Using Maestro 11.5 in Schrodinger suite 2018, available natural molecules with validated chemical structures collected from Eximed Laboratory were subjected to molecular docking and ADMET analysis against the highly conserved A42R Profilin-like Protein of Monkeypox Virus Zaire-96-I-16 (PDB: 4QWO) with resolution of 1.52Å solved 3D structure. Compared to the FDA-approved Tecovirimat, molecular docking revealed that Salsoline derivatives, Genistein, Semisynthetic derivative of kojic acid, and Naringenin had strengthened affinity (-8.9 to -10kcal/mol) to 4QWO, and the molecular dynamic's simulation confirmed their high binding stability. In support of these results, the hydrogen bond analysis indicated that the Salsoline derivative had the most robust interaction with the binding pockets of 4QWO among the four molecules. Moreover, the comparative free energy analyses using MM-PBSA revealed an average binding free energy of the complexes of Salsoline derivative, Genistein, Semisynthetic derivative of kojic acid, Naringenin, of -106.418, -46.808, -50.770, and -63.319kJ/mol, respectively which are lower than -33.855kJ/mol of the Tecovirimat complex. Interestingly, these results and the ADMET predictions suggest that the four compounds are promising inhibitors of 4QWO, which agrees with previous results showing their antiviral activities against other viruses.

Radiolabeled Probes from Derivatives of Natural Compounds Used in Nuclear Medicine.

Natural compounds are important precursors for the synthesis of new drugs. The development of novel molecules that are useful for various diseases is the main goal of researchers, especially for the diagnosis and treatment of many diseases. Some pathologies need to be treated with radiopharmaceuticals, and, for this reason, radiopharmaceuticals that use the radiolabeling of natural derivates molecules are arousing more and more interest. Radiopharmaceuticals can be used for both diagnostic and therapeutic purposes depending on the radionuclide. β+- and gamma-emitting radionuclides are used for diagnostic use for PET or SPECT imaging techniques, while α- and β--emitting radionuclides are used for in metabolic radiotherapy. Based on these assumptions, the purpose of this review is to highlight the studies carried out in the last ten years, to search for potentially useful radiopharmaceuticals for nuclear medicine that use molecules of natural origin as lead structures. In this context, the main radiolabeled compounds containing natural products as scaffolds are analyzed, in particular curcumin, stilbene, chalcone, and benzofuran. Studies on structural and chemical modifications are emphasized in order to obtain a collection of potential radiopharmaceuticals that exploit the biological properties of molecules of natural origin. The radionuclides used to label these compounds are 68Ga, 44Sc, 18F, 64Cu, 99mTc, and 125I for diagnostic imaging.

Vicinal Difunctionalization of Unactivated Alkenes Through Radical Addition/Remote (Hetero)Aryl Migration Cascade

Alkenes are ubiquitous in natural and synthetic molecules and constitute versatile building blocks. Remarkably, their radical 1,2‐difunctionalization offers a valuable synthetic tool for rapidly accessing multifunctional compounds through a step and atom‐ economy process. More particularly, the addition of (hetero)aromatic groups onto alkenes is of particular appeal given the numerous applications of aromatic compounds in various fields. However, such process becomes difficult when attempted on simple non‐conjugated aliphatic alkenes (unactivated alkenes). In this context, the (hetero)arylation of unactivated alkenes through the radical functionalization followed by remote (hetero)aryl migration has recently emerged as a powerful opportunity to address the lack of reactivity of such π systems. The advances in radical chemistry have led to a flood of synthetic methods to trigger the addition of a carbon‐ or heteroatom‐centered radical/(hetero)aryl migration sequence. Interestingly, the migration of the aromatic ring can take place from various atoms. This feature has spurred the design of several substrates allowing such a process to occur. This review intends to provide an overview of the contributions according to the type of substrates that have been employed. The reaction scope, limitations and mechanistic aspects will be discussed with the aim of stimulating efforts in this research area.

Hypocrellin A against intrahepatic Cholangiocarcinoma via multi-target inhibition of the PI3K-AKT-mTOR, MAPK, and STAT3 signaling pathways

BackgroundIntrahepatic cholangiocarcinoma (ICC) is an aggressive and highly lethal cancer with an increasing incidence worldwide that lacks effective treatment regimens. Hypocrellin A (HA), a natural small compound isolated from S. bambusicola, has multiple biomedical activities, including antitumor activity. PurposeWe intended to investigate the therapeutic effects of HA on ICC and its potential mechanisms. MethodsRBE and HuccT1 cell lines were utilized for in vitro experiments. CCK8 assay, colony formation analysis, RTCA, and immunofluorescence staining of ki67 were employed to evaluate the suppression effects of HA on proliferation. The inhibitory effects of HA on cell migration and invasion were evaluate through transwell and wound healing assays, and Hoechst 33,258 staining was performed to evaluate apoptosis. Additionally, we performed transcriptome sequencing and molecular docking for targeting identification, and immunoblotting and immunofluorescence of key molecules for validation. Two in vivo models, HuccT1 xenografts, and the primary ICC model (KRAS/P19/SB) established via hydrodynamic tail-vein injection were implemented. Multiplex immunohistochemistry (mIHC) was used to illustrate the multi-target inhibitory effects of HA. ResultsThe IC50 values of HA against RBE and HuccT1 cells were 4.612 μM and 10.01 μM for 24 h, as determined through the CCK8 assay. Our results confirmed that HA significantly repressed the proliferation, migration, invasion, and promoted the apoptosis of ICC cells at low concentrations. Moreover, HA exerted its anti-cancer effects through multi-target inhibition of the PI3K-AKT-mTOR, MAPK, and STAT3 signaling pathways. This inhibitory effect was rescued by Recilisib, an activator of the PI3K-AKT-mTOR pathway. Bioinformatics analysis of a multi-center RNA-Seq cohort (n = 90) demonstrated significant associations between these target pathways and the occurrence and poor prognosis of ICC. Animal studies suggested that HA strongly inhibited tumor growth in xenograft ICC models, and repressed the tumor number and size in the liver of primary ICC models by suppressing these three crucial pathways. ConclusionHA, a novel natural small molecule, demonstrated promising therapeutic efficacy against ICC through its multi-target inhibitory effects on the PI3K-AKT-mTOR, MAPK, and STAT3 signaling pathways. Moreover, it exhibited notable therapeutic benefits in a primary ICC model (KRAS/P19/SB), positioning it as a novel therapeutic agent for ICC.

Atroposelective Synthesis of Axial Biaryls by Dynamic Kinetic Resolution Using Engineered Imine Reductases

AbstractAxially chiral biaryl compounds are ubiquitous scaffolds in natural products, bioactive molecules, chiral ligands and catalysts, but biocatalytic methods for their asymmetric synthesis are limited. Herein, we report a highly efficient biocatalytic route for the atroposelective synthesis of biaryls by dynamic kinetic resolution (DKR). This DKR approach features a transient six‐membered aza‐acetal‐bridge‐promoted racemization followed by an imine reductase (IRED)‐catalyzed stereoselective reduction to construct the axial chirality under ambient conditions. Directed evolution of an IRED from Streptomyces sp. GF3546 provided a variant (S‐IRED‐Ss‐M11) capable of catalyzing the DKR process to access a variety of biaryl aminoalcohols in high yields and excellent enantioselectivities (up to 98 % yield and &gt;99 : 1 enantiomeric ratio). Molecular dynamics simulation studies on the S‐IRED‐Ss‐M11 variant revealed the origin of its improved activity and atroposelectivity. By exploiting the substrate promiscuity of IREDs and the power of directed evolution, our work further extends the biocatalysts’ toolbox to construct challenging axially chiral molecules.