Exploration and structure-activity relationship research of benzenesulfonamide derivatives as potent TRPV4 inhibitors for treating acute lung injury.

RN-9893, a TRPV4 antagonist identified by Renovis Inc., showcased notable inhibition of TRPV4 channels. This research involved synthesizing and evaluating three series of RN-9893 analogues for their TRPV4 inhibitory efficacy. Notably, compounds 1b and 1f displayed a 2.9 to 4.5-fold increase in inhibitory potency against TRPV4 (IC50 = 0.71 ± 0.21 µM and 0.46 ± 0.08 µM, respectively) in vitro, in comparison to RN-9893 (IC50 = 2.07 ± 0.90 µM). Both compounds also significantly outperformed RN-9893 in TRPV4 current inhibition rates (87.6 % and 83.2 % at 10 µM, against RN-9893's 49.4 %). For the first time, these RN-9893 analogues were profiled in an in vivo mouse model, where intraperitoneal injections of 1b or 1f at 10 mg/kg notably mitigated symptoms of acute lung injury induced by lipopolysaccharide (LPS). These outcomes indicate that compounds 1b and 1f are promising candidates for acute lung injury treatment.

Novel Scaffold Agonists of the α2A Adrenergic Receptor Identified via Ensemble-Based Strategy.

The α2A adrenergic receptor (α2A-AR) serves as a critical molecular target for sedatives and analgesics. However, α2A-AR ligands with an imidazole ring also interact with an imidazoline receptor as well as other proteins and lead to undesirable effects, motivating us to develop more novel scaffold α2A-AR ligands. For this purpose, we employed an ensemble-based ligand discovery strategy, integrating long-term molecular dynamics (MD) simulations and virtual screening, to identify new potential α2A-AR agonists with novel scaffold. Our results showed that compounds SY-15 and SY-17 exhibited significant biological effects in the preliminary evaluation of protein kinase A (PKA) redistribution assays. They also reduced levels of intracellular cyclic adenosine monophosphate (cAMP) in a dose-dependent manner. Upon treatment of the cells with 100 µM concentrations of SY-15 and SY-17, there was a respective decrease in the intracellular cAMP levels by 63.43% and 53.83%. Subsequent computational analysis was conducted to elucidate the binding interactions of SY-15 and SY-17 with the α2A-AR. The binding free energies of SY-15 and SY-17 calculated by MD simulations were -45.93 and -71.97 kcal/mol. MD simulations also revealed that both compounds act as bitopic agonists, occupying the orthosteric site and a novel exosite of the receptor simultaneously. Our findings of integrative computational and experimental approaches could offer the potential to enhance ligand affinity and selectivity through dual-site occupancy and provide a novel direction for the rational design of sedatives and analgesics.

Design of Photosensitive Cobalt Complex Intermediates and Their Application in the Green Syntheses of Molecules Containing the Quinazolin-4(3H)-imine Scaffold.

Cobalt/photoredox cooperative catalysis is a well-explored technology for visible-light photoredox catalysis. Recently, the photosensitivity of Co(II) complexes in homogeneous catalysis has aroused the interest of scientists. In this study, photosensitive Co(II) complex intermediates were designed to develop new synthetic methods. These intermediates, consisting of Co(II) and two substrate molecules, bind to O2 and absorb visible light over a wide spectral range, triggering in situ oxidative decarboxylation to produce molecules containing the quinazolin-4(3H)-imine scaffold. These reactions employed glyoxylic acid and ketoacids as new building blocks, and good to excellent yields of the corresponding products were obtained under mild reaction conditions using green and inexpensive reagents and solvents. These results are of importance since the design of Co-based photosensitive intermediates will aid in establishing novel methods for harnessing visible light and hence lead to innovation in organic syntheses.

Beneficial Effects of Theaflavins on Metabolic Syndrome: From Molecular Evidence to Gut Microbiome.

In recent years, many natural foods and herbs rich in phytochemicals have been proposed as health supplements for patients with metabolic syndrome (MetS). Theaflavins (TFs) are a polyphenol hydroxyl substance with the structure of diphenol ketone, and they have the potential to prevent and treat a wide range of MetS. However, the stability and bioavailability of TFs are poor. TFs have the marvelous ability to alleviate MetS through antiobesity and lipid-lowering (AMPK-FoxO3A-MnSOD, PPAR, AMPK, PI3K/Akt), hypoglycemic (IRS-1/Akt/GLUT4, Ca2+/CaMKK2-AMPK, SGLT1), and uric-acid-lowering (XO, GLUT9, OAT) effects, and the modulation of the gut microbiota (increasing beneficial gut microbiota such as Akkermansia and Prevotella). This paper summarizes and updates the bioavailability of TFs, and the available signaling pathways and molecular evidence on the functionalities of TFs against metabolic abnormalities in vitro and in vivo, representing a promising opportunity to prevent MetS in the future with the utilization of TFs.

Discovery of Novel Non-Oxime Reactivators Showing In Vivo Antidotal Efficiency for Sarin Poisoned Mice.

A family of novel efficient non-oxime compounds exhibited promising reactivation efficacy for VX and sarin inhibited human acetylcholinesterase was discovered. It was found that aromatic groups coupled to Mannich phenols and the introduction of imidazole to the ortho position of phenols would dramatically enhance reactivation efficiency. Moreover, the in vivo experiment was conducted, and the results demonstrated that Mannich phenol L10R1 (30 mg/kg, ip) could afford 100% 48 h survival for mice of 2*LD50 sarin exposure, which is promising for the development of non-oxime reactivators with central efficiency.

Combined scaffold hopping, molecular screening with dynamic simulation to screen potent CRBN ligands.

Thalidomide and its derivatives lenalidomide and pomalidomide, known as immunomodulatory drugs, (IMiDs) bind directly to cereblon (CRBN), a substrate receptor of an E3 ubiquitin ligase, resulting in the rapid ubiquitination and degradation of the substrate protein. With the discovery of the protein degradation mechanism of IMiDs, targeted protein degradation mediated by IMiDs via CRBN emerged and developed rapidly for the advantages of overcoming drug resistance and targeting undruggable. To date, almost all CRBN ligands are derived from thalidomide and there are few structural differences between them. Hence, we employed an accurate, effective, and rational approach to screen novel and potential CRBN ligands. In this study, we have built a molecular library by scaffold hopping with thalidomide. ADMET screening, virtual screening, and visual inspection screening were performed step-by-step to screen the molecular library and five molecules were hit. Furthermore, docking analysis and a period of 150 ns molecular dynamic (MD) simulation were performed to validate the accuracy of our screen. The docking results showed that molecular A (-10.42 kcal/mol), molecular B (-9.73 kcal/mol), molecular C (-9.25 kcal/mol), molecular D (-9.09 kcal/mol), and molecular E (-10.16 kcal/mol) have lower binding energy than thalidomide (-5.42 kcal/mol), lenalidomide (-5.74 kcal/mol), and pomalidomide (-5.51 kcal/mol). In the MD simulation, all the five screened molecules form key interactions with the active site amino acid residues (Trp380, Trp386, and Trp400) as well as the three marketed IMiDs. Besides, we found and explained that Pro352 was positive for ligand binding to CRBN and Glu377 in reverse, which has not been reported before. We believe that our findings and those five molecules can serve as further optimization of CRBN ligands and development of proteolysis targeting chimeras.

The effect of structural modification of antimicrobial peptides on their antimicrobial activity, hemolytic activity, and plasma stability.

In this article, a series of modifications were made on an antimicrobial peptide F2,5,12 W, including altering the amino acid sequence, introducing cysteine and other typical amino acids, developing peptide dimers via disulfide bonds, and conjugating with mPEG, in order to enhance the antimicrobial activity, plasma stability, and reduce the hemolytic activity of peptides. The results showed that mPEG conjugation could significantly improve the plasma stability and reduce the hemolytic activity of peptides, while the antimicrobial activity decreased meanwhile. However, altering the sequence of the peptide without changing its amino acid composition had little impact on its antimicrobial activity and plasma stability. The introduction of cysteine enhanced the plasma stability of peptides conspicuously, but at the same time, the increased hydrophobicity of peptides increased their hemolysis. The antimicrobial mechanism and cytotoxicity of the peptides with relatively high antimicrobial activity were also studied. In general, this study provided some ideas for the rational design and structure optimization of antimicrobial peptides.

Gene Expression Profiling and Biofunction Analysis of HepG2 Cells Targeted by Crocetin.

Crocetin is a carotenoid extracted from Gardenia jasminoides, one of the most popular traditional Chinese medicines, which has been used in the prevention and treatment of various diseases. The present study is aimed at clarifying the effect of crocetin on gene expression profiling of HepG2 cells by RNA-sequence assay and further investigating the molecular mechanism underlying the multiple biofunctions of crocetin based on bioinformatics analysis and molecular evidence. Among a total 23K differential genes identified, crocetin treatment upregulated the signals of 491 genes (2.14% of total gene probes) and downregulated the signals of 283 genes (1.24% of total gene probes) by ≥2-fold. The Gene Ontology analysis enriched these genes mainly on cell proliferation and apoptosis (BRD4 and DAXX); lipid formation (EHMT2); cell response to growth factor stimulation (CYP24A1 and GCNT2); and growth factor binding (ABCB1 and ABCG1), metabolism, and signal transduction processes. The KEGG pathway analysis revealed that crocetin has the potential to regulate transcriptional misregulation, ABC transporters, bile secretion, alcoholism, systemic lupus erythematosus (SLE), and other pathways, of which SLE was the most significantly disturbed pathway. The PPI network was constructed by using the STRING online protein interaction database and Cytoscape software, and 21 core proteins were obtained. RT-qPCR datasets serve as the solid evidence that verified the accuracy of transcriptome sequencing results with the same change trend. This study provides first-hand data for comprehensively understanding crocetin targeting on hepatic metabolism and its multiple biofunctions.

Dihydromyricetin Acts as a Potential Redox Balance Mediator in Cancer Chemoprevention.

Dihydromyricetin (DHM) is a flavonoid extracted from the leaves and stems of the edible plant Ampelopsis grossedentata that has been used for Chinese Traditional Medicine. It has attracted considerable attention from consumers due to its beneficial properties including anticancer, antioxidative, and anti-inflammatory activities. Continuous oxidative stress caused by intracellular redox imbalance can lead to chronic inflammation, which is intimately associated with the initiation, promotion, and progression of cancer. DHM is considered a potential redox regulator for chronic disease prevention, and its biological activities are abundantly evaluated by using diverse cell and animal models. However, clinical investigations are still scanty. This review summarizes the current potential chemopreventive effects of DHM, including its properties such as anticancer, antioxidative, and anti-inflammatory activities, and further discusses the underlying molecular mechanisms of DHM in cancer chemoprevention by targeting redox balance and influencing the gut microbiota.

A light- and heat-driven glycal diazidation approach to nitrogenous carbohydrate derivatives with antiviral activity.

The aminated mimetics of 2-keto-3-deoxy-sugar acids such as the anti-influenza clinical drugs oseltamivir (Tamiflu) and zanamivir (Relenza) are important bioactive molecules. Development of synthetic methodologies for accessing such compound collections is highly desirable. Herein, we describe a simple, catalyst-free glycal diazidation protocol enabled by visible light-driven conditions. This new method requires neither acid promoters nor transition-metal catalysts and takes place at ambient temperature within 1-2 hours. Notably, the desired transformations could be promoted by thermal conditions as well, albeit with lower efficacy compared to the light-induced conditions. Different sugar acid-derived glycal templates have been converted into a range of 2,3-diazido carbohydrate analogs by harnessing this mild and scalable approach, leading to the discovery of new antiviral agents.

Study of triaryl-based sulfamic acid derivatives as HPTPß inhibitors.

A series of novel triaryl-based sulfamic acid analogs was designed, synthesized and evaluated as inhibitors of human protein tyrosine phosphatase beta (HPTPß). A novel, easy and efficient synthetic method was developed for target compounds, and the activity determination results showed that most of compounds were good HPTPß inhibitors. Interestingly, the compounds G4 and G25 with simple structure not only showed potent inhibitory activity on HPTPß but also had good inhibitory selectivity over other PTPs (PTP1B, SHP2, LAR and TC-PTP). The molecular docking simulation of compounds with the protein HPTPß helped us understand the structure-activity relationship and clarify some confusing assay results. This research provides references for further drug design of HPTPß and other PTPs inhibitors.

Design, synthesis and evaluation of novel nonquaternary and 3 non-oxime reactivators for acetylcholinesterase inhibited by organophosphates.

A new series of novel nonquaternary conjugates and non-oxime reactivators for reactivation of both nerve agents and pesticides inhibited hAChE were described in this paper. Conjugates with piperazine linked to the substituted salicylaldoxime emerged as efficient reactivators for VX inhibited hAChE. The in vitro reactivation experiment showed that some of them were equal or more efficient reactivators for pesticides inhibited hAChE than obidoxime. It was also found that some non-oxime derivatives of Mannich phenols displayed obvious reactivation potency for VX, sarin and pesticides inhibited hAChE even in very low concentration. It has been proved that introduction of peripheral site ligands with widespread aromatic system and amide substitutions could increase binding affinity for inhibited hAChE in most cases, which contribute to the reactivation efficiency.

[Research progress on molecular mechanism of Dendrobium officinale and its active components to metabolic syndrome].

Metabolic syndrome,a kind of clinical syndrome marked by the presence of symptoms such as hyperglycemia,dyslipidemia and hypertension,has an increasing incidence and comes to be present in younger people. More importantly,prolonged maintenance of this condition can significantly increase the incidence of chronic diseases such as diabetes,cardiovascular disease and cancer.However,the formation mechanism of metabolic syndrome is very complex and has not been fully studied and revealed. Dendrobium officinale is a traditional medicine and food substance with multiple physiological functions. In recent years,D. officinale has attracted much attention from the scholars both at home and abroad due to its functions such as improving blood lipid,lowering blood pressure and regulating blood sugar. However,there is no systematic review on the current studies about D. officinale in intervening metabolic syndrome and its underlying molecular mechanism. In this paper,the biological activity of the main active components,and the research or application status of D. officinale extract in the recent years were reviewed. Then,we analyzed the digestion,absorption and the safety and toxicity of D. officinale and its active components in the body. Finally,we summarized the effects of D. officinale and its active components on metabolic syndrome in animals and human bodies,and discussed its possible molecular mechanisms at the cellular level. This paper provides solid theoretical guidance and reliable molecular basis for further research and advanced development of D. officinale and its active components,especially for its oncoming clinical application.

Synthesis and biological evaluation of (3'-amino-[1,1'-biphenyl]-4-yl) sulfamic acid derivatives as novel HPTPß inhibitors.

A series of novel (3'-amino-[1,1'-biphenyl]-4-yl) sulfamic acid derivatives were designed as nonphosphonate-based phosphotyrosy (pTyr) mimetics, synthesized and screened for use as HPTPß inhibitors. Compounds C22 and C2 showed favorable HPTPß inhibitory activity and better selectivity for HPTPß than for PTP1B and SHP2. Docking results suggested that compounds C2 and C22 could not only efficiently fit into the catalytic site of the HPTPß enzyme but also interact with the Lys1807, Arg1809 and Lys1811 residues of the secondary binding site, which was next to the catalytic center of the enzyme. The mode of interaction of the synthesized compound with the protein was different from the one found in a complex crystal of small molecules with HPTPß (2I4H), in which the inhibitory molecule formed hydrogen bonds with the Gln1948 and Asn1735 residues of the secondary binding site.

Design, synthesis and evaluation of new classes of nonquaternary reactivators for acetylcholinesterase inhibited by organophosphates.

A new series of nonquaternary conjugates for reactivation of both nerve agents and pesticides inhibited hAChE were described in this paper. It was found that substituted salicylaldehydes conjugated to aminobenzamide through piperidine would produce efficient reactivators for sarin, VX and tabun inhibited hAChE, such as L6M1R3, L6M1R5 to L6M1R7, L4M1R3 and L4M1R5 to L4M1R7. The in vitro reactivation experiment for pesticides inhibited hAChE of these new synthesized oximes were conducted for the first time. Despite they were less efficient than obidoxime, some of them were highlighted as equal or more efficient reactivators in comparison to 2-PAM. It was found that introduction of peripheral site ligands could increase oximes' binding affinity for inhibited hAChE in most cases, which resulted in greater reactivation ability.

Conjugates of salicylaldoximes and peripheral site ligands: Novel efficient nonquaternary reactivators for nerve agent-inhibited acetylcholinesterase.

A new family of nonquaternary reactivators for nerve agent-inhibited human acetylcholinesterase (hAChE) were designed, synthesized and tested in this paper. It was found that salicylaldoximes were able to quickly cleave the P-S bond of organophosphate and avoid the reinhibition phenomenon in the reactivation process, but they lacked reactivating ability due to poor affinity for AChE. Based on a dual site binding strategy, different peripheral site ligands of AChE were introduced to achieve extra affinity. The in vitro reactivation experiments demonstrated that some of the yielding conjugates exhibited similar or even superior ability to reactivate sarin-, VX- or tabun-inhibited hAChE in comparison with the mono- and bis-pyridinium aldoximes currently used. Moreover, due to greatly improved lipophilicity, these nonquaternary conjugates hold promise for the development of efficient centrally activating reactivators.

Raddeanoside R13 inhibits breast cancer cell proliferation, invasion, and metastasis.

Pulsatilla chinensis is one of the 50 famous fundamental herbs used in traditional Chinese medicine. Saponins are the main components of P. chinensis. Although the anti-proliferative function of saponins has been established in plenty types of cancer, the role of saponins on tumor invasion and metastasis has not been reported, and the mechanisms of how saponins exert the anti-tumor functions are still poorly characterized. Here, we demonstrate that, in breast cancer (BC) cells, raddeanoside R13, a component of saponins extracted from P. chinensis, exhibits strong anti-proliferative and anti-metastasis ability, accompanied by cell cycle arrest, apoptosis, autophagy, and reversion of epithelial-mesenchymal transition (EMT). Raddeanoside R13 (R13) inhibits BC cell proliferation via the activation of G1/S checkpoint transitions, concomitant with a marked decrease of the positive cell cycle regulators, including cyclin D1, cyclin A, and cyclin B1. R13 induces BC cell apoptosis accompanied by the increased levels of cleaved PARP and caspase-3. R13 inhibits BC cell migration and invasion and regulates the expression of the markers of EMT, which plays a critical role in cancer cell migration and invasion. Moreover, R13 suppresses BC tumor growth and metastasis in nude mice. These data highlight the important role of R13 in BC cell proliferation and progression and suggest that R13 may be a useful drug for BC therapy.

Design, Synthesis, and Biological Evaluation of Novel PARP-1 Inhibitors Based on a 1H-Thieno[3,4-d] Imidazole-4-Carboxamide Scaffold.

A series of poly(ADP-ribose)polymerase (PARP)-1 inhibitors containing a novel scaffold, the 1H-thieno[3,4-d]imidazole-4-carboxamide moiety, was designed and synthesized. These efforts provided some compounds with relatively good PARP-1 inhibitory activity, and among them, 16l was the most potent one. Cellular evaluations indicated that the anti-proliferative activities of 16g, 16i, 16j and 16l against BRCA-deficient cell lines were similar to that of olaparib, while the cytotoxicities of 16j and 16l toward human normal cells were lower. In addition, ADMET prediction results indicated that these compounds might possess more favorable toxicity and pharmacokinetic properties. This study provides a basis for our further investigation.

Improved synthesis and biological evaluation of Tc-99m radiolabeled AMO for miRNA imaging in tumor xenografts.

MicroRNAs (miRNAs) have been considered as important biomarkers for malignant tumors. In this study, we introduced an improved (99m)Tc labeling method for noninvasive visualization of overexpressed miRNAs in tumor-bearing mice. Anti-miRNA-21 oligonucleotide (AMO) with partial 2'-O-methyl and phosphorothioate modification was designed and chemically synthesized. After conjugated with NHS-MAG3, AMO was labeled with (99m)Tc. Optimization was made to shorten reaction time and to improve labeling efficiency. Labeling efficiency was 97%, and specific activity was 2.78 MBq/ng. During 12 h, (99m)Tc-AMO showed no significant degradation by gel electrophoresis. Its radiochemical purity was stable, between 95.8% and 99.1%. Further, (99m)Tc-AMO decreased the level of miR-21 and increased the expression of PTEN protein at cellular level, shown by qRT-PCR and Western blot. Fluorescent protein labeled AMO displayed specific distribution and good stability in tumor cells. After the administration in tumor-bearing mice, (99m)Tc-AMO showed more radioactive uptake in the miR-21 over-expressed tumors than scramble control. Biodistribution results further proved the significant difference of tumor uptake between (99m)Tc-AMO and (99m)Tc-control. Therefore, this study presents an improved method with shorten time to prepare a (99m)Tc radiolabeled AMO. In addition, it supports the role of (99m)Tc-AMO for noninvasive visualization of miR-21 in malignant tumors.

Synthesis and biological evaluation of substituted 4-(thiophen-2-ylmethyl)-2H-phthalazin-1-ones as potent PARP-1 inhibitors.

We have developed a series of substituted 4-(thiophen-2-ylmethyl)-2H-phthalazin-1-ones as potent PARP-1 inhibitors. Preliminary biological evaluation indicated that most compounds possessed inhibitory potencies comparable to, or higher than AZD-2281. Among these compounds, 18q appeared to be the most notable one, which displayed an 8-fold improvement in enzymatic activity compared to AZD-2281. These efforts lay the foundation for our further investigation.