Design, synthesis, in vitro and in vivo biological evaluation of pterostilbene derivatives for anti-inflammation therapy.

Pterostilbene (PST) is a naturally derived stilbene compound in grapes, blueberries, and other fruits. It is also a natural dietary compound with a wide range of biological activities such as antioxidant, anti-inflammatory, antitumor, and so on. Structural modifications based on the chemical scaffold of the pterostilbene skeleton are of great importance for drug discovery. In this study, pterostilbene skeletons were used to design novel anti-inflammatory compounds with high activity and low toxicity. A total of 30 new were found and synthesised, and their anti-inflammatory activity and safety were screened. Among them, compound E2 was the most active (against NO: IC50 = 0.7 µM) than celecoxib. Further studies showed that compound E2 exerted anti-inflammatory activity by blocking LPS-induced NF-κB/MAPK signalling pathway activation. In vivo experiments revealed that compound E2 had a good alleviating effect on acute colitis in mice. In conclusion, compound E2 may be a promising anti-inflammatory lead compound.

Discovery of pterostilbene analogs as novel NLRP3 inflammasome inhibitors for potential treatment of DSS-induced colitis in mice.

The pterostilbene skeleton is a promising chemical scaffold that exerts anti-inflammatory, anti-depressant, and anti-tumor effects. In this study, we aim to reduce in vivo and in vitro toxicity of compound 32 (preliminary work) and maintain its biological activity. A series of novel pterostilbene derivatives (D1-D43) were designed and synthesized, and their anti-inflammatory activities were screened. All compounds were screened to evaluate their inhibitory effect on LPS/Nigericin-induced IL-1ß production and pyroptosis. The structure-activity relationships was deduced, and finally 1-((E)-4-(2-ethoxyethoxy)styryl)-3,5-dimethoxy-2-((E)-2-nitrovinyl)benzene (D22) was found to be a low-toxic compound with most potent inhibitory efficacy (against IL-1ß: IC50 = 2.41 µM). Preliminary mechanism studies showed that compound D22 may affect the assembly of NLRP3 inflammasome by targeting NLRP3 protein, thereby inhibiting the activation of NLRP3 inflammasome. The in vivo anti-inflammatory activity indicated that compound D22 had significant therapeutic effects on DSS-induced mouse acute colitis models.

Advancements in Research on Constructing Physiological and Pathological Liver Models and Their Applications Utilizing Bioprinting Technology.

In recent decades, significant progress has been made in liver tissue engineering through the use of 3D bioprinting technology. This technology offers the ability to create personalized biological structures with precise geometric design capabilities. The complex and multifaceted nature of liver diseases underscores the need for advanced technologies to accurately mimic the physiological and mechanical characteristics, as well as organ-level functions, of liver tissue in vitro. Bioprinting stands out as a superior option over traditional two-dimensional cell culture models and animal models due to its stronger biomimetic advantages. Through the use of bioprinting, it is possible to create liver tissue with a level of structural and functional complexity that more closely resembles the real organ, allowing for more accurate disease modeling and drug testing. As a result, it is a promising tool for restoring and replacing damaged tissue and organs in the field of liver tissue engineering and drug research. This article aims to present a comprehensive overview of the progress made in liver tissue engineering using bioprinting technology to provide valuable insights for researchers. The paper provides a detailed account of the history of liver tissue engineering, highlights the current 3D bioprinting methods and bioinks that are widely used, and accentuates the importance of existing in vitro liver tissue models based on 3D bioprinting and their biomedical applications. Additionally, the article explores the challenges faced by 3D bioprinting and predicts future trends in the field. The progress of 3D bioprinting technology is poised to bring new approaches to printing liver tissue in vitro, while offering powerful tools for drug development, testing, liver disease modeling, transplantation, and regeneration, which hold great academic and practical significance.

Synthesis and Biological Evaluation of Novel Phthalide Analogs-1,2,4-Oxadiazole Hybrids as Potential Anti-Inflammatory Agents.

A series of novel pathalide-1,2,4-oxadiazole analogs were synthesized for discovering novel anti-inflammatory agents. After the assessment of their cytotoxicity in vitro, all compounds had been screened for their anti-inflammatory activity by evaluating their inhibitory effect on LPS-induced NO production in RAW 264.7 macrophages. SARs had been concluded, and finally compound E13 was found to be the most potent compound. This compound could also significantly decrease the production of iNOS and COX-2. Preliminary mechanism studies indicated that compound E13 could inhibit the TLR4/NF-κB and ERK/p38 signaling pathways. These findings indicate that E13 holds great potential to be a lead compound for discovering novel anti-inflammatory drugs.

P(NMe2)3 mediated cyclopropanation of α-methylene-ß-lactams for rapid syntheses of spirocyclopropyl ß-lactams.

An expedient cyclopropanation of α-methylene-ß-lactams with α-ketoesters mediated by P(NMe2)3 has been developed. This reaction enables rapid access to a series of functionalized spirocyclopropyl ß-lactams in good yields from bench-stable starting materials under mild conditions. The experimental results indicated that the C3-substituent of the α-methylene-ß-lactam not only significantly impacted the reaction efficiency and stereochemistry but also played a pivotal role in determining the chemoselectivity of the reaction.

Synthesis and in vitro and in vivo anti-inflammatory activity of novel 4-ferrocenylchroman-2-one derivatives.

A series of novel 4-ferrocenylchroman-2-one derivatives were designed and synthesised to discover potent anti-inflammatory agents for treatment of arthritis. All the target compounds had been screened for their anti-inflammatory activity by evaluating the inhibition effect of LPS-induced NO production in RAW 264.7 macrophages. Among them, 4-ferrocenyl-3,4-dihydro-2H-benzo[g]chromen-2-one (3h) was found to be the most potent compound in inhibiting the productions of NO with low toxicity. This compound also exhibited significant inhibition of the productions of IL-6 and TNF-α in RAW 264.7 macrophages. Preliminary mechanism studies indicated that compound 3h could inhibit the activation of LPS-induced NF-κB and MAPKs signalling pathways. The in vivo anti-inflammatory effect of this compound was determined in the rat adjuvant-induced arthritis model.

Modification, Biological Evaluation and SAR Studies of Novel 1H-Pyrazol Derivatives Containing N,N'-Disubstituted Urea Moiety as Potential Anti-melanoma Agents.

Malignant melanomas are amongst the most aggressive cancers. BRAF Inhibitors have exhibited therapeutic effects against BRAF-mutant melanoma. In continuation of our earlier studies on anti-melanoma agents based on 1H-pyrazole skeleton, two sets of novel compounds that include 1H-pyrazole-4-amines FA1 - FA13 and corresponding urea derivatives FN1 - FN13 have been synthesized and evaluated for their BRAFV600E inhibitory and antiproliferation activities. Compound FN10 displayed the most potent biological activity against BRAFV600E (IC50 = 0.066 µm) and the A375 human melanoma cell line (GI50 = 0.81 µm), which was comparable to the positive control vemurafenib, and more potent than our previously reported 1H-pyrazole-3-amines and their urea derivatives. The results of SAR studies and molecular docking can guide further optimization and may help to improve potency of these pyrazole-based anti-melanoma agents.

Resveratrol-based cinnamic ester hybrids: synthesis, characterization, and anti-inflammatory activity.

Twenty-three novel resveratrol-based cinnamic ester hybrids were designed and synthesized. All the compounds were evaluated for their anti-inflammatory activity using RAW264.7 cells. Among them, compound D15 was found to be the most potent one in inhibiting NO production in LPS-stimulated RAW264.7 cells. The further study indicated that compound D15 could suppress expression of proteins iNOS, COX-2, p-p65, and p-IκB LPS-induced. Immunofluorescence further revealed compound D15 could reduce activation p65 in nuclei. All the results indicated that the anti-inflammatory activity of title compound may partly due to its inhibitory effect on the NF-κB signaling pathway.

Discovery and pharmacophore studies of novel pyrazole-based anti-melanoma agents.

Due to the rising incidence and lack of effective treatments, malignant melanoma is the most dangerous form of skin cancer, so that new treatment strategies are urgently needed. Several recent developments indicate that the V600E mutant BRAF (BRAF(V600E) ) is a validated target for antimelanoma-drug development. Based on in silico screening results, a series of novel pyrazole derivatives has been designed, synthesized, and evaluated in vitro for their inhibitory activities against BRAF(V600E) melanoma cells. Compound 3d exhibited the most potent inhibitory activity with an IC50 value of 0.63 µM for BRAF(V600E) and a GI50 value of 0.61 µM for mutant BRAF-dependent cells. Furthermore, the QSAR modeling and the docking simulation of inhibitor analogs provide important pharmacophore clues for further structural optimization.

Drug discovery and optimization based on the co-crystal structure of natural product with target.

Due to their structural diversities and prevalent biological activities, natural products (NPs) are momentous resources for drug discovery. Although NPs have a wide range of biological activities, many exhibit structural complexity that leads to synthetic difficulties, which combines with inefficient biological activity, toxicity, and unfavorable pharmacokinetic characteristics and ultimately imparts poor safety and efficacy outcomes. Progress in crystallization and computational techniques allow crystallography to have a seasonable influences on drug discovery. By co-crystallizing with proteins, therapeutic targets of NPs in specific diseases can be identified. By analyzing the co-crystal information, the structure-activity relationships (SARs) of NPs targeting specific proteins can be grasped. Under the guidance of co-crystal information, directional structural modification and simplification are powerful strategies for overcoming limitations of NPs, improving the success rate of NP-based drug discovery, and obtaining NP-based drugs with high selectivity, low toxicity and favorable pharmacokinetic characteristics. Here, we review the co-crystal information of a selection of NPs, focusing on the SARs of NPs reflected by co-crystal information and the modification and simplification strategies of NPs, and discuss how to apply co-crystal information in the optimization of NP-based lead compound.

2,4-Dimeth-oxy-6-[(E)-2-(4-meth-oxy-phenyl)ethen-yl]benzaldehyde.

There are two conformationally similar mol-ecules in the asymmetric unit of he title compound, C18H18O4, in which the dihedral angles between the benzene rings are 23.54 (12) and 31.11 (12)°. In the crystal, C-H⋯π inter-actions (minimum H⋯ring centroid distance = 2.66 Å) link the mol-ecules into a layered structure extending down a.

Synthesis, Characterization, and in vitro Anti-Inflammatory Activity of Novel Ferrocenyl(Piperazine-1-Yl)Methanone-based Derivatives.

BACKGROUND: Inflammation is closely related to the occurrence and development of various diseases in the clinical scope. Finding effective anti-inflammatory agents is of great significance for clinical treatment. A series of novel ferrocenyl(piperazine-1-yl)methanone-based sulfamides and carboxamides were synthesized to discover potent anti-inflammatory agents. METHODS: The compounds were characterized by 1H NMR, 13C NMR, and MS spectra. Compound 5h was further determined by single crystal X-ray diffraction. All the target compounds were screened for anti-inflammatory activity by evaluating the inhibition effect of LPS-induced NO production in RAW264.7 macrophages. The novel compound (4i) is the preliminary anti-inflammatory mechanism detected by western blot. RESULTS: In a multi-stage screening campaign, compound 4i was shortlisted, which exhibited physicochemical properties suitable for human administration. Among them, compound 4i was found to be most potent in inhibiting NO production (IC50 = 7.65 µM) with low toxicity. This compound also exhibited significant inhibition of the production of iNOS and COX-2. Preliminary mechanism studies indicated that compound 4i could inhibit the activation of the LPS-induced TLR4/NF-κB signaling pathway. CONCLUSION: The promising anti-inflammatory activity of compound 4i compared with the reference drug suggests that this compound may contribute as a lead compound in the search for new potential anti-inflammatory agents.

Synthesis, biological evaluation and molecular docking studies of resveratrol derivatives possessing curcumin moiety as potent antitubulin agents.

A series of resveratrol derivatives possessing curcumin moiety were synthesized and evaluated for their antiproliferative activity against three cancer cell lines including murine melanoma B16-F10, human hepatoma HepG2 and human lung carcinoma A549. Among them, compound C5 displayed the most potent in vitro antiproliferative activity against B16-F10 with IC(50) value of 0.71 µg/mL. Compound C5 also exhibited good tubulin polymerization inhibitory activity with IC(50) value of 1.45 µg/mL. Furthermore, docking simulation was carried out to position C5 into the tubulin-colchicine binding site to determine the probable binding mode.

Synthesis and biological evaluation of novel N, N'-disubstituted urea and thiourea derivatives as potential anti-melanoma agents.

Two series of urea and thiourea derivatives (1a-11a, 1b-11b) have been synthesized; all the 22 compounds were reported for the first time. Their anti-proliferative activities against the melanoma cell line B16-F10 were evaluated. Among the compounds tested, compound 6b exhibited the most potent activity in melanoma cells growth inhibition (IC(50) = 0.33 µM). The bioassay tests showed that anti-proliferative activities of these novel compounds were possibly caused by inhibition of ERK1/2 phosphorylation level. Therefore, compound 6b can be a potential anti-melanoma agent and an inhibitor of ERK1/2 phosphorylation deserving further research.

A Review of the Biological Activities of Heterocyclic Compounds Comprising Oxadiazole Moieties.

The oxadiazole core is considered a privileged moiety in many medicinal chemistry applications. The oxadiazole class includes 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, and 1,2,5-oxadiazole. Compounds bearing an oxadiazole ring show a wide range of biological activities, such as anticancer, antibacterial, anti-inflammatory, anti-malarial, and insecticidal properties. Among oxadiazoles, the 1,3,4-oxadiazole has been the most widely explored moiety in medicinal chemistry research. This review is primarily focused on the anticancer, antibacterial, and anti-inflammatory activities of compounds containing 1,2,4-oxadiazole, 1,3,4-oxadiazole and 1,2,5-oxadiazole reported in the last five years.

Design and synthesis of N-phenylacetyl (sulfonyl) 4,5-dihydropyrazole derivatives as potential antitumor agents.

A series of novel N-phenylacetyl (sulfonyl) 4,5-dihydropyrazole derivatives as potential telomerase inhibitors were synthesized. The bioassay tests show that compound 4a exhibited high activity against human gastric cancer cell SGC-7901, liver cancer Hep-G2 and human prostate PC-3 cell lines with IC(50) values of 21.23±0.99, 29.43±0.32 and 30.89±1.07 µM, respectively. All title compounds were assayed for telomerase inhibition by a modified TRAP assay, the results show that compound 4a can inhibit telomerase with IC(50) value of 4.0±0.32 µM. Docking simulation was performed to position compound 4a into the telomerase (3DU6) active site to determine the probable binding model.

Synthesis, biological evaluation, and molecular docking studies of resveratrol derivatives possessing chalcone moiety as potential antitubulin agents.

Twenty-three resveratrol derivatives possessing chalcone moiety were synthesized and characterized, and their biological activities were also evaluated as potential antiproliferation and tubulin polymerization inhibitors. Compound C19 exhibited the most potent activity in vitro, which inhibited the growth of HepG2, B16-F10, and A549 cell lines with IC(50) values of 0.2, 0.1, and 1.4 µg/mL, respectively. Compound C19 also exhibited significant tubulin polymerization inhibitory activity (IC(50)=2.6 µg/mL). Docking simulation was performed to position compound C19 into the tubulin-colchicine binding site to determine the probable binding mode.

Design, synthesis and biological evaluation of pyridine acyl sulfonamide derivatives as novel COX-2 inhibitors.

A series of pyridine acyl sulfonamide derivatives (1-24) have been designed and synthesized and their biological activities were also evaluated as potential cyclooxygenase-2 (COX-2) inhibitors. Among all the compounds, compound 23 displayed the most potent COX-2 inhibitory activity with an IC(50) of 0.8 µM. Antitumor and anti-inflammatory assays indicated that compound 23 owned high antiproliferative activity against B16-F10, HepG2 and MCF-7 cancer cell lines as well as COX-2-derived prostaglandin E(2) (PGE(2)) inhibitory activity of murine macrophage RAW 264.7 cell line with IC(50) values of 2.8, 1.2, 1.8 and 0.15 µM, respectively. Docking simulation was performed to position compound 23 into the COX-2 active site to determine the probable binding model.

Discovery of Anticancer Agents from 2-Pyrazoline-Based Compounds.

As nitrogen-containing five-membered heterocyclic structural units, the substituted pyrazole derivatives have a broad spectrum of pharmacological activities, especially 4,5-dihydro-1H-pyrazoles that also commonly known as 2-pyrazolines. Since 2010, considerable studies have been found that the 2-pyrazoline derivatives possess potent anticancer activities. In the present review, it covers the pyrazoline derivatives reported by literature from 2010 till date (2010-2019). This review aims to establish the relationship between the anticancer activities variation and different substituents introduced into a 2-pyrazoline core, which could provide important pharmacophore clues for the discovery of new anticancer agents containing 2-pyrazoline scaffold.

Discovery of Novel Pterostilbene Derivatives That Might Treat Sepsis by Attenuating Oxidative Stress and Inflammation through Modulation of MAPKs/NF-κB Signaling Pathways.

Sepsis remains one of the most common life-threatening illnesses that is characterized by a systemic inflammatory response syndrome (SIRS) and usually arises following severe trauma and various septic infections. It is still in urgent need of new effective therapeutic agents, and chances are great that some candidates can be identified that can attenuate oxidative stress and inflammatory responses. Pterostilbene, which exerts attractive anti-oxidative and anti-inflammatory activities, is a homologue of natural polyphenolic derivative of resveratrol. Starting from it, we have made several rounds of rational optimizations. Firstly, based on the strategy of pharmacophore combination, indanone moiety was introduced onto the pterostilbene skeleton to generate a novel series of pterostilbene derivatives (PIF_1-PIF_16) which could possess both anti-oxidative and anti-inflammatory activities for sepsis treatment. Then, all target compounds were subjected to their structure-activity relationships (SAR) screening of anti-inflammatory activity in mouse mononuclear macrophage RAW264.7 cell line, and their cytotoxicities were determined after. Finally, an optimal compound, PIF_9, was identified. It decreased the mRNA levels of lipopolysaccharide (LPS)-induced interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS), and cyclooxygenase 2 (COX2). We also found that the anti-inflammatory effects might be contributed by its suppression on the nuclear factor-κB (NF-κB) and MAPKs signaling pathway. Moreover, PIF_9 also demonstrated potent anti-oxidative activity in RAW264.7 macrophages and the sepsis mouse model. Not surprisingly, with the benefits mentioned above, it ameliorated LPS-induced sepsis in C57BL/6J mice and reduced multi-organ toxicity. Taken together, PIF_9 was identified as a potential sepsis solution, targeting inflammation and oxidative stress through modulating MAPKs/NF-κB.