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1.
Molecules ; 29(9)2024 Apr 26.
Article En | MEDLINE | ID: mdl-38731476

Although the wide variety of bioactivities of curcumin has been reported by researchers, the clinical application of curcumin is still limited due to its poor aqueous solubility. In view of this, a series of dimethylaminomethyl-substituted curcumin derivatives were designed and synthesized (compounds 1-15). Acetate of these derivatives were prepared (compounds 1a-15a). The Mannich reaction and aldol condensation reaction are the main reactions involved in this study. Compounds 6, 10, 12, 3a, 5a, 6a, 7a, 8a, 10a, 11a, 12a, 13a, 14a, and 15a exhibited better in vitro anti-inflammatory activity compared to curcumin in the RAW264.7 cell line. Compounds 5, 1a, 5a, 8a, and 12a exhibited better in vitro antioxidant activity compared to curcumin in the PC 12 cell line. Compounds 11, 13, 5a, 7a, and 13a exhibited better in vitro radiation protection compared to curcumin in the PC 12 cell line. The aqueous solubilities of all the curcumin derivative acetates were greatly improved compared to curcumin.


Anti-Inflammatory Agents , Antioxidants , Curcumin , Radiation-Protective Agents , Solubility , Curcumin/pharmacology , Curcumin/chemistry , Curcumin/chemical synthesis , Curcumin/analogs & derivatives , Animals , Mice , Antioxidants/pharmacology , Antioxidants/chemistry , Antioxidants/chemical synthesis , RAW 264.7 Cells , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/chemical synthesis , Radiation-Protective Agents/pharmacology , Radiation-Protective Agents/chemical synthesis , Radiation-Protective Agents/chemistry , Drug Design , Structure-Activity Relationship , Molecular Structure , PC12 Cells , Rats , Water/chemistry
2.
J Med Chem ; 67(10): 8060-8076, 2024 May 23.
Article En | MEDLINE | ID: mdl-38722184

Interleukin-1 receptor-associated kinase 4 (IRAK4) is a promising therapeutic target in inflammation-related diseases. However, the inhibition of IRAK4 kinase activity may lead to moderate anti-inflammatory efficacy owing to the dual role of IRAK4 as an active kinase and a scaffolding protein. Herein, we report the design, synthesis, and biological evaluation of an efficient and selective IRAK4 proteolysis-targeting chimeric molecule that eliminates IRAK4 scaffolding functions. The most potent compound, LC-MI-3, effectively degraded cellular IRAK4, with a half-maximal degradation concentration of 47.3 nM. LC-MI-3 effectively inhibited the activation of downstream nuclear factor-κB signaling and exerted more potent pharmacological effects than traditional kinase inhibitors. Furthermore, LC-MI-3 exerted significant therapeutic effects in lipopolysaccharide- and Escherichia coli-induced acute and chronic inflammatory skin models compared with kinase inhibitors in vivo. Therefore, LC-MI-3 is a candidate IRAK4 degrader in alternative targeting strategies and advanced drug development.


Interleukin-1 Receptor-Associated Kinases , Interleukin-1 Receptor-Associated Kinases/antagonists & inhibitors , Interleukin-1 Receptor-Associated Kinases/metabolism , Animals , Humans , Mice , Inflammation/drug therapy , Inflammation/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Administration, Oral , Lipopolysaccharides/pharmacology , NF-kappa B/metabolism , NF-kappa B/antagonists & inhibitors , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacokinetics , Biological Availability , Drug Discovery , Proteolysis/drug effects , Structure-Activity Relationship , Male , Mice, Inbred C57BL
3.
Bioorg Med Chem Lett ; 107: 129777, 2024 Jul 15.
Article En | MEDLINE | ID: mdl-38692522

Inflammation is the body's defense response to stimuli. When the homeostatic balance is disturbed, disease may result. Flavonoids have clear anti-inflammatory effects and the isopentenyl group significantly enhances the pharmacological activity of flavonoids. Therefore, isopentenyl flavonoids have the potential to serve as lead compounds for the development of anti-inflammatory drugs. Throughout this research, eight natural compounds were synthesized, including 5,7-dihydroxy-4'-methoxy-8-prenylflavonoid (1), 4'-O-Methylatalantoflavone (2), Kushenol W (3) and Racemoflavone (5), which were totally synthesized for the first time. Additionally, three flavonols: Licoflavonol (6), 3,5,7,3',4'-pentahydroxy-6-prenylflavonol (7) and Macarangin (8), can be one-step synthesized by direct C-isopentenylation. In the process, an economical and efficient C-isopentenylation method was also simultaneously explored that could facilitate the efficient synthesis of natural products. These compounds were evaluated for their potential anti-inflammatory activities via the NLRP3 signaling pathway. Notably, Macarangin (8) manifested the most potent inhibitory effect. The SAR (Structure-Activity Relationships) also showed the introduction of the isopentenyl group was determined to enhance these effects, whereas simple flavonoid frameworks or cyclization of isopentenyl groups all diminished anti-inflammatory activity.


Flavonoids , Inflammasomes , NLR Family, Pyrin Domain-Containing 3 Protein , NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Flavonoids/pharmacology , Flavonoids/chemistry , Flavonoids/chemical synthesis , Inflammasomes/metabolism , Inflammasomes/drug effects , Structure-Activity Relationship , Molecular Structure , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/chemistry , Animals , Biological Products/pharmacology , Biological Products/chemistry , Biological Products/chemical synthesis , Mice , Dose-Response Relationship, Drug , Humans
4.
Eur J Med Chem ; 272: 116463, 2024 Jun 05.
Article En | MEDLINE | ID: mdl-38704944

Butyrylcholinesterase (BChE) has attracted wide interest as a promising target in Alzheimer's disease (AD) investigation. BChE is considered to play a compensable role of hydrolyzing acetylcholine (ACh), and its positive correlation with ß-amyloid (Aß) deposition also promotes disease progression. Herein, we uncovered a selective potent BChE inhibitor S21-1011 (eqBChE IC50 = 0.059 ± 0.006 µM, hBChE IC50 = 0.162 ± 0.069 µM), which presented satisfactory druggability and therapeutic efficacy in AD models. In pharmacokinetics (PK) studies, S21-1011 showed excellent blood-brain barrier (BBB) permeability, metabolism stability and high oral-bioavailability. In pharmacodynamic (PD) studies, it protected neural cells from toxicity and inflammation stimulation in vitro. Besides, it also exerted anti-inflammatory effect and alleviated cognitive impairment in mice models induced by lipopolysaccharides (LPS) and Aß. Generally, this compound has been confirmed to function as a neuroprotector and cognition improver in various AD pathology-like models. Therefore, S21-1011, a novel potent BChE inhibitor, could be considered as a potential anti-AD candidate worthy of more profound investigation.


Alzheimer Disease , Butyrylcholinesterase , Cholinesterase Inhibitors , Quinolines , Butyrylcholinesterase/metabolism , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Animals , Cholinesterase Inhibitors/pharmacology , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/chemical synthesis , Mice , Humans , Structure-Activity Relationship , Quinolines/chemistry , Quinolines/pharmacology , Quinolines/chemical synthesis , Drug Discovery , Molecular Structure , Male , Lipopolysaccharides/pharmacology , Lipopolysaccharides/antagonists & inhibitors , Dose-Response Relationship, Drug , Neuroprotective Agents/pharmacology , Neuroprotective Agents/chemistry , Neuroprotective Agents/chemical synthesis , Piperazines/pharmacology , Piperazines/chemistry , Piperazines/chemical synthesis , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/chemical synthesis , Inflammation/drug therapy , Blood-Brain Barrier/metabolism , Blood-Brain Barrier/drug effects
5.
Eur J Med Chem ; 272: 116460, 2024 Jun 05.
Article En | MEDLINE | ID: mdl-38704943

It has been reported that 4,5-dihydropyrazole and thiazole derivatives have many biological functions, especially in the aspect of anti-inflammation. According to the strategy of pharmacophore combination, we introduced thiazolinone and dihydropyrazole moiety into steroid skeleton to design and synthesize a novel series of D-ring substituted steroidal 4,5-dihydropyrazole thiazolinone derivatives, and assessed their in vitro anti-inflammatory profiles against Lipopolysaccharide (LPS)-induced inflammation in RAW 264.7 macrophage cells. The anti-inflammatory activities assay demonstrated that compound 12e was considered as the most effective anti-inflammatory drug, which suppressed the expression of pro-inflammatory mediators including nitric oxide (NO), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), it also dose-dependently inhibited the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in LPS-induced RAW 264.7 macrophage cells. Furthermore, the results of the Western blot analysis showed a correlation between the inhibition of the Nuclear factor-kappa B (NF-κB) and Mitogen-activated protein kinases (MAPKs) signaling pathways and the suppressive effects of compound 12e on pro-inflammatory cytokines. Molecular docking studies of compound 12e into the COX-2 protein receptor (PDB ID: 5IKQ) active site was performed to rationalize their COX-2 inhibitory potency. The results were found to be in line with the biological findings as they exerted more favorable interactions compared to that of dexamethasone (DXM), explaining their remarkable COX-2 inhibitory activity. The findings revealed that these candidates could be identified as potent anti-inflammatory agents, compound 12e could be a promising drug for the treatment of inflammatory diseases.


Cyclooxygenase 2 , Down-Regulation , Drug Design , Lipopolysaccharides , Macrophages , NF-kappa B , Nitric Oxide Synthase Type II , Pyrazoles , Animals , Mice , Lipopolysaccharides/pharmacology , Lipopolysaccharides/antagonists & inhibitors , RAW 264.7 Cells , Cyclooxygenase 2/metabolism , NF-kappa B/metabolism , NF-kappa B/antagonists & inhibitors , Nitric Oxide Synthase Type II/metabolism , Nitric Oxide Synthase Type II/antagonists & inhibitors , Structure-Activity Relationship , Pyrazoles/pharmacology , Pyrazoles/chemistry , Pyrazoles/chemical synthesis , Macrophages/drug effects , Macrophages/metabolism , Down-Regulation/drug effects , Molecular Structure , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Models, Molecular , Dose-Response Relationship, Drug , Cyclooxygenase 2 Inhibitors/pharmacology , Cyclooxygenase 2 Inhibitors/chemical synthesis , Cyclooxygenase 2 Inhibitors/chemistry , Mitogen-Activated Protein Kinases/metabolism , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Thiazoles/pharmacology , Thiazoles/chemistry , Thiazoles/chemical synthesis , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/chemistry , Steroids/pharmacology , Steroids/chemistry , Steroids/chemical synthesis , Molecular Docking Simulation
6.
Eur J Med Chem ; 272: 116471, 2024 Jun 05.
Article En | MEDLINE | ID: mdl-38704945

Honokiol (HNK) is a typical natural biphenyl polyphenol compound. It has been proven to have a wide range of biological activities, including pharmacological effects such as anti-cancer, anti-inflammatory, neuroprotective, and antimicrobial. However, due to the poor stability, water solubility, and bioavailability of HNK, HNK has not been used in clinical treatment. This article reviews the latest research on the pharmacological activity of HNK and summarizes the HNK derivatives designed and improved by several researchers. Reviewing these contents could promote the research process of HNK and guide the design of better HNK derivatives for clinical application in the future.


Biphenyl Compounds , Lignans , Lignans/pharmacology , Lignans/chemistry , Lignans/chemical synthesis , Biphenyl Compounds/pharmacology , Biphenyl Compounds/antagonists & inhibitors , Biphenyl Compounds/chemistry , Humans , Structure-Activity Relationship , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Neuroprotective Agents/pharmacology , Neuroprotective Agents/chemistry , Neuroprotective Agents/chemical synthesis , Molecular Structure , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/chemical synthesis , Anti-Infective Agents/pharmacology , Anti-Infective Agents/chemistry , Anti-Infective Agents/chemical synthesis , Allyl Compounds , Phenols
7.
Eur J Med Chem ; 272: 116487, 2024 Jun 05.
Article En | MEDLINE | ID: mdl-38759452

Acute lung injury (ALI) and inflammatory bowel disease (IBD) are common inflammatory illnesses that seriously affect people's health. Herein, a series of 4-hydroxylcoumarin (4-HC) derivatives were designed and synthesized. The inhibitory effects of these compounds on LPS-induced interleukin-6 (IL-6) release from J774A.1 cells were then screened via ELISA assay, compound B8 showed 3 times more active than the lead compound 4-HC. The most active compound B8 had the IC50 values of 4.57 µM and 6.51 µM for IL-6 release on mouse cells J774A.1 and human cells THP-1, respectively. Furthermore, we also found that B8 could act on the MAPK pathway. Based on the target prediction results of computer virtual docking, kinase inhibitory assay was carried out, and it revealed that targeting IRAK1 was a key mechanism for B8 to exert anti-inflammatory activity. Moreover, B8 exerted a good therapeutic effect on the dextran sulfate sodium (DSS)-induced colitis model and liposaccharide (LPS)-induced ALI mouse models. The acute toxicity experiments indicated that high-dose B8 caused no adverse reactions in mice, confirming its safety in vivo. Additionally, the preliminary pharmacokinetic (PK) parameters of B8 in SD rats were also examined, revealing a bioavailability (F) of 28.72 %. In conclusion, B8 is a potential candidate of drug for the treatment of ALI and colitis.


4-Hydroxycoumarins , Acute Lung Injury , Colitis , Drug Design , Acute Lung Injury/drug therapy , Acute Lung Injury/chemically induced , Animals , Colitis/drug therapy , Colitis/chemically induced , Mice , Humans , Structure-Activity Relationship , 4-Hydroxycoumarins/pharmacology , 4-Hydroxycoumarins/chemistry , 4-Hydroxycoumarins/chemical synthesis , Molecular Structure , Dextran Sulfate , Male , Dose-Response Relationship, Drug , Rats , Lipopolysaccharides/pharmacology , Lipopolysaccharides/antagonists & inhibitors , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/therapeutic use , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Interleukin-6/metabolism , Interleukin-6/antagonists & inhibitors , Interleukin-1 Receptor-Associated Kinases/antagonists & inhibitors , Interleukin-1 Receptor-Associated Kinases/metabolism , Molecular Docking Simulation , Mice, Inbred C57BL , Cell Line
8.
Sci Rep ; 14(1): 11079, 2024 05 14.
Article En | MEDLINE | ID: mdl-38745047

N-acetyl glucosamine (NAG) is a natural amino sugar found in various human tissues with previously described anti-inflammatory effects. Various chemical modifications of NAG have been made to promote its biomedical applications. In this study, we synthesized two bi-deoxygenated NAG, BNAG1 and BNAG2 and investigated their anti-inflammatory properties, using an in vivo and in vitro inflammation mouse model induced by lipopolysaccharide (LPS). Among the parent molecule NAG, BNAG1 and BNAG2, BNAG1 showed the highest inhibition against serum levels of IL-6 and TNF α and the leukocyte migration to lungs and peritoneal cavity in LPS challenged mice, as well as IL-6 and TNF α production in LPS-stimulated primary peritoneal macrophages. BNAG2 displayed an anti-inflammatory effect which was comparable to NAG. These findings implied potential application of these novel NAG derivatives, especially BNAG1, in treatment of certain inflammation-related diseases.


Acetylglucosamine , Anti-Inflammatory Agents , Lipopolysaccharides , Macrophages, Peritoneal , Tumor Necrosis Factor-alpha , Animals , Acetylglucosamine/pharmacology , Mice , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/chemical synthesis , Macrophages, Peritoneal/drug effects , Macrophages, Peritoneal/metabolism , Tumor Necrosis Factor-alpha/metabolism , Interleukin-6/metabolism , Interleukin-6/blood , Inflammation/drug therapy , Male , Disease Models, Animal
9.
Bioorg Med Chem Lett ; 106: 129770, 2024 Jul 01.
Article En | MEDLINE | ID: mdl-38677560

We have previously reported the total synthesis and structure-activity relationships (SAR) of 2-prenylated benzopyrans with PPAR agonist activity. Herein, we have described the synthesis and PPAR activity of 2-prenylated benzopyrans and 2-prenylated quinolines. The benzopyran nucleus was generated via enamine-catalyzed Kabbe condensation, and the quinoline nucleus via Friedländer condensation. Results demonstrated that both benzopyran (5a) and quinoline (4b) derivatives bearing a γ,δ-unsaturated ester displayed a pan-PPAR agonism. They were full PPARα agonists, but showed different preferences for PPARγ and PPARß/δ activation. It was noteworthy that quinoline 4b displayed full hPPARα activation (2-fold than WY-14,643), weak PPARß/δ and partial PPARγ activation. In addition, quinoline 4b showed anti-inflammatory effects on macrophages by reducing LPS-induced expression of both MCP-1 and IL-6. Therefore, 4b emerges as a first-in-class promising hit compound for the development of potential therapeutics aimed at treating metabolic syndrome, metabolic dysfunction-associated fatty liver disease (MAFLD), and its associated cardiovascular comorbidities.


Metabolic Syndrome , Quinolines , Metabolic Syndrome/drug therapy , Metabolic Syndrome/metabolism , Quinolines/chemistry , Quinolines/pharmacology , Quinolines/chemical synthesis , Structure-Activity Relationship , Humans , Peroxisome Proliferator-Activated Receptors/metabolism , Peroxisome Proliferator-Activated Receptors/agonists , Molecular Structure , Lipopolysaccharides/pharmacology , Lipopolysaccharides/antagonists & inhibitors , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/chemistry , Macrophages/drug effects , Macrophages/metabolism , Dose-Response Relationship, Drug , Benzopyrans/pharmacology , Benzopyrans/chemical synthesis , Benzopyrans/chemistry , Animals , Mice
10.
Bioorg Chem ; 147: 107362, 2024 Jun.
Article En | MEDLINE | ID: mdl-38615474

Excessive peroxynitrite (ONOO-) is closely related to the occurrence and progression of inflammation. Therefore, the development of an efficacious ONOO- activatable probe holds great potential for the early diagnosis of pathological inflammation, and the direct evaluation of the therapeutic efficacy of active protectants. In this work, a new ONOO--activated fluorescent probe (SZP) which greatly improved the specificity and sensitivity (LOD = 8.03 nM) with large Stokes shift (150 nm) through introducing two reaction triggers (diphenyl phosphinate moiety, CC unsaturated bond) was rationally designed for rapid detecting ONOO- (within 2 min). The excellent properties of probe SZP enable it to realize the fluorescence-guided diagnosis of inflammation. More importantly, probe SZP has also been utilized to assess the anti-inflammatory efficacy of traditional Chinese medicines (TCMs) active ingredients for the remediation of inflammation by monitoring ONOO- fluctuation for the first time.


Fluorescent Dyes , Inflammation , Peroxynitrous Acid , Peroxynitrous Acid/analysis , Peroxynitrous Acid/antagonists & inhibitors , Fluorescent Dyes/chemistry , Fluorescent Dyes/chemical synthesis , Fluorescent Dyes/pharmacology , Inflammation/drug therapy , Animals , Molecular Structure , Mice , Humans , RAW 264.7 Cells , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/therapeutic use , Optical Imaging , Dose-Response Relationship, Drug , Structure-Activity Relationship , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Male
11.
Bioorg Chem ; 147: 107312, 2024 Jun.
Article En | MEDLINE | ID: mdl-38599053

A series of water-soluble PEGylated 1,2,4-triazoles 5-8 were successfully synthesized from methyl 5-(chloromethyl)-1-aryl-1H-1,2,4-triazole-3-carboxylates 1. All of the water-soluble PEGylated 1,2,4-triazoles were characterized by FT-IR and 1H NMR spectroscopy. The solubility, in vitro plasma stability, and anti-inflammatory activity were also determined and compared to original methyl 5-(halomethyl)-1-aryl-1H-1,2,4-triazole-3-carboxylates. For SAR study, all PEGylated 1,2,4-triazoles 5-8 performed potential anti-inflammatory activity on LPS-induced RAW 264.7 cells (IC50 = 3.42-7.81 µM). Moreover, the western blot result showed PEGylated 1,2,4-triazole 7d performed 5.43 and 2.37 folds inhibitory activity over iNOS and COX-2 expressions. On the other hand, the cell viability study revealed PEGylated 1,2,4-triazoles 7 and 8 with PEG molecular weight more than 600 presented better cell safety (cell viability > 95 %). Through the solubility and in vitro plasma stability studies, PEGylated 1,2,4-triazoles 7a-d exhibited higher hydrophilicity and prolonged 2.01 folds of half-life in compound 7d. Furthermore, the in vivo anti-inflammatory and gastric safety results indicated PEGylated 1,2,4-triazole 7d more effectively decreased the inflammatory response in edema and COX-2 expression and exhibited higher gastric safety than Indomethacin. Following the in vitro and in vivo study results, PEGylated 1,2,4-triazole 7d possessed favorable solubility, plasma stability features, safety, and significant anti-inflammatory activity to become the potential water-soluble anti-inflammatory candidate.


Polyethylene Glycols , Solubility , Triazoles , Water , Triazoles/chemistry , Triazoles/pharmacology , Triazoles/chemical synthesis , Animals , Mice , Water/chemistry , Polyethylene Glycols/chemistry , Structure-Activity Relationship , Edema/drug therapy , Edema/chemically induced , Cyclooxygenase 2/metabolism , Cell Survival/drug effects , RAW 264.7 Cells , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/chemistry , Molecular Structure , Lipopolysaccharides/pharmacology , Lipopolysaccharides/antagonists & inhibitors , Rats , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Male , Dose-Response Relationship, Drug , Carrageenan
12.
J Am Chem Soc ; 146(17): 11811-11822, 2024 May 01.
Article En | MEDLINE | ID: mdl-38635880

The development of novel agents with immunoregulatory effects is a keen way to combat the growing threat of inflammatory storms to global health. To synthesize pseudo-steroidal glycosides tethered by ether bonds with promising immunomodulatory potential, we develop herein a highly effective deoxygenative functionalization of a novel steroidal donor (steroidation) facilitated by strain-release, leveraging cost-effective and readily available Sc(OTf)3 catalysis. This transformation produces a transient steroid-3-yl carbocation which readily reacts with O-, C-, N-, S-, and P-nucleophiles to generate structurally diverse steroid derivatives. DFT calculations were performed to shed light on the mechanistic details of the regioselectivity, underlying an acceptor-dependent steroidation mode. This approach can be readily extended to the etherification of sugar alcohols to enable the achievement of a diversity-oriented, pipeline-like synthesis of pseudo-steroidal glycosides in good to excellent yields with complete stereo- and regiospecific control for anti-inflammatory agent discovery. Immunological studies have demonstrated that a meticulously designed cholesteryl disaccharide can significantly suppress interleukin-6 secretion in macrophages, exhibiting up to 99% inhibition rates compared to the negative control. These findings affirm the potential of pseudo-steroidal glycosides as a prospective category of lead agents for the development of novel anti-inflammatory drugs.


Anti-Inflammatory Agents , Glycosides , Steroids , Glycosides/chemistry , Glycosides/chemical synthesis , Glycosides/pharmacology , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/chemical synthesis , Steroids/chemistry , Steroids/pharmacology , Steroids/chemical synthesis , Mice , Animals , Humans , Density Functional Theory , Molecular Structure , Interleukin-6/antagonists & inhibitors , Interleukin-6/metabolism , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Macrophages/drug effects
13.
Eur J Med Chem ; 271: 116427, 2024 May 05.
Article En | MEDLINE | ID: mdl-38657479

Glucocorticoids (GCs) have been used in the treatment of sepsis because of their potent anti-inflammatory effects. However, their clinical efficacy against sepsis remains controversial because of glucocorticoid receptor (GR) downregulation and side effects. Herein, we designed and synthesized 30 ocotillol derivatives and evaluated their anti-inflammatory activities. Ocotillol 24(R/S) differential isomers were stereoselective in their pharmacological action. Specifically, 24(S) derivatives had better anti-inflammatory activity than their corresponding 24(R) derivatives. Compound 20 most effectively inhibited NO release (85.97% reduction), and it exerted dose-dependent inhibitory effects on interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) levels. Mechanistic studies revealed that compound 20 reduces the degradation of GR mRNA and GR protein. Meanwhile, compound 20 inhibited the activation of nuclear factor-κB (NF-κB) signaling, thereby inhibiting the nuclear translocation of p65 and attenuating the inflammatory response. In vivo studies revealed that compound 20 attenuated hepatic, pulmonary, and renal pathology damage in mice with sepsis and suppressed the production of inflammatory mediators. These results indicated that compound 20 is a promising lead compound for designing and developing anti-sepsis drugs.


NF-kappa B , Receptors, Glucocorticoid , Sepsis , Signal Transduction , Receptors, Glucocorticoid/metabolism , Receptors, Glucocorticoid/antagonists & inhibitors , Sepsis/drug therapy , Animals , NF-kappa B/metabolism , NF-kappa B/antagonists & inhibitors , Mice , Signal Transduction/drug effects , Structure-Activity Relationship , Humans , Molecular Structure , RAW 264.7 Cells , Drug Discovery , Male , Dose-Response Relationship, Drug , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/therapeutic use , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis
14.
Org Biomol Chem ; 22(18): 3708-3724, 2024 05 08.
Article En | MEDLINE | ID: mdl-38639206

Despite the high global prevalence, rheumatoid arthritis lacks a satisfactory treatment. Hence, the present study is undertaken to design and synthesize novel anti-inflammatory compounds. For this, quinoline and anthranilic acid, two medicinally-privileged moieties, were linked by pharmacophore hybridization, and following their computational assessments, three hybrids 5a-c were synthesized in good over all yields. The in vitro and in vivo anti-inflammatory potential of these hybrids was determined by anti-denaturation and anti-proteinase, and carrageenan-induced paw edema models. The computational studies of these hybrids revealed their drug-likeness, optimum pharmacokinetics, and less toxicity. Moreover, they demonstrated high binding affinity (-9.4 to -10.6 kcal mol-1) and suitable binding interactions for TNF-α, FLAP, and COX-II. A three-step synthetic route resulted in the hybrids 5a-c with 83-86% yield of final step. At 50 µg mL-1, the antiprotease and anti-denaturation activity of compound 5b was significantly higher than 5a and 5c. Furthermore, 5b significantly reduced the edema in the right paw of the rats that received carrageenan. The results of this study indicate the medicinal worth of the novel hybrids in treating inflammatory disorders such as rheumatoid arthritis.


Drug Design , Edema , Molecular Docking Simulation , Quinolines , ortho-Aminobenzoates , Quinolines/chemistry , Quinolines/pharmacology , Quinolines/chemical synthesis , Animals , Edema/drug therapy , Edema/chemically induced , ortho-Aminobenzoates/chemistry , ortho-Aminobenzoates/pharmacology , ortho-Aminobenzoates/chemical synthesis , Rats , Carrageenan , Male , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/chemical synthesis , Molecular Structure , Rats, Wistar , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Dose-Response Relationship, Drug , Structure-Activity Relationship , Cyclooxygenase 2/metabolism , Cyclooxygenase 2/chemistry
15.
Molecules ; 29(8)2024 Apr 10.
Article En | MEDLINE | ID: mdl-38675532

Pyxinol, an active metabolite of ginsenosides in human hepatocytes, exhibits various pharmacological activities. Here, a series of C-3 modified pyxinol derivatives was designed and virtually screened by molecular docking with the key inflammation-related proteins of the nuclear factor kappa B (NF-κB) pathway. Some of the novel derivatives were synthesized to assess their effects in inhibiting the production of nitric oxide (NO) and mitochondrial reactive oxygen species (MtROS) in lipopolysaccharide-triggered RAW264.7 cells. Derivative 2c exhibited the highest NO and MtROS inhibitory activities with low cytotoxicity. Furthermore, 2c decreased the protein levels of interleukin 1ß, tumor necrosis factor α, inducible nitric oxide synthase, and cyclooxygenase 2 and suppressed the activation of NF-κB signaling. Cellular thermal shift assays indicated that 2c could directly bind with p65 and p50 in situ. Molecular docking revealed that 2c's binding to the p65-p50 heterodimer and p50 homodimer was close to their DNA binding sites. In summary, pyxinol derivatives possess potential for development as NF-κB inhibitors.


Anti-Inflammatory Agents , Molecular Docking Simulation , NF-kappa B , Nitric Oxide , NF-kappa B/metabolism , NF-kappa B/antagonists & inhibitors , Mice , Animals , RAW 264.7 Cells , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/chemistry , Nitric Oxide/metabolism , Reactive Oxygen Species/metabolism , Signal Transduction/drug effects , Lipopolysaccharides/pharmacology , Humans , Nitric Oxide Synthase Type II/metabolism , Nitric Oxide Synthase Type II/antagonists & inhibitors , Structure-Activity Relationship
16.
J Med Chem ; 67(9): 7385-7405, 2024 May 09.
Article En | MEDLINE | ID: mdl-38687956

Anemoside B4 (AB4), a triterpenoidal saponin from Pulsatilla chinensis, shows significant anti-inflammatory activity, and may be used for treating inflammatory bowel disease (IBD). Nevertheless, its application is limited due to its high molecular weight and pronounced water solubility. To discover new effective agents for treating IBD, we synthesized 28 AB4 derivatives and evaluated their cytotoxic and anti-inflammatory activities in vitro. Among them, A3-6 exhibited significantly superior anti-inflammatory activity compared to AB4. It showed a significant improvement in the symptoms of DSS-induced colitis in mice, with a notably lower oral effective dose compared to AB4. Furthermore, we discovered that A3-6 bound with pyruvate carboxylase (PC), then inhibited PC activity, reprogramming macrophage function, and alleviated colitis. These findings indicate that A3-6 is a promising therapeutic candidate for colitis, and PC may be a potential new target for treating colitis.


Anti-Inflammatory Agents , Colitis , Pyruvate Carboxylase , Saponins , Animals , Humans , Mice , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/chemical synthesis , Colitis/drug therapy , Colitis/chemically induced , Dextran Sulfate , Drug Discovery , Mice, Inbred C57BL , Pyruvate Carboxylase/antagonists & inhibitors , Pyruvate Carboxylase/metabolism , RAW 264.7 Cells , Saponins/pharmacology , Saponins/chemistry , Saponins/therapeutic use , Saponins/chemical synthesis , Structure-Activity Relationship
17.
J Med Chem ; 67(9): 7088-7111, 2024 May 09.
Article En | MEDLINE | ID: mdl-38634624

The novel metal(II)-based complexes HA-Cu, HA-Co, and HA-Ni with phenanthroline, sulfamethazine, and aromatic-aromatic coupled disulfamethazines as ligands were synthesized and characterized. HA-Cu, HA-Co, and HA-Ni all showed a broad spectrum of cytotoxicity and antiangiogenesis. HA-Cu was superior to HA-Co and HA-Ni, and even superior to DDP, showing significant inhibitory effect on the growth and development of tripe-negative breast cancer in vivo and in vitro. HA-Cu exhibited observable synergistic effects of antiproliferation, antiangiogenesis, anti-inflammatory, pro-apoptosis, and cuproptosis to effectively inhibited tumor survival and development. The molecular mechanism was confirmed that HA-Cu could downregulate the expression of key proteins in the VEGF/VEGFR2 signaling pathway and the expression of inflammatory cytokines, enhance the advantage of pro-apoptotic protein Bax, and enforce cuproptosis by weakening the expression of FDX1 and enhancing the expression of HSP70. Our research will provide a theoretical and practical reference for the development of metal-sulfamethazine and its derivatives as chemotherapy drugs for cancer treatment.


Angiogenesis Inhibitors , Antineoplastic Agents , Apoptosis , Coordination Complexes , Phenanthrolines , Triple Negative Breast Neoplasms , Apoptosis/drug effects , Humans , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/chemical synthesis , Coordination Complexes/therapeutic use , Animals , Phenanthrolines/pharmacology , Phenanthrolines/chemistry , Phenanthrolines/chemical synthesis , Female , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/pathology , Triple Negative Breast Neoplasms/metabolism , Angiogenesis Inhibitors/pharmacology , Angiogenesis Inhibitors/chemical synthesis , Angiogenesis Inhibitors/chemistry , Angiogenesis Inhibitors/therapeutic use , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Mice , Cell Line, Tumor , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/chemistry , Drug Synergism , Structure-Activity Relationship , Mice, Inbred BALB C , Drug Screening Assays, Antitumor
18.
J Steroid Biochem Mol Biol ; 240: 106478, 2024 Jun.
Article En | MEDLINE | ID: mdl-38430971

Inflammation, an important biological protective response to tissue damage or microbial invasion, is considered to be an alarming signal for the progress of varied biological complications. Based on the previous reports in the literature that proved the noticeable efficacy of pyrazole and thiazole scaffold as well as nitrogen heterocyclic based compounds against acute and chronic inflammatory disease, a new set of novel D-ring substituted steroidal 4,5-dihydropyrazole thiazole derivatives were synthesized and evaluated their anti-inflammatory activities in vitro. Preliminary structure-activity relationship (SAR) analysis was conducted by their inhibitory activities against nitric oxide (NO) release in lipopolysaccharide (LPS)-induced RAW 264.7 cells, and the optimal compound 12b [3ß-hydroxy-pregn-5-en-17ß-yl-5'- (o- chlorophenyl)- 1'-(4''- phenyl -[1'', 3'']- thiazol-2''- yl) - 4',5'-dihydro - 1'H-pyrazol - 3'- yl] exhibited more potent anti-inflammatory activity than the positive control treatment methylprednisolone (MPS), with an IC50 value of 2.59 µM on NO production and low cytotoxicity against RAW 264.7 cells. In further mechanism study, our results showed that compound 12b significantly suppressed the production of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and inhibited the expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) through blocking NF-κB p65 nuclear translocation and phosphorylation of IκBα. Compound 12b also attenuated LPS-induced activation of c-Jun amino-terminal kinase (JNK) and p38 phosphorylation in RAW 264.7 cells. Molecular docking study revealed the strong binding affinity of compound 12b to the active site of the COX-2 proteins, which confirmed that compound 12b acted as an anti-inflammatory mediator. These results indicate that steroidal derivatives bearing 4,5-dihydropyrazole thiazole structure might be considered for further research and scaffold optimization in designing anti-inflammatory drugs and compound 12b might be a promising therapeutic anti-inflammatory drug candidate.


Anti-Inflammatory Agents , Cyclooxygenase 2 , Drug Design , Lipopolysaccharides , Molecular Docking Simulation , Nitric Oxide Synthase Type II , Pyrazoles , Thiazoles , Animals , Mice , Lipopolysaccharides/pharmacology , RAW 264.7 Cells , Nitric Oxide Synthase Type II/metabolism , Cyclooxygenase 2/metabolism , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/chemical synthesis , Pyrazoles/pharmacology , Pyrazoles/chemistry , Pyrazoles/chemical synthesis , Thiazoles/pharmacology , Thiazoles/chemistry , Thiazoles/chemical synthesis , Structure-Activity Relationship , Nitric Oxide/metabolism , Macrophages/drug effects , Macrophages/metabolism , Cyclooxygenase 2 Inhibitors/pharmacology , Cyclooxygenase 2 Inhibitors/chemical synthesis , Cyclooxygenase 2 Inhibitors/chemistry
19.
Chem Biodivers ; 21(5): e202400031, 2024 May.
Article En | MEDLINE | ID: mdl-38448389

Ulcerative colitis has been widely concerned for its persistent upward trend, and the sustained overproduction of pro-inflammatory cytokines such as IL-6 remains a crucial factor in the development of UC. Therefore, the identification of new effective drugs to block inflammatory responses is an urgent and viable therapeutic strategy for UC. In our research, twenty-three 6-acylamino/sulfonamido benzoxazolone derivatives were synthesized, characterized, and evaluated for anti-inflammatory activity against NO and IL-6 production in LPS-induced RAW264.7 cells. The results demonstrated that most of the target compounds were capable of reducing the overexpression of NO and IL-6 to a certain degree. For the most active compounds 3i, 3j and 3 l, the inhibitory activities were superior or equivalent to those of the positive drug celecoxib with a dose-dependent relationship. Furthermore, animal experiments revealed that active derivatives 3i, 3j and 3 l exhibited definitive therapeutical effect on DSS induced ulcerative colitis in mice by mitigating weight loss and DAI score while decreasing levels of pro-inflammatory cytokines such as IL-6 and IFN-γ, simultaneously increasing production of anti-inflammatory cytokines IL-10. In addition, compounds 3i, 3j and 3 l could also inhibit the oxidative stress to alleviate ulcerative colitis by decreasing MDA and MPO levels. These finding demonstrated that compounds 3i, 3j and 3 l hold significant potential as novel therapeutic agents for ulcerative colitis.


Benzoxazoles , Colitis, Ulcerative , Interleukin-6 , Animals , Colitis, Ulcerative/drug therapy , Mice , Interleukin-6/antagonists & inhibitors , Interleukin-6/metabolism , Benzoxazoles/chemistry , Benzoxazoles/pharmacology , Benzoxazoles/chemical synthesis , RAW 264.7 Cells , Structure-Activity Relationship , Lipopolysaccharides/antagonists & inhibitors , Lipopolysaccharides/pharmacology , Nitric Oxide/antagonists & inhibitors , Nitric Oxide/metabolism , Nitric Oxide/biosynthesis , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/therapeutic use , Dextran Sulfate , Drug Discovery , Molecular Structure , Dose-Response Relationship, Drug
20.
Chem Biodivers ; 21(5): e202400030, 2024 May.
Article En | MEDLINE | ID: mdl-38511964

A traditional Chinese medicine ingredient, dendrobine, has been demonstrated to have anti-inflammatory properties. However, due to its poor anti-inflammatory properties, its clinical use is limited. Consequently, we have designed and synthesized 32 new amide/sulfonamide dendrobine derivatives and screened their anti-inflammatory activities in vitro. Experiments showed that nitric oxide (NO) generation in lipopolysaccharide (LPS)-induced RAW264.7 cells was strongly reduced by derivative 14, with an IC50 of 2.96 µM. Western blot research revealed that 14 decreased the concentration-dependent expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (INOS). Molecular docking was used to predict the binding of the inflammation-associated proteins COX-2 and INOS to compound 14.


Amides , Cyclooxygenase 2 , Lipopolysaccharides , Molecular Docking Simulation , Nitric Oxide Synthase Type II , Nitric Oxide , Sulfonamides , Animals , Mice , RAW 264.7 Cells , Sulfonamides/chemistry , Sulfonamides/pharmacology , Sulfonamides/chemical synthesis , Lipopolysaccharides/antagonists & inhibitors , Lipopolysaccharides/pharmacology , Nitric Oxide Synthase Type II/metabolism , Nitric Oxide Synthase Type II/antagonists & inhibitors , Nitric Oxide/antagonists & inhibitors , Nitric Oxide/biosynthesis , Nitric Oxide/metabolism , Cyclooxygenase 2/metabolism , Amides/chemistry , Amides/pharmacology , Amides/chemical synthesis , Structure-Activity Relationship , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/chemical synthesis , Molecular Structure , Dose-Response Relationship, Drug , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry
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