Chemical Biology & Drug Design
·
2024
·Vol. 103
·期 1
·e14437
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IF 3.2
Junde Xu,Keshuang Tang,Zhiran Ju
The adverse effects caused by nonselective and selective cyclooxygenase-2 (COX-2) inhibitors remain a challenge for current anti-inflammatory medications. A balanced inhibition of COX-1/−2 represents a promising strategy for the development of novel COX-2 inhibitors. In this study, we present the design and synthesis of a novel series of firocoxib analogues incorporating an amide bond to facilitate essential hydrogen bonding with amino residues in COX-2. The synthesized analogs were evaluated for their inhibitory activity against both COX-1 and COX-2 enzymes. Among them, compound 9d demonstrated potent and balanced inhibition. Inhibition of COX enzymes by 9d in lipopolysaccharide (LPS)-stimulated murine RAW264.7 macrophages resulted in the suppression of the NF- κ B signaling pathway to reduced expression of pro-inflammatory factors such as inducible nitric oxide synthase (iNOS), COX-2, nitric oxide (NO), and reactive oxygen species (ROS). The remarkable in vitro anti-inflammatory activity exhibited by 9d positions it as a promising candidate for further development as a novel lead compound for inflammation treatment.
研究领域:
药理学
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药物化学
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炎症研究
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DOI
PubMed
高影响因子
PLoS One
·
2014
·Vol. 9
·期 6
·e98513
·
IF 3.534
Xi-E Zhen,Ming Zong,Sai-Nan Gao,Yong-Gang Cao,Lei Jiang,Shu-Xin Chen,Kuan Wang,Shi-Qin Sun,Hai-Sheng Peng,Yu-Hua Bai,Sen Li
The use of acetylsalicylic acid (ASP) is limited by its adverse effects, especially the effect on the gastric mucosa. To address this problem, we synthesized a derivative form of ASP, prepared by modification of ASP with nano-hydroxyapatite (a kind of inorganic particle containing Ca 2+ ). The derivative was named Ca-ASP. Structural study showed that Ca-ASP was a kind of carboxylate containing intramolecular hydrogen bonds. Rats given a high dose of Ca-ASP (5 mmol per kg body weight) showed similar anti-thrombotic activity as those given the same dose of ASP, but had much lower gastric mucosal damage than ASP (UI: 2 versus UI: 12.5). These rats also showed reduced expression of COX-2, but their COX-1 expression was similar to that of control rats, but significantly higher than that of ASP-administered rats. Furthermore, the level of prostaglandin E2 (PGE2) was up-regulated in Ca-ASP-administered rats compared to ASP-administered rats. Taken together, the results showed that Ca-ASP possessed similar antithrombotic activity as ASP but without the side effect associated with ASP, and the underlying mechanism may center on inhibiting COX-2 without inhibiting COX-1, and thus favouring the production of PGE2, the prostaglandin that plays a vital role in the suppression of platelet aggregation and thrombosis, as well as in the repair of gastric damage.
研究领域:
药学
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药物化学
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药理学
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产品关联
DOI
PubMed
高影响因子
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
·
2019
·Vol. 393
·期 6
·967-978
·
IF 2.058
Rong Rong,Zhang Rui-zhen,Wang Xin,Dan Yu-han,Zhao Yun-li,Yu Zhi-guo
R -/ S -2-(2-hydroxypropanamido) benzoic acid ( R -/ S -HPABA), marine-derived anti-inflammatory antiplatelet drugs, were initially synthesised in our group. However, preliminary research showed that R -/ S -HPABA were eliminated rapidly because of extensive hydroxylation metabolism of phenyl ring in vivo. In order to reduce significant hydroxylation metabolism to improve pharmacological activity and bioavailability, trifluoromethyl group was incorporated into R -/ S -HPABA to synthesise R -/ S -2-(2-hydroxypropanamido)-5-trifluoromethyl benzoic acid ( R -/ S -HFBA), respectively. The purposes of this study were to report the synthesis of R -/ S -HFBA and compare the anti-inflammatory antiplatelet effect and pharmacokinetic properties of R -/ S -HFBA with those of R -/ S -HPABA. Carrageenan-induced rat paw edema assay was used for the evaluation of the anti-inflammatory activity. R -/ S -HFBA showed better results in inhibiting edema and were able to prolong the anti-inflammatory effect after carrageenan injection. The antiplatelet aggregation activity of R -/ S -HFBA and R -/ S -HPABA was studied on arachidonic acid-induced platelet aggregation of rabbit platelet-rich plasma. The aggregation inhibition rate of R- / S -HFBA was significantly ( p < 0.05) higher than that of R- / S -HPABA, respectively. Molecular docking study revealed that R -/ S -HFBA possess more potent binding affinity with COX-1/COX-2 than R -/ S -HPABA, respectively, and that the presence of trifluoromethyl group leads to increase in activity of R -/ S -HFBA. R -/ S -HFBA also afford more favorable pharmacokinetic properties than R- / S -HPABA, respectively, such as higher C max , larger AUC 0-∞ , and longer t 1/2 , which, as expected, are more metabolically stable.
研究领域:
药理学
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药物化学
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药物设计
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产品关联
DOI
PubMed
高影响因子
Frontiers in Molecular Biosciences
·
2023
·
IF 5
Xue Zhichao,Zeng Jiaming,Yin Xinchi,Li Yongshu,Meng Bo,Zhao Yang,Fang Xiang,Gong Xiaoyun,Dai Xinhua
Palbociclib is a specific CDK4/6 inhibitor that has been widely applied in multiple types of tumors. Different from cytotoxic drugs, the anticancer mechanism of palbociclib mainly depends on cell cycle inhibition. Therefore, the resistance mechanism is different. For clinical cancer patients, drug resistance is inevitable for almost all cancer therapies including palbociclib. We have trained palbociclib resistant cells in vitro to simulate the clinical situation and applied LC-MS multi-omics analysis methods including proteomic, metabolomic, and glycoproteomic techniques, to deeply understand the underly mechanism behind the resistance. As a result of proteomic analysis, the resistant cells were found to rely on altered metabolic pathways to keep proliferation. Metabolic processes related to carbohydrates, lipids, DNA, cellular proteins, glucose, and amino acids were observed to be upregulated. Most dramatically, the protein expressions of COX-1 and NDUFB8 have been detected to be significantly overexpressed by proteomic analysis. When a COX-1 inhibitor was hired to combine with palbociclib, a synergistic effect could be obtained, suggesting the altered COX-1 involved metabolic pathway is an important reason for the acquired palbociclib resistance. The KEGG pathway of N-glycan biosynthesis was identified through metabolomics analysis. N-glycoproteomic analysis was therefore included and the global glycosylation was found to be elevated in the palbociclib-resistant cells. Moreover, integration analysis of glycoproteomic data allowed us to detect a lot more proteins that have been glycosylated with low abundances, these proteins were considered to be overwhelmed by those highly abundant proteins during regular proteomic LC-MS detection. These low-abundant proteins are mainly involved in the cellular biology processes of cell migration, the regulation of chemotaxis, as well as the glycoprotein metabolic process which offered us great more details on the roles played by N-glycosylation in drug resistance. Our result also verified that N-glycosylation inhibitors could enhance the cell growth inhibition of palbociclib in resistant cells. The high efficiency of the integrated multi-omics analysis workflow in discovering drug resistance mechanisms paves a new way for drug development. With a clear understanding of the resistance mechanism, new drug targets and drug combinations could be designed to resensitize the resistant tumors.
研究领域:
肿瘤学
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药理学
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分子生物学
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系统生物学
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生物信息学
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产品关联
DOI
PubMed
高影响因子
ChemMedChem
·
2023
·Vol. 18
·期 23
·e202300468
·
IF 3.4
Jingjie Fang,Ziyi Shang,Kumaravel Kaliaperumal,Zhiran Ju,Fen-Er Chen
Graphical This study presents a design strategy, synthesis, and evaluation of balanced COX inhibitors derived from natural anti-inflammatory ascidian metabolites and celecoxib, highlighting their potential therapeutic value in the context of inflammation. The serious adverse effects caused by non-selective and selective cyclooxygenase-2 (COX-2) inhibitors remain significant concerns for current anti-inflammatory drugs. In this study, we present the design and synthesis of a novel series of celecoxib analogs incorporating a hydrazone linker, which were subjected to in silico analysis to compare their binding poses with those of clinically used nonsteroidal anti-inflammatory drugs (NSAIDs) against COX-1 and COX-2. The synthesized analogs were evaluated for their inhibitory activity against both COX enzymes, and compound 6 m , exhibiting potent balanced inhibition, was selected for subsequent in vitro anti-inflammatory assays. Treatment with 6 m effectively suppressed the NF-κB signaling pathway in lipopolysaccharide (LPS)-stimulated murine RAW264.7 macrophages, resulting in reduced expression of pro-inflammatory factors such as inducible nitric oxide synthase (iNOS), COX-2, tumor necrosis factor- α (TNF-α), interleukin-6 (IL-6), IL-1β, as well as decreased production of prostaglandin E 2 (PGE 2 ), nitric oxide (NO), and reactive oxygen species (ROS). However, 6 m has no effect on the MAPK signaling pathway. Therefore, due to its potent in vitro anti-inflammatory activity coupled with lack of cytotoxicity, 6 m represents a promising candidate for further development as a new lead compound targeting inflammation.
研究领域:
药理学
·
药物化学
·
炎症研究
·
药物设计
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）