Discovery of dibenzyl amide derivatives as novel CXCR4 modulators against inflammatory bowel disease
The CXCR4/CXCL12 chemokine axis demonstrates significant potential in the treatment of inflammatory bowel disease (IBD) due to its crucial roles in inflammatory and immune responses. Modulating the CXCR4/CXCL12 pathway can be an effective therapeutic approach to ameliorate the inflammatory state of...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-04-01
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| Series: | European Journal of Medicinal Chemistry Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2772417424000062 |
| _version_ | 1797262782765203456 |
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| author | Xiaoying Jiang Liuxin Lu Jiahui Wang Meng Yu Rui Wu Rui Zhao Hao Wen Renren Bai |
| author_facet | Xiaoying Jiang Liuxin Lu Jiahui Wang Meng Yu Rui Wu Rui Zhao Hao Wen Renren Bai |
| author_sort | Xiaoying Jiang |
| collection | DOAJ |
| description | The CXCR4/CXCL12 chemokine axis demonstrates significant potential in the treatment of inflammatory bowel disease (IBD) due to its crucial roles in inflammatory and immune responses. Modulating the CXCR4/CXCL12 pathway can be an effective therapeutic approach to ameliorate the inflammatory state of IBD. In this study, a novel series of meta-dibenzyl amide derivatives were designed and synthesized based on the lead compound AMD3100 and its structurally modified derivatives. Both in vitro and in vivo assays conclusively established that these compounds exhibited potent CXCR4 antagonism and anti-inflammatory activity. Compound 5t demonstrated superior inhibitory rates of binding affinity and chemotaxis of CXCR4+ cells compared to AMD3100. Furthermore, compound 5t notably reduced swelling volume and tissue thickness in the carrageenan-induced mouse paw edema model. Most importantly, in the dextran sodium sulfate (DSS)-induced colitis model, compound 5t significantly mitigated colonic inflammation on both macroscopic and microscopic levels, while suppressing the expression of inflammatory factors and myeloperoxidase (MPO). These findings unequivocally establish the immense potential of compound 5t in the treatment of IBD. |
| first_indexed | 2024-03-08T10:18:40Z |
| format | Article |
| id | doaj.art-50d75d3d886e4d9eb6536b9a8ab59689 |
| institution | Directory Open Access Journal |
| issn | 2772-4174 |
| language | English |
| last_indexed | 2024-04-25T00:02:35Z |
| publishDate | 2024-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | European Journal of Medicinal Chemistry Reports |
| spelling | doaj.art-50d75d3d886e4d9eb6536b9a8ab596892024-03-14T06:17:05ZengElsevierEuropean Journal of Medicinal Chemistry Reports2772-41742024-04-0110100134Discovery of dibenzyl amide derivatives as novel CXCR4 modulators against inflammatory bowel diseaseXiaoying Jiang0Liuxin Lu1Jiahui Wang2Meng Yu3Rui Wu4Rui Zhao5Hao Wen6Renren Bai7School of Pharmacy, Hangzhou Normal University, Hangzhou, 311121, PR China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, 311121, PR ChinaSchool of Pharmacy, Hangzhou Normal University, Hangzhou, 311121, PR China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, 311121, PR ChinaSchool of Pharmacy, Hangzhou Normal University, Hangzhou, 311121, PR China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, 311121, PR ChinaSchool of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, PR ChinaSchool of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, PR ChinaSchool of Pharmacy, Hangzhou Normal University, Hangzhou, 311121, PR China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, 311121, PR ChinaSchool of Pharmacy, Hangzhou Normal University, Hangzhou, 311121, PR China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, 311121, PR ChinaSchool of Pharmacy, Hangzhou Normal University, Hangzhou, 311121, PR China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, 311121, PR China; Corresponding author. School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, PR China.The CXCR4/CXCL12 chemokine axis demonstrates significant potential in the treatment of inflammatory bowel disease (IBD) due to its crucial roles in inflammatory and immune responses. Modulating the CXCR4/CXCL12 pathway can be an effective therapeutic approach to ameliorate the inflammatory state of IBD. In this study, a novel series of meta-dibenzyl amide derivatives were designed and synthesized based on the lead compound AMD3100 and its structurally modified derivatives. Both in vitro and in vivo assays conclusively established that these compounds exhibited potent CXCR4 antagonism and anti-inflammatory activity. Compound 5t demonstrated superior inhibitory rates of binding affinity and chemotaxis of CXCR4+ cells compared to AMD3100. Furthermore, compound 5t notably reduced swelling volume and tissue thickness in the carrageenan-induced mouse paw edema model. Most importantly, in the dextran sodium sulfate (DSS)-induced colitis model, compound 5t significantly mitigated colonic inflammation on both macroscopic and microscopic levels, while suppressing the expression of inflammatory factors and myeloperoxidase (MPO). These findings unequivocally establish the immense potential of compound 5t in the treatment of IBD.http://www.sciencedirect.com/science/article/pii/S2772417424000062CXCR4 modulatorsDibenzyl amide derivativesInflammatory bowel disease (IBD)Anti-inflammatory activity |
| spellingShingle | Xiaoying Jiang Liuxin Lu Jiahui Wang Meng Yu Rui Wu Rui Zhao Hao Wen Renren Bai Discovery of dibenzyl amide derivatives as novel CXCR4 modulators against inflammatory bowel disease European Journal of Medicinal Chemistry Reports CXCR4 modulators Dibenzyl amide derivatives Inflammatory bowel disease (IBD) Anti-inflammatory activity |
| title | Discovery of dibenzyl amide derivatives as novel CXCR4 modulators against inflammatory bowel disease |
| title_full | Discovery of dibenzyl amide derivatives as novel CXCR4 modulators against inflammatory bowel disease |
| title_fullStr | Discovery of dibenzyl amide derivatives as novel CXCR4 modulators against inflammatory bowel disease |
| title_full_unstemmed | Discovery of dibenzyl amide derivatives as novel CXCR4 modulators against inflammatory bowel disease |
| title_short | Discovery of dibenzyl amide derivatives as novel CXCR4 modulators against inflammatory bowel disease |
| title_sort | discovery of dibenzyl amide derivatives as novel cxcr4 modulators against inflammatory bowel disease |
| topic | CXCR4 modulators Dibenzyl amide derivatives Inflammatory bowel disease (IBD) Anti-inflammatory activity |
| url | http://www.sciencedirect.com/science/article/pii/S2772417424000062 |
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