Synthesis and activity of N-(5-hydroxy-3,4,6-trimethylpyridin-2-yl) acetamide analogues as anticolitis agents via dual inhibition of TNF-alpha- and IL-6-induced cell adhesions
DC Field | Value | Language |
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dc.contributor.author | Karmacharya, Ujjwala | - |
dc.contributor.author | Regmi, Sushil Chandra | - |
dc.contributor.author | Awasthi, Bhuwan Prasad | - |
dc.contributor.author | Chaudhary, Prakash | - |
dc.contributor.author | Kim, Ye Eun | - |
dc.contributor.author | Lee, Iyn-Hyang | - |
dc.contributor.author | Nam, Tae-gyu | - |
dc.contributor.author | Kim, Jung-Ae | - |
dc.contributor.author | Jeong, Byeong-Seon | - |
dc.date.accessioned | 2021-07-28T08:07:22Z | - |
dc.date.available | 2021-07-28T08:07:22Z | - |
dc.date.created | 2021-07-22 | - |
dc.date.issued | 2021-07 | - |
dc.identifier.issn | 0960-894X | - |
dc.identifier.uri | https://scholarworks.bwise.kr/erica/handle/2021.sw.erica/105724 | - |
dc.description.abstract | Tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) are the critical pro-inflammatory cytokines involved in the pathogenesis of inflammatory bowel disease (IBD). Inhibition of these cytokines and related signaling pathways has been a target for the development of IBD therapeutics. In the current study, 6-acetamido2,4,5-trimethylpyridin-3-ol (1) and various analogues with the amido scaffold were synthesized and examined for their inhibitory activities in in vitro and in vivo IBD models. The parent compound 1 (1 mu M) showed an inhibitory activity against TNF-alpha- and IL-6-induced adhesion of monocytes to colon epithelial cells, which was similar to tofacitinib (1 mu M), a JAK inhibitor, but much better than mesalazine (1,000 mu M). All the analogues showed a positive relationship (R-2 = 0.8943 in a linear regression model) between the inhibitory activities against TNF-alpha-induced and those against IL-6-induced adhesion. Compound 2-19 turned out to be the best analogue and showed much better inhibitory activity against TNF-alpha- and IL-6-induced adhesion of the cells than tofacitinib. In addition, oral administration of compound 1 and 2-19 resulted in a significant suppression of clinical signs of TNBS-induced rat colitis, including weight loss, colon tissue edema, and myeloperoxidase activity, a marker for inflammatory cell infiltration in colon tissues. More importantly, compound 2-19 (1 mg/kg) was more efficacious in ameliorating colitis than compound 1 and sulfasalazine (300 mg/kg), the commonly prescribed oral IBD drug. Taken together, the results suggest that compound 2-19 can be a novel platform for dual-acting IBD drug discovery targeting both TNF-alpha and IL-6 signaling. | - |
dc.language | 영어 | - |
dc.language.iso | en | - |
dc.publisher | PERGAMON-ELSEVIER SCIENCE LTD | - |
dc.title | Synthesis and activity of N-(5-hydroxy-3,4,6-trimethylpyridin-2-yl) acetamide analogues as anticolitis agents via dual inhibition of TNF-alpha- and IL-6-induced cell adhesions | - |
dc.type | Article | - |
dc.contributor.affiliatedAuthor | Nam, Tae-gyu | - |
dc.identifier.doi | 10.1016/j.bmcl.2021.128059 | - |
dc.identifier.scopusid | 2-s2.0-85105521351 | - |
dc.identifier.wosid | 000663580200010 | - |
dc.identifier.bibliographicCitation | BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, v.43, pp.1 - 6 | - |
dc.relation.isPartOf | BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | - |
dc.citation.title | BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | - |
dc.citation.volume | 43 | - |
dc.citation.startPage | 1 | - |
dc.citation.endPage | 6 | - |
dc.type.rims | ART | - |
dc.type.docType | Article | - |
dc.description.journalClass | 1 | - |
dc.description.isOpenAccess | N | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
dc.relation.journalResearchArea | Pharmacology & Pharmacy | - |
dc.relation.journalResearchArea | Chemistry | - |
dc.relation.journalWebOfScienceCategory | Chemistry, Medicinal | - |
dc.relation.journalWebOfScienceCategory | Chemistry, Organic | - |
dc.subject.keywordPlus | INFLAMMATORY-BOWEL-DISEASE | - |
dc.subject.keywordPlus | T-CELLS | - |
dc.subject.keywordPlus | NECROSIS | - |
dc.subject.keywordPlus | DERIVATIVES | - |
dc.subject.keywordPlus | CYTOKINES | - |
dc.subject.keywordPlus | TARGETS | - |
dc.subject.keywordPlus | IMMUNE | - |
dc.subject.keywordPlus | IL-6 | - |
dc.subject.keywordAuthor | Inflammatory bowel disease | - |
dc.subject.keywordAuthor | TNF-alpha | - |
dc.subject.keywordAuthor | IL-6 | - |
dc.subject.keywordAuthor | Amidopyridinol | - |
dc.subject.keywordAuthor | TNBS-induced colitis | - |
dc.identifier.url | https://www.sciencedirect.com/science/article/pii/S0960894X21002857?via%3Dihub#! | - |
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