Rational design, synthesis and in vitro evaluation of novel exo-methylene butyrolactone salicyloylamide as NF-κB inhibitor

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• 作者：Kulrawee Sidthipong^a ; Jun Ma^b ; Wei Lin Yu^b ; Yan Feng Wang^b ; Susumu Kobayashi^c ; Satoshi Kishino^d ; Naoki Koide^e ; Takashi Yokochi^e ; Kuniki Kato^a ; Shoshiro Okada^f ; Kazuo Umezawa^a ; ^{umezawa@aichi-med-u.ac.jp}
• 关键词：(&minus ; )-DHMEQ ; Cysteine ; NF-κB ; α-Exomethylene-γ-lactone ; Bioconjugate
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2017
• 出版时间：1 February 2017
• 年：2017
• 卷：27
• 期：3
• 页码：562-566
• 全文大小：1094 K
• 卷排序：27

文摘

(−)-Dehydroxymethylepoxyquinomicin ((−)-DHMEQ, 1) is a specific inhibitor of NF-κB. It binds to SH group in the specific cysteine residue of NF-κB components with its epoxide moiety to inhibit DNA binding. In the present research, we have designed and synthesized an epoxide-free analog called (S)-β-salicyloylamino-α-exo-methylene-ƴ-butyrolactone (SEMBL, 3). SEMBL inhibited DNA binding of NF-κB component p65 in vitro. It inhibited LPS-induced NF-κB activation, iNOS expression, and inflammatory cytokine secretions. It also inhibited NF-κB and cellular invasion in ovarian carcinoma ES-2 cells. Moreover, its stability in aqueous solution was greatly enhanced compared with (−)-DHMEQ. Thus, SEMBL has a potential to be a candidate for a new anti-inflammatory and anticancer agent.