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

Kulrawee Sidthipong; Jun Ma; Wei Lin Yu; Yan Feng Wang; Susumu Kobayashi; Satoshi Kishino; Naoki Koide; Takashi Yokochi; Kuniki Kato; Shoshiro Okada; Kazuo Umezawa

doi:10.1016/j.bmcl.2016.12.017

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

Bioorg Med Chem Lett. 2017 Feb 1;27(3):562-566. doi: 10.1016/j.bmcl.2016.12.017. Epub 2016 Dec 8.

Authors

Affiliations

¹ Department of Molecular Target Medicine, Aichi Medical University School of Medicine, 1-1 Yazako-Karimata, Nagakute 480-1195, Japan.
² Shenzhen Wanhe Pharmaceutical Co., Ltd., Hi-tech Industrial Park, Nanshan District, Shenzhen, China.
³ Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641, Chiba 278-8510, Japan.
⁴ Department of Medication Use Analysis and Clinical Research, Meiji Pharmaceutical University, 2-522-1, Kiyose, Tokyo 204-0004, Japan.
⁵ Department of Microbiology and Immunology, Aichi Medical University School of Medicine, 1-1 Yazako-Karimata, Nagakute 480-1195, Japan.
⁶ Department of Pharmacology, Aichi Medical University School of Medicine, 1-1 Yazako-Karimata, Nagakute 480-1195, Japan.
⁷ Department of Molecular Target Medicine, Aichi Medical University School of Medicine, 1-1 Yazako-Karimata, Nagakute 480-1195, Japan. Electronic address: [email protected].

PMID: 28003138
DOI: 10.1016/j.bmcl.2016.12.017

Abstract

(-)-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.

Keywords: (−)-DHMEQ; Bioconjugate; Cysteine; NF-κB; α-Exomethylene-γ-lactone.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

4-Butyrolactone / chemical synthesis
4-Butyrolactone / chemistry
4-Butyrolactone / pharmacology*
Animals
Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
Anti-Inflammatory Agents, Non-Steroidal / chemistry
Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
Cell Line, Tumor
Dose-Response Relationship, Drug
Drug Design*
Humans
Lipopolysaccharides / antagonists & inhibitors
Lipopolysaccharides / pharmacology
Macrophages / drug effects
Macrophages / metabolism
Mice
Molecular Structure
NF-kappa B / antagonists & inhibitors*
NF-kappa B / metabolism
RAW 264.7 Cells
Salicylamides / chemical synthesis
Salicylamides / chemistry
Salicylamides / pharmacology*
Structure-Activity Relationship

Substances

Anti-Inflammatory Agents, Non-Steroidal
Lipopolysaccharides
NF-kappa B
Salicylamides
beta-salicyloylamino-alpha-exo-methylene-gamma-butyrolactone
4-Butyrolactone