Bioorganic & Medicinal Chemistry Letters 10 (2000) 865±869
Synthesis of NF-ꢀB Activation Inhibitors Derived from
Epoxyquinomicin C
Naoki Matsumoto, a Akiko Ariga, b Sakino To-e, b Hikaru Nakamura, a Naoki Agata, c
Shin-ichi Hirano, c Jun-ichiro Inoue d and Kazuo Umezawa b,*
aInstitute of Microbial Chemistry, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
bDepartment of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi,
Kohoku-ku, Yokohama 223-0061, Japan
cCentral Research Laboratories, Mercian Corp., 4-9-1 Johnan, Fujisawa, Kanagawa 251-0057, Japan
dInstitute of Medical Science, University of Tokyo, 4-6-8 Shirokanedai, Minato-ku, Tokyo 108-0071, Japan
Received 22 November 1999; accepted 11 February 2000
AbstractÐIn order to develop new inhibitors of NF-kB activation, we designed and synthesized dehydroxymethyl derivatives of
epoxyquinomicin C, namely, DHM2EQ and its regioisomer DHM3EQ. These derivatives were synthesized from 2,5-dimethoxy-
aniline in 5 steps. Since DHM2EQ was more active and less toxic than DHM3EQ, its stereochemical con®guration was determined
by X-ray crystallographic analysis. Each enantiomer of the protected DHM2EQ was separated by a chiral column and deprotected.
DHM2EQ inhibited TNF-a-induced activation of NF-kB in human T cell leukemia cells, and also inhibited collagen-induced
arthritis in a rheumatoid model in mice. # 2000 Elsevier Science Ltd. All rights reserved.
Introduction
additional hydroxymethyl group compared with pane-
poxydone that inhibits NF-kB. Therefore, we designed
and synthesized 5-dehydroxymethyl derivatives of
epoxyquinomicin C.
NF-kB is a transcription factor that mediates the
expression of a variety of cellular genes regulating the
in¯ammatory response. For example, the expression of
various cytokines such as IL-1, IL-2, IL-8 and TNF-a is
regulated by NF-kB. NF-kB is located in the cytoplasm
along with its endogenous inhibitor, I-kB. Stimulatory
signals such as TNF-a and phorbol esters induce
degradation of I-kB, and NF-kB consequently activated
enters the nucleus to bind to the kB site of DNA. Inhi-
bitors of this process of NF-kB activation are likely to
become new anti-in¯ammatory and anti-rheumatoid
agents.1 Recently, panepoxydone2 and cycloepoxydon3
were reported to inhibit NF-kB activation, both of
which have the 4-hydroxy-5,6-epoxycyclohexenone
structure. We previously isolated four novel 5,6-epox-
ycyclohexenone compounds named epoxyquinomicins
from Amycolatopsis sp. MK299-95F4 as antibiotics and
anti-in¯ammatory agents.4,5 Epoxyquinomicin C was
the simplest among them, having a 4-hydroxy-5,6-
epoxycyclohexenone structure, however, it did not inhi-
bit activation of NF-kB. Epoxyquinomicin C has an
Synthesis
The synthetic route for DHM2EQ and DHM3EQ is
outlined in Scheme 1. We employed the Wipf method6
with modi®cations for the preparation of the quinone
monoketal structure. Commercially available 2,5-dime-
thoxyaniline, 3, and acetylsalicyloyl chloride were cou-
pled in pyridine to give salicylamide 4, which was
subsequently oxidized by iodobenzenediacetate in
methanol to yield quinone monoketal 5, in 50% yield.
Epoxidation of 5 with alkaline hydrogen peroxide in
aqueous THF gave epoxide 6 in 53% yield con-
comitant with deprotection of the phenolic acetyl
group. Although the condition was strongly basic, no
*Corresponding author. Tel.: +81-45-563-1141; fax: +81-45-562-
7625; e-mail: umezawa@applc.keio.ac.jp
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00114-1