Novel cyclohexene derivatives as anti-sepsis agents: synthetic studies and inhibition of NO and cytokine production.
In order to develop an anti-sepsis agent, a series of cyclohexene derivatives were synthesized and evaluated for their biological activities. Through modification of the sulfonamide spacer moiety depicted by formula II, it was found that the benzylsulfone derivative 10a had potent inhibitory activity against the production of NO. Further modifications of the phenyl ring, ester moiety, and benzyl position of benzylsulfone derivatives III were carried out. Among these compounds, (R)-(+)-10a and (6R, 1S)-(+)-22a showed strong inhibitory activity not only against NO production but also against inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in vitro. Furthermore, (R)-(+)-10a and (6R, 1S)-(+)-22a protected mice from LPS-induced lethality in a dose-dependent manner.
Yamada
Masami
M
Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd, 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan. Yamada_Masami1@takeda.co.jp
Ichikawa
Takashi
T
Ii
Masayuki
M
Itoh
Katsumi
K
Tamura
Norikazu
N
Kitazaki
Tomoyuki
T
D000818:Animals; D002460:Cell Line; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D003432:Cross-Linking Reagents / Q000737:chemistry; D018360:Crystallography, X-Ray; D053138:Cyclohexenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D015195:Drug Design; D015850:Interleukin-6 / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009569:Nitric Oxide / Q000096:biosynthesis*; D018805:Sepsis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D003432:Cross-Linking Reagents; D053138:Cyclohexenes; D015850:Interleukin-6; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; C052568:cyclohexene; D009569:Nitric Oxide