Synthesis of NF-kappaB activation inhibitors derived from epoxyquinomicin C.
In order to develop new inhibitors of NF-kappaB activation, we designed and synthesized dehydroxymethyl derivatives of epoxyquinomicin C, namely, DHM2EQ and its regioisomer DHM3EQ. These derivatives were synthesized from 2,5-dimethoxyaniline in 5 steps. Since DHM2EQ was more active and less toxic than DHM3EQ, its stereochemical configuration was determined by X-ray crystallographic analysis. Each enantiomer of the protected DHM2EQ was separated by a chiral column and deprotected. DHM2EQ inhibited TNF-alpha-induced activation of NF-kappaB in human T cell leukemia cells, and also inhibited collagen-induced arthritis in a rheumatoid model in mice.
Matsumoto
N
N
Institute of Microbial Chemistry, Tokyo, Japan.
Ariga
A
A
To-e
S
S
Nakamura
H
H
Agata
N
N
Hirano
S
S
Inoue
J
J
Umezawa
K
K
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018501:Antirheumatic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000517:prevention & control; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001711:Biotransformation / Q000187:drug effects; D002942:Circular Dichroism; D006801:Humans; D019169:Jurkat Cells; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010084:Oxidation-Reduction; D011809:Quinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000970:Antineoplastic Agents; D018501:Antirheumatic Agents; D001549:Benzamides; D016328:NF-kappa B; D011809:Quinones; D014409:Tumor Necrosis Factor-alpha; C111288:epoxyquinomicin C