Synthesis of NF-κB activation inhibitors derived from epoxyquinomicin C

In order to develop new inhibitors of NF-kappa B 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-kappa B in human T cell leukemia cells, and also inhibited collagen-induced arthritis in a rheumatoid model in mice. (C) 2000 Elsevier Science Ltd. All rights reserved.