epoxyquinomicin-c and Arthritis--Rheumatoid

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.

Topics: Animals; Antineoplastic Agents; Antirheumatic Agents; Arthritis, Rheumatoid; Benzamides; Biotransformation; Circular Dichroism; Humans; Jurkat Cells; Magnetic Resonance Spectroscopy; Mice; NF-kappa B; Oxidation-Reduction; Quinones; Stereoisomerism; Structure-Activity Relationship; Tumor Necrosis Factor-alpha

The anti-arthritic effects of epoxyquinomicins on type II collagen-induced arthritis in DBA/1J mice were examined. Prophylactic treatment with epoxyquinomicins A, B, C and D (1-4 mg/kg) had potent inhibitory effects on type II collagen-induced arthritis. In contrast to nonsteroidal anti-inflammatory drugs (NSAIDs), epoxyquinomicin C (1-30 mg/kg) had neither an anti-inflammatory effect on carrageenan-induced paw edema in rats nor an analgesic effect on acetic acid-induced writhing in mice. These results suggest that the mode of action of epoxyquinomicins is different from that of NSAIDs and that epoxyquinomicins may become useful drugs for the treatment of rheumatoid arthritis.

Topics: Actinobacteria; Animals; Antirheumatic Agents; Arthritis, Rheumatoid; Benzamides; Carrageenan; Collagen; Edema; Male; Mice; Mice, Inbred DBA; Quinones; Rats; Rats, Sprague-Dawley