EI-1941-1

EI-1941-1 and -2, novel interleukin-1 beta converting enzyme (ICE) inhibitors, were isolated from the culture broths of Farrowia sp. E-1941. EI-1941-1 and -2 selectively inhibited the human recombinant ICE activity with IC50 values of 0.086 and 0.006 microM, respectively. Taxonomy and fermentation of the producing strain and isolation, physico-chemical properties, structure elucidation, and biological properties of EI-1941-1 and -2 are described.

[reaction: see text] The first asymmetric total synthesis of EI-1941-1, -2, and -3, inhibitors of the interleukin-1beta converting enzyme (ICE), has been accomplished, starting from a chiral epoxy iodoquinone 11, a key intermediate in our total synthesis of epoxyquinols A and B. Despite a failure to synthesize the inhibitors by our postulated biosynthetic route, we were able to diastereoselectively synthesize them via an intramolecular carboxypalladation with the key steps being a 6-endo cyclization mode followed by beta-hydride elimination. The investigation of the biological properties of EI-1941-1, -2, and -3 and their derivatives disclosed them to be potent and effective ICE inhibitors with less cytotoxicity than EI-1941-1 and -2 in a cultured cell system.

EI-1941-1 and -2 isolated from the culture broths of Farrowia sp. selectively inhibited the human recombinant ICE activity with IC50 values of 0.086 and 0.006 microM, respectively, without inhibiting elastase and cathepsin B. EI-1941-1 and -2 also inhibited mature interleukin-1beta secretion from THP-1 cells induced by LPS with IC50 values of 5.0 and 10.3 microM, respectively. Biochemical characterizations of EI-1941-1 and -2 are described in this article.