Depsides as non-redox inhibitors of leukotriene B4 biosynthesis and HaCaT cell growth. 1. Novel analogues of barbatic and diffractaic acid

Aseries of barbatic and diffractaic acid analogues has been synthesized and evaluated as inhibitors of leukotriene B₄ (LTB₄) biosynthesis and as antiproliferative agents. The 4-O-demethyl barbatic and diffractaic acid derivatives were among the most active compounds in both assays. In particular, ethyl 4-O-demethylbarbatate was the most potent LTB₄ biosynthesis inhibitor of this series, with an IC₅₀ value in the submicromolar range. Because the compounds did not show appreciable reactivity against a stable free radical, 2,2-diphenyl-1-picrylhydrazyl, and did not produce appreciable amounts of deoxyribose degradation as a measure of their potency to generate hydroxyl radicals, a simple redox effect could not explain their biological activity. Also, there was no nonspecific cytotoxicity as documented by the activity of lactate dehydrogenase released from the cytoplasm of keratinocytes, which was in the control range.