Anti-inflammatory effects of benzotropolone derivatives

Therapeutic effects of black tea theaflavines (TFs) containing the benzotropolone (BZ) core structure of polyphenols are well established. In our study, we synthesized nine different BZ derivatives and tested them for anti-proliferative and anti-inflammatory bioactivities employing cell-based and in vivo models for inflammation. Three low molecular weight derivatives such as the natural-derived purpurogallin (BZ-5), 3,4,6-trihydroxy-5H-benzo[7]-annulen-5-one (BZ-6) and 3,4,6-trihydroxy-5-oxo-5H-benzo[7]annulen-1-yl)acrylic acid (BZ-7) showed strong anti-inflammatory effects. TaqMan qPCR demonstrated a prominent downregulation of COX-2, TNF-α, ICAM-1, IL-1ß and IL-8. Intriguingly, the new described compound BZ-7 showed strongest anti-inflammatory effects and only mild toxicity as compared to the others. Structure-activity relationship analysis revealed that placement of functional groups around the benzotropolone core moiety strongly affected anti-proliferative and anti-inflammatory bioactivities. Further analysis of BZ-6 representing the benzotropolone core moiety showed a significant downregulation of COX-2 in colonic carcinoma cells (Caco-2). Strong anti-inflammatory effects correlated in a mouse edema model where BZ-6 gave comparable effects to ibuprofen. In summary, our results indicate an inhibitory interaction of the BZ core moiety with cellular targets of inflammatory pathways as potential executioner of theaflavins through biotransformation. Thus, specific benzotropolones might be good candidate compounds with a therapeutic potential against diseases associated with chronic inflammation.