Synthesis and evaluation of xanthone derivatives as acid sphingomyelinase inhibitors: potential treatment for UV-induced skin damage.

AIM: ASM, which hydrolyzes sphingomyelin into ceramide, is recognized as a therapeutic target for UV-induced skin damage. Direct inhibitors for this enzyme are rare. Here we synthesized several series of 1,3,6,7-tetrahydroxy-xanthone derivatives as novel ASM inhibitors.

RESULTS: Several compounds were more potent than the lead compound, among which 5b was found competitively inhibiting the enzyme and dose-dependently reducing ceramide generation. Furthermore, 5b and 5c showed excellent protective effect to skin keratinocytes against UV. Quantitative structure-activity relationship investigation revealed detail relationships between molecular structure and biological activity. Insight into the binding mode was precisely illuminated by molecule docking.

CONCLUSION: This work would provide fresh ideas and strong supports for further development of ASM inhibitors and drug candidates for skin damage.