Synthesis, cytotoxicity, anti-oxidative and anti-inflammatory activity of chalcones and influence of A-ring modifications on the pharmacological effect.
Besides 2',4'-dihydroxy-4,6'-dimethoxy-3'-prenylchalcone (1) and 4-acetoxy-2',4'-dihydroxy-6'-methoxy-3'-prenylchalkon (2), both phase II metabolites of xanthohumol in rats, also a principally new chalcone 3'-coumaroyl-2',4,4'-trihydroxy-6'-methoxychalcone (3), structurally derived from helichrysetin (4) by introducing a second coumaroyl substructure at C-3' was synthesized. Furthermore new chalcones were synthesized by combination of the B-Ring fragments of helichrysetin, xanthohumol, xanthohumol C and xanthohumol H with ferulic or caffeic acid moieties in Ring A. Compound 3 showed the highest cytotoxic activity against HeLa cells with an IC50 value of 7.3+/-0.4 microM. Anti-oxidative effects were determined in the ORAC assay and revealed very strong activity for 3 and 3-methoxyhelichrysetin (6) exhibiting 7.7+/-0.3 and 6.0+/-1.3 Trolox equivalents, respectively. The anti-inflammatory activity of all compounds was measured in an in vitro ICAM-1 assay with human microvascular endothelial cells (HMEC-1) and compared with the activity of other structurally related chalcones. The results showed increasing anti-inflammatory activity for the new synthetic chalcones exhibiting a caffeoyl substructure with 3-hydroxyhelichrysetin (5) and 3-hydroxyxanthohumol H (14) being the most active. At 10 microM the TNFalpha induced expression of ICAM-1 was significantly reduced to 65.8 and 69.6% of control, respectively.
Institute of Pharmacy, Chair of Pharmaceutical Biology, University of Regensburg, Universitätsstr. 31, 93053 Regensburg, Germany.
Susanne
S
Vogel
Matej
M
Barbic
Guido
G
Jürgenliemk
Jörg
J
Heilmann
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D047188:Chalcones / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D051381:Rats; D013329:Structure-Activity Relationship
D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D000975:Antioxidants; D047188:Chalcones