Selective synthesis and biological evaluation of sulfate-conjugated resveratrol metabolites.
Five resveratrol sulfate metabolites were synthesized and assessed for activities known to be mediated by resveratrol: inhibition of tumor necrosis factor (TNF) alpha induced NFkappaB activity, cylcooxygenases (COX-1 and COX-2), aromatase, nitric oxide production in endotoxin-stimulated macrophages, proliferation of KB or MCF7 cells, induction of quinone reductase 1 (QR1), accumulation in the sub-G(1) phase of the cell cycle, and quenching of 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical. Two metabolites showed activity in these assays; the 3-sulfate exhibited QR1 induction, DPPH free radical scavenging, and COX-1 and COX-2 inhibitory activities and the 4'-sulfate inhibited NFkappaB induction, as well as COX-1 and COX-2 activities. Resveratrol and its 3'-sulfate and 4-sulfate inhibit NO production by NO scavenging and down-regulation of iNOS expression in RAW 264.7 cells. Resveratrol sulfates displayed low antiproliferative activity and negligible uptake in MCF7 cells.
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences and the Purdue University Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907, USA.
Juma
J
Hoshino
Eun-Jung
EJ
Park
Tamara P
TP
Kondratyuk
Laura
L
Marler
John M
JM
Pezzuto
Richard B
RB
van Breemen
Shunyan
S
Mo
Yongchao
Y
Li
Mark
M
Cushman
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001141:Aromatase / Q000378:metabolism; D001713:Biphenyl Compounds / Q000037:antagonists & inhibitors / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010851:Picrates / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077185:Resveratrol; D021241:Spectrometry, Mass, Electrospray Ionization; D017550:Spectroscopy, Fourier Transform Infrared; D013267:Stilbenes / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D013463:Sulfuric Acid Esters / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D010851:Picrates; D013267:Stilbenes; D013463:Sulfuric Acid Esters; C004931:1,1-diphenyl-2-picrylhydrazyl; D019001:Nitric Oxide Synthase; D001141:Aromatase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D016660:NAD(P)H Dehydrogenase (Quinone); D000077185:Resveratrol