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.
Hoshino
Juma
J
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.
Park
Eun-Jung
EJ
Kondratyuk
Tamara P
TP
Marler
Laura
L
Pezzuto
John M
JM
van Breemen
Richard B
RB
Mo
Shunyan
S
Li
Yongchao
Y
Cushman
Mark
M
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