Structural determinants of resveratrol for cell proliferation inhibition potency: experimental and docking studies of new analogs.
Resveratrol is the subject of intense research because of the abundance of this compound in the human diet and as one of the most valuable natural chemopreventive agents. Further advances require new resveratrol analogs be used to identify the structural determinants of resveratrol for the inhibition potency of cell proliferation by comparing experimental and docking studies. Therefore, we synthesized new trans/(E)- and cis/(Z)-resveratrol - analogs not reported to date - by modifying the hydroxylation pattern of resveratrol and a double bond geometry. We included them in a larger panel of 14 molecules, including (Z)-3,5,4'-trimethoxystilbene, the most powerful molecule that is used as reference. Using a docking model complementary to experimental studies on the proliferation inhibition of the human colorectal tumor SW480 cell line, we show that methylation is the determinant substitution in inhibition efficacy, but only in molecules bearing a Z configuration. Most of the synthetic methylated derivatives (E or Z) stop mitosis at the M phase and lead to polyploid cells, while (E)-resveratrol inhibits cells at the S phase. Docking studies show that almost all of the docked structures of (Z)-polymethoxy isomers, but not most of the (E)-polymethoxy isomers substantially overlap the docked structure of combretastatin A-4, taken as reference ligand at the colchicine-tubulin binding site.
Mazué
Frédéric
F
INSERM U 866, University of Burgundy, Laboratory of Biochemistry of Metabolism and Nutrition, 6, Bd Gabriel, F-21000 Dijon, France.
Colin
Didier
D
Gobbo
Jessica
J
Wegner
Maria
M
Rescifina
Antonio
A
Spatafora
Carmela
C
Fasseur
Dominique
D
Delmas
Dominique
D
Meunier
Philippe
P
Tringali
Corrado
C
Latruffe
Norbert
N
D001665:Binding Sites; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003078:Colchicine / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D006801:Humans; D006878:Hydroxides / Q000737:chemistry; D008958:Models, Molecular; D000077185:Resveratrol; D013237:Stereoisomerism; D013267:Stilbenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism
D006878:Hydroxides; D013267:Stilbenes; D014404:Tubulin; D004247:DNA; C031356:hydroxide ion; D000077185:Resveratrol; D003078:Colchicine