Structural determinants of resveratrol for cell proliferation inhibition potency: Experimental and docking studies of new analogs

Abstract

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.

A Resveratrol Analogue Promotes ERKMAPK–Dependent Stat3 Serine and Tyrosine Phosphorylation Alterations and Antitumor Effects In Vitro against Human Tumor Cells

“…1). This is supported by the similar antitumor potency of pterostilbene, which shares the 3,5-dimethoxy groups, and the published reports that methoxylated resveratrol analogs have increased activity against cell viability compared with the parent compound (Mazué et al, 2010). However, pterostilbene had a moderate effect on Stat3 tyrosine705 phosphorylation compared with Cmpd1, underscoring the differences in the underlying molecular mechanisms between the two compounds.…”

Tubulin-interactive stilbene derivatives as anticancer agents

“…In most studies, trans isomers of stilbene derivatives enhanced the process of tubulin polymerization, while cis isomers -analogs of CA-4 promoted the process of depolymerization, inhibiting the formation of microtubules. Mazue et al [53] studied the anti-mitotic activity of a series of both cis-and trans-resveratrol analogs. Using a molecular docking method as a complement to experimental studies on the proliferation inhibition of the human colorectal tumor SW480 cell line, they showed that the cis configuration associated with the substitution of hydroxy groups with methoxy groups is crucial and increases inhibition efficacy.…”

“…The docked structures of cis-polymethoxy isomers overlap with the docked structure of CA-4 at the tubulin colchicine-binding site, while transpolymethoxy isomers do not fit CA-4. However, isomers of both conformations induced polyploidy resulting from the blocking of cell divisions at the mitosis level [53]. 3,4,4',5-tetramethoxy-trans-stilbene (MR-4; DMU-212; 3; Fig.…”

Design, synthesis, and biological evaluation of benzoselenazole-stilbene hybrids as multi-target-directed anti-cancer agents

“…[30][31][32] To evaluate the substituted group effect of the benzoselenazole moiety in antiproliferative activity, we introduced a series of groups, including fluorine, chlorine and methoxy, into the C ring. In addition, to evaluate the steric effect of the stilbene backbone on the cytotoxic activity of the compounds, we changed the trans configuration of compound 6a to yield 9 (cis configuration).…”