Synthesis and Biological Evaluation of Resveratrol and Analogues as Apoptosis-Inducing Agents

Abstract

Resveratrol 1 (3,4',5-trihydroxy-trans-stilbene), a phytoalexin present in grapes and other food products, has recently been suggested as a potential cancer chemopreventive agent based on its striking inhibitory effects on cellular events associated with cancer initiation, promotion, and progression. This triphenolic stilbene has also displayed in vitro growth inhibition in a number of human cancer cell lines. In this context, a series of cis- and trans-stilbene-based resveratrols were prepared with the aim of discovering new lead compounds with clinical potential. All the synthesized compounds were tested in vitro for cell growth inhibition and the ability to induce apoptosis in HL60 promyelocytic leukemia cells. The tested trans-stilbene derivatives were less potent than their corresponding cis isomers, except for trans-resveratrol, whose cis isomer was less active. The best results were obtained with compounds 11b and 7b, the cis-3,5-dimethoxy derivatives of rhapontigenin 10a (3,5,3'-trihydroxy-4'methoxy-trans-stilbene) and its 3'-amino derivative 10b, respectively, which showed apoptotic activity at nanomolar concentrations. The corresponding trans isomers 12b and 8b were less active both as antiproliferative and as apoptosis-inducing agents. Of interest, 11b and 7b were active toward resistant HL60R cells and their activity was higher than that of several classic chemotherapeutic agents. The flow cytometry assay showed that at 50 nM compounds 7b or 11b were able to recruit almost all cells in the apoptotic sub-G(0)-G(1) peek, thus suggesting that the main mechanism of cytotoxicity of these compounds could be the activation of apoptosis. These data indicate unambiguously that structural alteration of the stilbene motif of resveratrol can be extremely effective in producing potent apoptosis-inducing agents.

Suppression of human monocyte tissue factor induction by red wine phenolics and synthetic derivatives of resveratrol

“…Resveratrol derivatives were synthesized as described earlier [23,25]. Recombinant factor VIIa was a kind gift from Novo Nordisk (Copenhagen, Denmark).…”

“…A number of cis-and trans-stilbene-based resveratrol derivatives were synthesized with aim of improving the effectiveness of resveratrol in modulating various cellular activities [23][24][25]. In the present study, we investigated the ability of some of the analogues (Fig.…”

“…In most of the studies described above, relatively high concentrations of resveratrol (10 to 100 µM range) were required to modulate various cellular effects. In order to improve the efficacy of the resveratrol, with the aim of discovering new lead compounds with the clinical treatment potential, a series of cis-and trans-stilbene-based resveratrols were synthesized [23][24][25]. Of the compounds tested for the anti-proliferative and apoptotic activity on HL60 promyelocytic leukemia cells, cis-3, 4′ , 5-trimethoxy-3′ -aminostilbene (7b) and cis-3, 4′, 5-trimethoxy-3′-hydroxystilbene (11b) were effective at the nanomolar concentrations [23].…”

“…In order to improve the efficacy of the resveratrol, with the aim of discovering new lead compounds with the clinical treatment potential, a series of cis-and trans-stilbene-based resveratrols were synthesized [23][24][25]. Of the compounds tested for the anti-proliferative and apoptotic activity on HL60 promyelocytic leukemia cells, cis-3, 4′ , 5-trimethoxy-3′ -aminostilbene (7b) and cis-3, 4′, 5-trimethoxy-3′-hydroxystilbene (11b) were effective at the nanomolar concentrations [23]. Resveratrol derivative, R3 (cis-Z-3, 5, 4′ -trimethoxystilbene) was shown to be 100-fold more active than resveratrol in causing cell cycle arrest in colon cancer cells [25].…”

“…Further, we have tested for the first time, whether chemically modified derivatives of resveratrol, which were shown to be highly effective in inhibiting cancer cell proliferation than resveratrol [23,25], could inhibit LPS-induced TF expression in peripheral blood mononuclear cells at much lower doses than resveratrol.…”