Synthesis and biological evaluation of resveratrol and analogues as apoptosis-inducing agents

被引:209
作者
Roberti, M
Pizzirani, D
Simoni, D
Rondanin, R
Baruchello, R
Bonora, C
Buscemi, F
Grimaudo, S
Tolomeo, M
机构
[1] Univ Ferrara, Dipartimento Sci Farmaceut, I-44100 Ferrara, Italy
[2] Policlin Palermo, Div Ematol & Serv AIDS, Palermo, Italy
[3] Univ Bologna, Dipartimento Sci Farmaceut, I-40126 Bologna, Italy
关键词
D O I
10.1021/jm030785u
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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.
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页码:3546 / 3554
页数:9
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