Resveratrol and Synthetic Analogues: From Cardioprotective Effects to Anticancer Activities

Date

2015-05-04

Advisors

Journal Title

Journal ISSN

ISSN

DOI

Volume Title

Publisher

The Athens Institute for Education and Research

Type

Conference

Peer reviewed

Abstract

It has been widely acknowledged that regular consumption of fresh fruits and vegetables is linked with a relatively low incidence of cancers (e.g. breast, cervix, and colon). Notably, dietary polyphenolic compounds have been proposed to play a role in cancer prevention. However, at present there is no satisfactory explanation for the cancer preventative properties of the group of compounds. Whereas polyphenolic compounds have been shown to inhibit proliferation of tumor cells in vitro, the results of in vivo tests have mostly been disappointing in this respect. It seems that mammalian phase I and phase II detoxification mechanisms make that dietary polyphenols are rapidly and effectively removed from the body, i.e. their concentration in the blood plasma hardly ever reaches levels high enough to have a possible effect on tumor growth. Despite the experimental evidence regarding the antitumor activity of resveratrol, stilbene found in red grapes, the clinical effectiveness of the natural product is limited because of its low bioavailability. Resveratrol, however, has demonstrated antioxidant and antiproliferative activity in in-vitro models and mice. Although resveratrol exhibits significant anticancer activity, its efficacy in-vivo is limited due to its poor pharmacokinetic properties. In order to improve the pharmacokinetic properties of resveratrol and to increase the chemopreventive activity, several methoxylated resveratrol analogues were designed, synthesized and ested in vitro models. These analogues included a synthetic anticancer prodrug based on the structure of the natural product resveratrol namely DMU-212 or trans 3, 4, 4’ 5 -tetramethoxy stilbene. DMU-212 has considerable potency in submicromolar IC50 in cancer cell lines that renders it an important candidate for further studies, as it deviates from the classical acute toxicity of standard chemotherapeutic drugs. These synthesized analogues have been tested for their antitumor activity and in vitro biological assays have been exerted in order to assess the cardiovascular effects of the compounds. In particular, Structure Activity relationships have been studied in relation to their effects towards cardiovascular parameters. The cardiac activity of these compounds, using in vitro biological assays, on guinea-pig left and right atria, as well as their relaxant activity on guinea-pig vascular (aorta) and nonvascular (ileum) smooth muscle has been studied. The chemical modifications of the resveratrol have been made in order to maintain the stilbene scaffold that is crucial for heart selectivity. All the tested compounds exert a cardiovascular pattern activity similar to that of resveratrol. Heart and smooth muscle activity profile is similar for all tested compounds. The same modifications leading to an antitumor activity increase do not affect cardiovascular parameters. Resveratrol is devoid of relaxing effects towards vascular smooth muscle, while it relaxes non vascular smooth muscle with a low potency (EC50 = 24.34 μM (c.l 16.15-29.87)). All the resveratrol analogues have a similar activity pattern, showing selectivity towards non-vascular smooth muscle.

Description

Università degli Studi dell'Aquila, Department of Life, Health, and Environmental Sciences Università di Bologna, Department of Pharmacy and Biotechnology

Keywords

Stilbenes, Medicinal Chemistry

Citation

Ruparelia, K., Micucci, M., Chiarini, A., Baccherini, G., Budriesi, R., Arroo, R., Zeka, K., Continenza, M.A., Beresford, K. (2015) Resveratrol and Synthetic Analogues: From Cardioprotective Effects to Anticancer Activities. In: Pharmaceutical Sciences Abstracts - Second Annual International Conference on Pharmaceutical Sciences. 1-4 May 2017, Athens, Greece (G.T. Papanikos ed.) The Athens Institute for Education and Research.

Rights

Research Institute

Leicester Institute for Pharmaceutical Innovation - From Molecules to Practice (LIPI)