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RESVERATROL-LIKE COMPOUNDS AS CERAMIDE-MEDIATED APOPTOSIS INDUCERS

By ISABELLA CARBONI

Abstract

A deficiency in apoptosis is one of the key events in the proliferation and resistance of malignant cells to antitumor agents; for these reasons, the search for apoptosis-inducing drugs represents a valuable approach for the development of novel anticancer therapies1. Within the past decade ceramide, a proapoptotic natural sphingolipid, emerged as active participants in the regulation of key biologic functions, including cell growth, differentiation, transformation, apoptosis. Resveratrol, a naturally occurring phytoalexin (3,5,4-trans-trihydroxystilbene) present in medicinal plants, grape skin, peanuts, and red wine, has been reported to have chemopreventive activity, by exerting antiproliferative and proapoptotic effects in human cancer cells2. The antiproliferative and proapoptotic properties of resveratrol have been shown to be due to an accumulation of endogenous ceramide in cancer cell lines. In particular, the apoptotic cell death has been attributed more likely to the de novo synthesized ceramide3. Nevertheless, the trihydroxylated trans-stilbene chemical structure of resveratrol may undergo, as well as most stilbene derivatives, to several chemical and metabolic degradations. One well-known transformation is represented by the photochemical (E)/(Z)-isomerization of the double bond, to produce compounds of (Z)-configuration that are generally less active to inhibit cellular growth and promote apoptosis. The main metabolic reactions on stilbene derivatives involve oxidation reactions on the double bond and on the electron-rich phenolic rings, producing highly reactive oxidized metabolites (e.g. epoxides, arene oxides, benzylic alcohols, etc.). For these reasons we initially decided to investigate the possibility of preparing resveratrol analogues possessing a more rigid and stable scaffold, by replacing the 4-hydroxy-styrene portion with a beta-naphthol portion. We then designed and synthesized a series of naphthalene-based resveratrol analogues, which possess either “all-free” hydroxyls, or various combinations of O-methylated OH substituents, to assess the importance of the phenolic groups also in this new class of resveratrol analogues. These analogues were then tested for their ceramide-mediated proapoptotic activity, and we found that the analogue with three hydroxyls and a naphthalene ring was the most effective in triggering apoptosis coupled to the induction of endogenous ceramide in the human breast cancer cell line (IC50 =12.7 ìM versus IC50 = 20.5 ìM of resveratrol ). Based on these findings, we have then designed and synthesized a new series of resveratrol analogues by replacing the naphthol moiety with other heterocycles, in order to to increase polarity and conseguently hydrosolubility. Contemporarily we substituted the metabolically unstable stilbene double bond present in resveratrol with a more stable amido or thioamido moiety. All the new compounds were evaluated for their antiproliferative effects and ceramide accumulation in human cancer cell lines. Since, resveratrol acts as a BK channel opener, evoking a vasorelaxing effect comparable, in potency, to that of the synthetic reference drug NS 16194 . Resveratrol structural analogues could hence represent a promising approach in order to develop a new class of potential BK openers. Large-conductance calcium-activated (BK) potassium channels are involved in many fundamental cell functions. Consistently, the ability to activate BK channels by exogenous compounds is considered as a promising pharmacodynamic pattern for the potential treatment of several pathologies (such as hypertension, neurodegenerative disease etc)5,6. On these bases the synthesised compounds were subjected to a functional evaluation of their vasorelaxing properties in in vitro assays on rat aortic rings, in the presence or in the absence of selective potassium channels blockers, as a preliminary screening test to point out their potential activation of potassium channels

Topics: CHIM/08
Publisher: Pisa University
Year: 2008
OAI identifier: oai:etd.adm.unipi.it:etd-03102008-094052
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