Abstract
Resveratrol (1) is a naturally occurring phytoalexin that affects a variety of human disease models, including cardio- and neuroprotection, immune regulation, and cancer chemoprevention. One of the possible mechanisms by which resveratrol affects these disease states is by affecting the cellular signaling network involving protein kinase C (PKC). PKC is the family of serine/threonine kinases, whose activity is inhibited by resveratrol. To develop PKC isotype selective molecules on the resveratrol scaffold, several analogs (2–5) of resveratrol with a long aliphatic chain varying with number of unsaturated doubled bonds have been synthesized, their cytotoxic effects on CHO-K1 cells are measured and their effects on the membrane translocation properties of PKCα and PKCε have been determined. The analogs showed less cytotoxic effects on CHO-K1 cells. Analog 4 with three unsaturated double bonds in its aliphatic chain activated PKCα, but not PKCε. Analog 4 also activated ERK1/2, the downstream proteins in the PKC signaling pathway. Resveratrol analogs 2–5, however, did not show any inhibition of the phorbol ester-induced membrane translocation for either PKCα or PKCε. Molecular docking of 4 into the activator binding site of PKCα revealed that the resveratrol moiety formed hydrogen bonds with the activator binding residues and the aliphatic chain capped the activator binding loops making its surface hydrophobic to facilitate its interaction with the plasma membrane. The present study shows that subtle changes in the resveratrol structure can have profound impact on the translocation properties of PKCs. Therefore, resveratrol scaffold can be used to develop PKC selective modulators for regulating associated disease states.
Highlights
Resveratrol (1, Figure 1) is a naturally occurring phytoalexin found in grapes, red wine, peanuts, olive oil, cranberries, and other food [1,2]
We describe the synthesis of several resveratrol derivatives having unsaturated aliphatic chain and their effects on the translocation properties of PKCa and PKCe in the presence and absence of a phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA)
The present study represents our ongoing effort of developing isoform selective protein kinase C (PKC) regulator using simpler chemical scaffolds
Summary
Resveratrol (1, Figure 1) is a naturally occurring phytoalexin found in grapes, red wine, peanuts, olive oil, cranberries, and other food [1,2]. Numerous studies highlighted the effects of resveratrol in a variety of human disease models, including cardio- and neuroprotection, immune regulation, and cancer chemoprevention [3,4,5,6,7,8]. Resveratrol showed chemopreventive activities against human degenerative diseases such as atherosclerosis [15] and cancer [16]. Resveratrol showed cancer chemopreventive activity in assays representing antiinitiation, anti-promotion and antiprogression activity, inhibiting the development of preneoplastic lesions and tumorigenesis [16]. Further evidence showed that it inhibits cell growth and induces apoptosis in various human cancer cell lines [17,18,19,20,21]. A number of studies reported the chemopreventive activity of resveratrol against prostate cancer [22,23,24]. Resveratrol is currently in clinical phase II trials as an anti-cancer drug for treatment of human colon cancer [25,26]
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