Abstract
Two series of amino-modified derivatives of (S)-perillyl alcohol were designed and synthesized using (S)-perillaldehyde as the starting material. These derivatives showed increased antiproliferative activity in human lung cancer A549 cells, human melanoma A375-S2 cells and human fibrosarcoma HT-1080 cells comparing with that of (S)-perillyl alcohol. Among these derivatives, compounds VI5 and VI7 were the most potent agents, with the IC50s below 100 μM. It was demonstrated that the antiproliferative effect of VI5 was mediated through the induction of apoptosis in A549 cells.
Highlights
In recent decades natural products continue to attract intense attention due to their various bioactivities
The synthetic route of the perillyl alcohol derivatives starting with (S)-perillaldehyde is outlined in Scheme 1, where the substituent groups are listed. (S)-Perillyl alcohol (I) was obtained from (S)-perillaldehyde via reduction with sodium borohydride
It was found that the replacement of the hydroxyl group of (S)-perillyl alcohol with an amino moiety was more favorable to improving cytotoxic activity than the introduction of an amino moiety at the terminal allyl group, by comparing the IC50s of the two kinds of derivatives bearing the same substitutes (VI1 vs. IV1, VI2 vs. IV2, VI4 vs. IV6)
Summary
In recent decades natural products continue to attract intense attention due to their various bioactivities. Since the potency of perillyl alcohol is modest compared to many antitumor agents [10], structural modification of perillyl alcohol has been carried out in recent years, and several kinds of perillyl alcohol derivatives have been synthesized. Among these derivatives, the perillyl alcohol carbamates, which were conjugated compounds of perillyl alcohol with some therapeutic agents, were found to be more active compounds [11], whereas other perillyl alcohol esters [12,13] and glucosides [14] were proved to be less potent than perillyl alcohol in vitro
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