Anticancer Activities of Polyynes from the Root Bark of Oplopanax horridus and Their Acetylated Derivatives

Abstract

Six polyynes OH-1~6, some of which are occur naturally in acetylated form, had been isolated and identified from the root bark of Oplopanax horridus (Devil's Club), a natural dietary supplement and medicinal plant in North America. During the evaluation of the polyynes' potential anticancer activities, sixteen more acetylated derivatives OHR-1~16 have synthesized and their anti-proliferation activity on MCF-7, MDA-MB-231, A549, HepG2 and LO2 cells assayed to elucidate their structure-activity relationships. The results showed that OH-1 ((3S, 8S)-falcarindiol) had the most potent anticancer activity, with IC50 values of 15.3, 23.5, 7.7 and 4.7 μM on MCF-7, A549, HepG2 and MDA-MB-231 cells, respectively. For the primary structure-activity relationship, the anticancer activities of polyynes become weaker if their hydroxyl groups are acetylated, the terminal double bonds transformed into single bonds or they contain one more methylene group in the main skeleton chain.

Oplopanax horridus: Phytochemistry and Pharmacological Diversity and Structure‐Activity Relationship on Anticancer Effects

“…Among them, C 17 and C 18 -polyynes were predominantly reported for their anticancer effects [ 55 – 58 ]. In the tested cancer lines, the antiproliferation effects of polyyne 1 displayed stronger effects than 3 and 5 , while polyyne 2 exhibited greater activities than 4 and 6 [ 48 , 59 ]. Among these polyynes, 1 (FAD) shows the strongest anticancer activity, suggesting that FAD is a candidate for chemical modification [ 60 – 62 ].…”

“…Regarding the chemical structures of these polyynes, they could be divided into three pairs grouped by their terminal bond moieties, i.e., 1 vs. 2 ; 3 vs. 4 ; and 5 vs. 6 . With regard to their anticancer effects, polyyne 1 , 3 , and 5 showed greater potent activity, suggesting that the terminal ethenyl group improved anticancer activity [ 48 , 59 ]. Recently, it is reported that the pharmacokinetic parameters between 1 and 2 had significant differences.…”

“…The number and location of hydroxyl groups in polyynes influenced its anticancer activity [ 72 , 73 ]. In the natural polyynes, if the hydroxyl group at C-1 was substituted with an acetyl group, the antiproliferative effect of polyyne was decreased, but if the hydroxyl group at C-11 or C-16 was acetylated, the antiproliferative activity would be significantly suppressed [ 59 ]. The anticancer activities of polyyne 3 , 4 , 5 , and 6 have been systematically compared.…”

“…In order to investigate the contribution of hydroxyl groups to the antiproliferation on cancer cells, sixteen more acetylated derivatives have been synthesized for the evaluation of potential anticancer activities. The polyynes do not have any inhibitory effects of the adopted cancer cells if all the hydroxyl groups of the polyynes were acetylated [ 59 ]. However, compared to hydroxyl group at C-1, the terminal ethenyl group contribute more significance for maintaining anticancer potential.…”

Total Synthesis of Chiral Falcarindiol Analogues Using BINOL-Promoted Alkyne Addition to Aldehydes

“…Primary structure-activity analysis suggested that the terminal ethylenic bonds of polyacetylenes ( Figure 1) would influence their activity while the protection of single hydroxyl group might not influence the inhibitions very much [25,26]. Inspired by these results, we designed the synthetic route of falcarindiol analogues by constructing the first chiral center at the C-8 with an alkyne addition to aldehyde.…”