Antiproliferative cardenolides from Periploca graeca

Abstract

Nine cardiotonic steroids, six 17β-cardenolides (2, 4, 6 - 9) and three 17α-cardenolides (1, 3, 5) have been identified from the chloroform and chloroform-methanol extracts of Periploca graeca L. (Asclepiadaceae) stems. Among these, compound 5, the 17α-isomer of periplocin 6, was identified as a new compound. The antiproliferative effects of these compounds were tested in vitro in the hormone-independent prostate cancer cell line PC-3. Five of these compounds, all 17β-isomers with a 14β-OH group and at least one sugar molecule (4, 6 - 9), showed a very strong antiproliferative effect, with IC₅₀ values between 18 and 50 nM. Compound 2, the only 17β-cardenolide aglycone, had an IC₅₀ value of 0.6 μM, which is 13 to 16 times higher than the values found for the corresponding cardenolides with one or two sugars. The IC₅₀ values found for the three 17α-isomers were significantly higher (5.4 and 7.3 μM), with IC₅₀ ratios (17α-cardenolide/ 17β-cardenolide) of up to 192. In the 17α-cardenolide series, the presence of a sugar unit does not seem to have a significant effect on the IC₅₀ values. This is the first report showing a markedly different cytotoxicities between the 17α- and 17β-isomers in the cardenolide series.

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