25-Methoxylprotopanaxadiol derivatives and their anti-proliferative activities

• A series of 25-OCH3-PPD analogues incorporating fatty acids have been synthesized.
• The longer the fatty acid chain is, the lower the antitumor activity would be.
• Some compounds displayed potent cytotoxic activity compared with 25-OCH3-PPD.

(20R)-25-Methoxyl-dammarane-3β,12β,20-triol (25-OCH3-PPD) is a dammarane-type sapogenin showing anti-proliferative potential. In our study, two series of analogs substituted at the C-3 or C-3 and C-12 positions with fatty acids were prepared conveniently. The cytotoxic activity of these compounds was evaluated using four different human tumor cell lines (A549, Hela, HT-29 and MCF-7) and a normal cell line (IOSE144). As compared with 25-OCH3-PPD, compounds 1a, 1b, 2a and 2b showed better anti-proliferative activities against all tumor cell lines and all the derivatives, with low toxicities in the normal cell line. Compound 1a (C-3 monoformiate) exhibited the strongest activity with the IC50 value of 5.2 μM towards HT29 cells. The results indicated that the difference in the substituents may affect the anti-proliferative activity of the compounds. The longer the side chain of 25-OCH3-PPD is, the lower the anti-proliferative activity would be. This information may be useful for evaluating the structure–activity relationship of other dammarane-type sapogenins and for development of novel antineoplastic agents.