Incorporation of amino moiety to alepterolic acid improve activity against cancer cell lines: Synthesis and biological evaluation

Aleuritopteris argentea (S. G. Gmél.) Fée is a medicinal fern consisting of an ent-labdane diterpene, i.e. alepterolic aicd, as the major metabolite. We recently isolated grams of alepterolic acid from A. argentea enabling subsequent structural modification. By incorporation of amino moiety to alepterolic acid, fifteen amide derivatives were synthesized, characterized, and further biological evaluated regarding their activity against four Cancer cells and normal human liver cells. The potency of synthesized amides dramatically improved as compared to alepterolic aicd itself. The best hit (compound 11) inhibits HeLa cells with an IC₅₀ of 7.39 ± 0.80 μM, and is nearly nontoxic to normal cells. Compound 11 exhibits an inhibitory effect on the colony forming ability of the four Cancer cells, especially of HeLa cells. Moreover, it induces Apoptosis of HeLa cells by decreasing mitochondrial membrane potential and altering expression of apoptosis-associated proteins. Release of cytochrome c, activation of caspases-3, caspases-9 and alteration of Bax/Bcl-2 balance was detected in the biological assays. These results imply that compound 11 can inhibit the proliferation of cervical Cancer cell line HeLa and induce Apoptosis through the mitochondrial pathway. These findings encourage further rational structural modification of 15- carboxyl group of alepterolic acid.