Synthesis, structural characterization and antiproliferative evaluation of phenylalkylamino‐containing alepterolic acid derivatives.

• A series of novel alepterolic acid derivatives incorporated with phenylalkylamino moiety were designed, synthesized and charaterized. • Active compounds against MCF-7 cells with IC 50 values less than 10 µM were obtianed. • N -(o -bromo)phenylethylamino alepterolamide (4r) displays the best antiproliferative activity in HepG2 cells. • In silico ADMET analysis suggests compound 4r is unlikely to toxic to normal organs. • Molecular docking study indicates that compound 4r could directly bind to the phosphorylation pocket of HSP27. Aleuritopteris argentea (S. G. Gmél.) Fée is a medicinal fern, the main metabolite of which is an ent - labdane diterpene, i.e. , alepterolic acid. Previous studies showed that this compound featured various biological activities and that the derivatives obtained by introducing an amino moiety on alepterolic acid exhibited better anticancer activity. In order to seek potent anticancer drug candidates, a series of novel alepterolic acid derivatives incorporated with phenylalkylamino moiety were designed, synthesized, and the antiproliferative activity of the obtained compounds against human cancer cell lines (A549, MCF-7, HepG2) was evaluated via MTT assay. The results show that some compounds are active on MCF-7 cells with IC 50 values less than 10 µM, and the activity is better than both that of alepterolic acid and the positive control cisplatin. N -(o -bromo)phenylethylamino alepterolamide (4r) displays the best antiproliferative activity in HepG2 cells, with an IC 50 value of 1.92 ± 0.22 µM. Further mechanistic study reveals that 4r inhibited colony formation and metastasis and induced apoptosis in HepG2 cells via inhibition of Akt. In silico ADMET analysis suggests compound 4r is unlikely to toxic to normal organs. Molecular docking study indicates that compound 4r could directly bind to the phosphorylation pocket of HSP27 to inhibit its phosphorylation. These results implyes that this series of novel alepterolic acid derivatives is worthy to be further explored to seek novel drug candidates for the treatment of cancer. [ABSTRACT FROM AUTHOR]