Design, semi-synthesis and bioactivity evaluation of novel podophyllotoxin derivatives as potent anti-tumor agents

In this study, a series of potential candidate molecules with excellent antitumor activity targeting tubulin and PTEN/PI3K/Akt signaling pathway was synthesized by modifying the molecule structure of podophyllotoxin (PPT) at the C-4 position via a structure-guided drug design approach. MTT assay results indicated that compound 12c had stronger anti-proliferative activities against HGC-27, MCF-7 and H460 cell lines than etoposide (VP-16), especially for HGC-27 (12c: IC50 = 0.89 +/- 0.023 mu M; PPT: IC50 = 6.54 +/- 0.69 mu M, VP-16: IC50 = 2.66 +/- 0.28 mu M) with lower affect in healthy human cells (293 T and GES-1). Further pharmacological analysis exhibited that 12c could bind the tubulin at the colchicine site and disrupt the dynamic equilibrium of microtubules. Moreover, 12c also suppressed the expressions/activities of matrix metalloprotease (MMP)-2, vimentin and up regulation E-cadherin suggesting that 12c could block the epithelial-mesenchymal transition (EMT). The increased cell survival and invasion/migration were associated with the inactivation of PTEN/PI3K/Akt, 12c could regulate this pathway and cascade influence on the mitochondrial pathway, eventually, leading to the cell apoptosis. Thus, 12c may have the potential to become a candidate molecule in gastric cancer clinical treatment.

Automated summary

A series of potential candidate molecules with excellent antitumor activity targeting tubulin and PTEN/PI3K/Akt signaling pathway were synthesized by modifying the molecule structure of podophyllotoxin (PPT) at the C-4 position. Compound 12c showed stronger antiproliferative activities against HGC-27, MCF-7, and H460 cell lines than etoposide (VP-16), with lower toxicity in healthy human cells. Further analysis revealed that 12c disrupted the dynamic equilibrium of microtubules and inhibited the process of epithelial-mesenchymal transition. The downregulation of PTEN/PI3K/Akt signaling pathway and cascade influence on the mitochondrial pathway contributed to the apoptosis of cancer cells. Therefore, 12c has the potential to be a candidate molecule for gastric cancer clinical treatment.