Synthesis and structure-activity relationships of a series of epipodophyllotoxin polyamine conjugated derivatives vectorized for active polyamine transporter system in tumor cells, leading to the selection of F14512 for clinical trials

One of the major concerns for chemotherapy is the selective targeting of drugs into highly proliferative cancer cells. Natural polyamines (spermine, spermidine, putrescine) are essential for the regulation of cellular growth and differentiation. Due to their highly proliferative nature, cancer cells have a pronounced need to import polyamines from their external environment, through the polyamine transporter system (PTS). On the basis of this biological mechanism, we vectorized the new cytotoxic anticancer compound F14512, a epipodophyllotoxin — spermine conjugate, into tumor cells.1 Here we present the synthesis and the structure‐activity relationships of a new series of compounds constituted by an podophyllotoxin core tethered with a polyamine moiety with a variable spacer. Two synthetic strategies with protected polyamines, and a direct 3 steps synthesis of F14512 from natural podophyllotoxin and spermine without any protection are presented.2 This series of topoisomerase II inhibitors were checked for their cytotoxicity on A549 lung cancer cell line, displaying marked potency up to nM range. Cancer cell internalization through PTS was assessed by selective cytotoxicity on different PTS expressing cell lines, and by competition experiments. Our results displayed a potent specificity for the conjugated tetramine (spermine) compounds, which were more recognized than the triamine (spermidine) ones, while mono and diamines showed no selectivity. Lead compounds were also tested in vivo and proved potent antitumor activity. This series of new water‐soluble cytotoxic compounds culminates with the selection of F14512 for clinical trials. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A87.