Anticancer efficacy of unique pyridine-based tetraindoles

• Two series of pyridine based tetraindoles were designed and synthesized.
• 3f (FCW81) was observed to display the highest antiproliferative activity.
• Cell cycle analysis revealed G2/M arrest and 3f was found to induce apoptosis.
• In vivo tests indicated that 3f displayed anticancer efficacy.

Results of previous studies demonstrated that the tetraindole, SK228, which has a high lipid but low water solubility, displayed moderate anticancer efficacy in a xenograft model of breast cancer. This finding led to the proposal that new, pyridine based tetraindole (PBT) analogs of SK228, containing tetraindole moieties distributed about central protonated pyridine cores, would have enhanced bioavailabilities and anticancer efficacies. Among the PBTs prepared and subjected to biological studies, 3f (FCW81) was observed to display the highest antiproliferative activity against the two triple negative breast cancer (TNBCs) cell lines, MDA-MB-231 and BT549. In addition, its mode of action was shown to involve G2/M arrest of the cell cycle along with the promotion of increased levels of cyclin B1 and p-chk2 and a decreased level of p-cdc2. DNA damage and induction of apoptosis caused by FCW81 was found to be associated with a decrease in DNA repair. Significantly, FCW81 displays therapeutic efficacy in a xenograft model of human breast cancer by not only serving to inhibit markedly the growth of cancer cells but also to block effectively cancer cell metastasis. Collectively, the results of these studies have led to the identification of novel pyridine-tetraindole based anticancer agents with potential use in TNBC therapy.

We report the discovery and synthesis of pyridine-tetraindoles (2a−h and 3a−h). FCW81, with IC50 values of 0.8–20 μM, was demonstrated to have therapeutic potential against tumor growth and cancer cell metastasis through induction of apoptosis.Figure optionsDownload as PowerPoint slide