Synthesis and evaluation of novel polyaminocarboxylate-based antitumor agents

Iron depletion, using iron chelators targeting transferrin receptor (TfR) and ribonucleotide reductase (RR), is proven to be effective in the treatment of cancer. We synthesized and evaluated novel polyaminocarboxylate-based chelators NETA, NE3TA, and NE3TA-Bn and their bifunctional versions C-NETA, C-NE3TA, and N-NE3TA for use in iron depletion tumor therapy. The cytotoxic activities of the novel polyaminocarboxylates were evaluated in the HeLa and HT29 colon cancer cell lines and compared to the clinically available iron depletion agent DFO and the frequently explored polyaminocarboxylate DTPA. All new chelators except C-NETA displayed enhanced cytotoxicities in both HeLa and HT29 cancer cells compared to DFO and DTPA. Incorporation of the nitro functional unit for conjugation to a targeting moiety into the two potent non-functionalized chelators NE3TA and NE3TA-Bn (C-NE3TA and N-NE3TA) was well-tolerated and resulted in a minimal decrease in cytotoxicity. Cellular uptake of C-NE3TA, examined using a confocal microscope, indicates that the chelator is taken up into HT29 cancer cells.