title: Synthesis and evaluation of novel polyaminocarboxylate-based antitumor agents.
abstract: 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.
authors.affiliation: Chemistry Division, Biological, Chemical, and Physical Sciences Department, Illinois Institute of Technology, Chicago, Illinois, USA. chong@iit.edu
authors.forename: Hyun-Soon
authors.initials: HS
authors.lastname: Chong
authors.forename: Xiang
authors.initials: X
authors.lastname: Ma
authors.forename: Haisung
authors.initials: H
authors.lastname: Lee
authors.forename: Phuong
authors.initials: P
authors.lastname: Bui
authors.forename: Hyun A
authors.initials: HA
authors.lastname: Song
authors.forename: Noah
authors.initials: N
authors.lastname: Birch
mesh_terms: D000085:Acetates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002614:Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D003676:Deferoxamine / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006573:Heterocyclic Compounds, 1-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D004369:Pentetic Acid / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000085:Acetates; D000970:Antineoplastic Agents; D002614:Chelating Agents; D006573:Heterocyclic Compounds, 1-Ring; D004369:Pentetic Acid; D003676:Deferoxamine