Probing platinum-adenine-n3 adduct formation with DNA minor-groove binding agents.

Abstract

Me-lex(py/py), an adenine-N3-selective alkylating agent, and the reversible minor-groove binder netropsin were used to probe the formation of unusual minor-groove adducts by the cytotoxic hybrid agent PT-ACRAMTU ([PtCl(en)(ACRAMTU)](NO(3))(2); en = ethane-1,2-diamine, ACRAMTU = 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea). PT-ACRAMTU was found by chemical footprinting to inhibit specific Me-lex-mediated DNA cleavage at several adenine sites but not at nonspecific guanine, which is consistent with the platination of adenine-N3. In a cell proliferation assay, a significant decrease in cytotoxicity was observed for PT-ACRAMTU, when cancer cells were pretreated with netropsin, suggesting that minor-groove adducts in cellular DNA contribute to the biological activity of the hybrid agent.

• Authors: Lu Rao, Tiffany K West, Gilda Saluta, Gregory L Kucera, Ulrich Bierbach
• Journal: Chemical research in toxicology (Chem Res Toxicol) Vol. 23 Issue 7 Pg. 1148-50 (Jul 19 2010) ISSN: 1520-5010 [Electronic] United States
• PMID: 20578739 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Alkylating Agents
• DNA Adducts
• Organoplatinum Compounds
• Netropsin
• Adenine

Topics

• Adenine (chemistry)
• Alkylating Agents (chemistry, toxicity)
• DNA Adducts (chemistry)
• DNA Cleavage (drug effects)
• Netropsin (pharmacology)
• Organoplatinum Compounds (chemistry, toxicity)