Probing platinum-adenine-n3 adduct formation with DNA minor-groove binding agents.
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.
Rao
Lu
L
Department of Chemistry, Wake Forest University, Winston-Salem, NC 27109, USA.
West
Tiffany K
TK
Saluta
Gilda
G
Kucera
Gregory L
GL
Bierbach
Ulrich
U
D000225:Adenine / Q000737:chemistry*; D000477:Alkylating Agents / Q000737:chemistry / Q000633:toxicity*; D018736:DNA Adducts / Q000737:chemistry*; D053837:DNA Cleavage / Q000187:drug effects; D009429:Netropsin / Q000494:pharmacology; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000633:toxicity
D000477:Alkylating Agents; D018736:DNA Adducts; D009944:Organoplatinum Compounds; D009429:Netropsin; D000225:Adenine