Anthracycline antibiotics and their synthetic analogs, an important class of anti-tumor agents, contain nucleophilic amines. Abasic (AP) sites, formed in DNA upon exposure to a variety of alkylating agents, interconvert between α and β anomers via an aldehydic intermediate susceptible to nucleophilic attack. We identified unique regiosiomeric imine conjugates between two reactive amines in pixantrone and AP sites in DNA. These were treated in the presence of sodium cyanoborohydride to form reduced conjugates suitable for structural analyses. NMR spectroscopy in the sequence 5’-d(GTTGC<u>X</u>CGTATG)-3’:5’-d(CACACGCGCAAC)-3’ [X = PIX-AP conjugate] revealed that both regioisomers of the PIX-AP conjugate intercalated into DNA. One of the two regioisomers was thermodynamically favored. It may hydrogen bond with the complementary cytosine. The stacking tendency of pixantrone was revealed by X-ray crystallography in the sequence 5’-d(CGCXAATTCGCG)-3’ [X = PIX-AP conjugate]. Looped-out pixantrones from neighboring duplexes engaged in a distinct stacking interaction. Anthracycline agents are frequently administered in combination chemotherapy with nitrogen mustard alkylating agents. Thus, these unique pixantrone AP-site conjugates may contribute to the cytotoxicity of this synthetic anthracycline.

Conjugation of the synthetic anthracycline chemotherapeutic pixantrone with an apurinic site in DNA

ACS Fall 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.