Synthesis and Antitumor Evaluation of Bis Aza-anthracene-9,10-diones and Bis Aza-anthrapyrazole-6-ones

• Published in: Journal of medicinal chemistry 2008-02, Vol.51 (4), p.997-1006
• Main Authors: Antonini, Ippolito, Santoni, Giorgio, Lucciarini, Roberta, Amantini, Consuelo, Dal Ben, Diego, Volpini, Rosaria, Cristalli, Gloria
• Format: Article
• Language: English
• Subjects: Anthracenes - chemical synthesis; Anthracenes - chemistry; Anthracenes - pharmacology; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Aza Compounds - chemical synthesis; Aza Compounds - chemistry; Aza Compounds - pharmacology; Biological and medical sciences; DNA - chemistry; Drug Screening Assays, Antitumor; Gene Expression Profiling; General aspects; HT29 Cells; Humans; Medical sciences; Pharmacology. Drug treatments; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; RNA, Messenger - biosynthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm7013937

The good results obtained as potential antitumor drugs with aza-anthracenediones and aza-anthrapyrazoles, e.g. pixantrone, 1a, and 1b (Chart ), prompted us to design and synthesize a series of symmetrical bis derivatives, compounds 7–10 (Chart ). These compounds are dimers of different aza-anthracenedione and aza-anthrapyrazolone monomers connected by the linker found to be the most appropriate among potential bis intercalators synthesized by us. The DNA-binding properties of bis derivatives 7 and 8 have been examined using fluorometric techniques: these target compounds are excellent DNA ligands, with a clear binding site preference for AT-rich duplexes. In vitro cytotoxic activity of all target compounds 7–10 and of reference compound pixantrone toward human cancer adenocarcinoma cell line HT29 is also described. Two selected compounds have been investigated for their capacity of inducing early apoptosis.