Mechanisms of Action of Imidazoacridinone and Triazoloacridinone Derivatives in View of their Biological Activity

Marcin      Koba; Tomasz      Baczek

Abstract

Imidazoacridinones and triazoloacridinones are acridinone derivatives characterized by potent antitumor activity. From those, two of the most active compounds are C-1305 and C-1311. C-1305 was selected for extended preclinical trials, and C-1311 underwent phase II clinical trials for colon and breast cancers. These compounds exhibit biological (cytotoxic and/or antitumor) activity against various tumors including leukemia, melanoma, colon adenocarcinoma, lung carcinoma, breast carcinoma, and colon carcinoma. There are several suggested mechanisms of action that could be responsible for acridinones cytotoxic and antitumor actions, most of which are associated with the interactions with DNA and its proper functionality. It has been shown that triazoloacridinones and imidazoacridinones inhibit the interactions between cleavable complexes of topoisomerase II with DNA. They also inhibit nucleic acid or protein synthesis induced by G2 block of cell cycle, which is followed by apoptosis or mitotic catastrophe, intercalating to DNA, binding in minor groove, and forming of interstrand DNA crosslinks. In the literature, there is not enough convincing evidence indicating that only one particular mechanism of action is responsible for the biological activity of presented acridinone derivatives. This article is a review of the information concerning imidazoacridinones and triazoloacridinones mechanisms of action in view of their biological activity. Further information concerning the potential pharmacological activity of acridinone derivatives in view of the quantitative structure-activity relationships studies (QSAR) is presented.

Keywords: Imidazoacridinones, Triazoloacridinones, Acridinones, Mechanisms of action, Biological activity

« Previous