New Anthracenedione Derivatives with Improved Biological Activity by Virtue of Stable Drug−DNA Adduct Formation

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• 作者：Oula C. Mansour ; Benny J. Evison ; Brad E. Sleebs ; Keith G. Watson ; Abraham Nudelman ; Ada Rephaeli ; Damian P. Buck ; J. Grant Collins ; Rebecca A. Bilardi ; Don R. Phillips ; Suzanne M. Cutts
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：October 14, 2010
• 年：2010
• 卷：53
• 期：19
• 页码：6851-6866
• 全文大小：1317K
• 年卷期：v.53,no.19(October 14, 2010)
• ISSN：1520-4804

文摘

Mitoxantrone is an anticancer agent that acts as a topoisomerase II poison, however, it can also be activated by formaldehyde to form DNA adducts. Pixantrone, a 2-aza-anthracenedione with terminal primary amino groups in its side chains, forms formaldehyde-mediated adducts with DNA more efficiently than mitoxantrone. Molecular modeling studies indicated that extension of the “linker” region of anthracenedione side arms would allow the terminal primary amino greater flexibility and thus access to the guanine residues on the opposite DNA strand. New derivatives based on the pixantrone and mitoxantrone backbones were synthesized, and these incorporated primary amino groups as well as extended side chains. The stability of DNA adducts increased with increasing side chain length of the derivatives. A mitoxantrone derivative bearing extended side chains (7) formed the most stable adducts with 100-fold enhanced stability compared to mitoxantrone. This finding is of great interest because long-lived drug−DNA adducts are expected to perturb DNA-dependent functions at all stages of the cell cycle.