Book of Abstracts: Albany 2003

category image Albany 2003
Conversation 13
Abstract Book
June 17-21 2003

Non-covalent Interactions of Highly Charged Polynuclear Platinum Compounds with DNA. Chemical and Biological Effects.

The phase II clinical agent, BBR3464, is a polynuclear platinum compound, which is active against a spectrum of tumors different from cisplatin while still targeting DNA. Pre-association by electrostatic interaction in the minor groove through charge and hydrogen bonding is an important first step in the interaction of BBR 3464 and other polynuclear platinum compounds with DNA, as observed by {1H,15N} HSQC NMR studies (1, 2). To study the pre-association independent of covalent binding we have prepared a series of complexes capable only of non-covalent interactions, with the chloride leaving groups replaced by additional ammonia ligands. The DNA binding of these compounds has been examined through circular dichroism, fluorescence, NMR, and melting point elevation. An unusual cooperative effect with Hoechst Dye 33258 was seen as indicated by fluorescence and a great enhancement of hydrogen bonding by the dye imino protons. This effect may be related to the minor groove binding capabilities of these compounds. The chemical and biological properties of these novel cation-DNA conjugates will be described - in addition to their value as a model system these compounds are also cytotoxic. The nature of this cytotoxicity is being studied both to understand the contribution of electrostatic interaction to BBR 3464?s cytotoxicity and to aid in the development of new DNA modifying drug candidates.

Amanda Harris
Yun Qu
Alexander Hegmans
Andrea Petz
Nicholas Farrell

Department of Chemistry
Virginia Commonwealth University
Richmond, VA, 23284

References and Footnotes
  1. Cox, J. W., Bernes-Price, S. J., Davies, M. S., Qu, Y., Farrell, N., J. Am. Chem. Soc. 123, 5576-5577 (2001).
  2. Qu, Y., Scarsdale, N. J., Tran, M., Farrell, N. P., J. Biol. Inorg. Chem. 8, 19-28 (2003).