Abstract: Meredith Skiba
Mentor: Sharon Burgmayer
Following the success of the chemotherapeutic drug cisplatin, there is an increased curiosity regarding the effects of other transition metal complexes on normal cellular structures and functions. Complexes with the ability to distort and cleave DNA are of particular interest as they may inhibit the activity of DNA replication enzymes, disrupting cell growth and thus have potential anti-tumor properties. The Burgmayer lab has synthesized a family of ruthenium (II) tris-chelate complexes containing a pteridinyl-phenanthroline ligand based upon the well known and studied DNA intercalator and photocleaver Ru(bpy)2(L-DPPZ). Previous work has indicated that all of our synthesized ruthenium complexes intercalate into the DNA helix, disrupting DNA’s helical shape. Traditionally, ruthenium based intercalators cleave DNA via photoactivation of reactive oxygen species (ROS). While some of our complexes support this mechanism of DNA cleavage, others do not have the ability to photocleave under aerobic conditions. However, the DNA cleaving ability of these compounds can be activated by the addition of other compounds such as copper salts and NADH, a vital coenzyme found in cells. Interestingly, the mechanism by which DNA cleavage occurs in these activating conditions does not seem to require oxygen. This ability to cleave DNA under low oxygen conditions is noteworthy, as tumor cells under hypoxic conditions are often fairly resistant to traditional radiotherapy and chemotherapy and tend to metastasize easily1. Through the use of gel electrophoresis, the cleavage ability of the ruthenium complexes will be evaluated under aerobic and anaerobic conditions, as well as under the influence of various biological reductants. Upon confirmation of optimum conditions for DNA cleavage, reactive oxygen species inhibitors and TEMPO, a carbon radical trap, will be used to further probe the cleavage mechanism.
1. Janaratne, T; Ongeri, F; Yadav, A; MacDonnell, F. Inorg Chem. 2007, 46, 3420.