Current research in our laboratory is primarily concerned with the design, preparation, and mechanism of action of DNA-targeted inorganic - organic hybrid anticancer agents structurally and functionally dissimilar to existing clinical treatments (see for instance, Barry, C. G. et al., J. Am. Chem. Soc. 125:9629 (2003)). Novel metal - intercalator conjugates are synthesized and characterized and their interactions with DNA studied at atomic resolution using analytical and structural methods. These include electrospray ionization mass spectrometry, X-ray crystallography, and NMR spectroscopy in conjunction with molecular dynamics/mechanics calculations. Biophysical and molecular biology assays complement these techniques. Studies of the biological activity of the new compounds are carried out in collaboration with the Comprehensive Cancer Center of Wake Forest University. While the ultimate goal is to identify an agent for phase I clinical studies, the research also contributes to the fundamental understanding of small molecule - DNA interactions and their consequences for nucleic acid structure and recognition. Metal complexes that irreversibly bind to DNA in a sequence- and groove-specific manner are potential modulators of gene-regulatory processes. We have now started using the platinum - intercalator technology to develop agents capable of inhibiting the transcription of specific genes (see, e. g., Baruah, H. et al., Curr. Topics Med. Chem. 4 (2004), in press).

Recently, our research interests have gravitated into the field of chelation therapy. Polydentate ligands capable of interfering with metal-containing enzyme cofactors or modulating (toxic) free metal ion concentration have potential clinical applications. Future research on this project will explore the utility of novel sulfur-containing chelating agents in the therapy of cancer, neurodegenerative diseases, and viral infections. In particular, we are interested in the development of suicide substrates that can be chemically tuned and targeted to specific enzymes without indiscriminately depleting cellular metal pools.

Representative Publications

H. Baruah, C. S. Day, M. W. Wright and U. Bierbach: Metal - intercalator-mediated self-association and one-dimensional aggregation in the structure of the excised major DNA adduct of a platinum - acridine agent. J. Am. Chem. Soc., 126:4492 (2004).

M. E. Budiman, R. W. Alexander and U. Bierbach: Unique base-step recognition by a platinum - acridinylthiourea conjugate leads to a DNA damage profile complementary to that of the anticancer drug cisplatin. Biochemistry, 43:8560 (2004).

M. C. Ackley, C. G. Barry, A. M. Mounce, M. C. Farmer, B.-E. Springer, C. S. Day, M. W. Wright, S. J. Berners-Price, S. M. Hess and U. Bierbach: Structure - activity relationships in platinum - acridinylthiourea conjugates: effect of the thiourea nonleaving group on drug stability, nucleobase affinity, and in vitro cytotoxicity. J. Biol. Inorg. Chem., 9:453 (2004).

C. G. Barry, H. Baruah and U. Bierbach: Unprecedented monofunctional metalation of adenine nucleobase in guanine and thymine containing dinucleotide sequences by a cytotoxic platinum - acridine hybrid agent. J. Am. Chem. Soc. , 125:9629 (2003).

H. Baruah and U. Bierbach: Unusual intercalation of acridin-9-ylthiourea into the 5'-GA/TC DNA base step from the minor groove: Implications for the covalent DNA adduct profile of a novel platinum - intercalator conjugate. Nucleic Acids Res ., 31:4138 (2003).

E. T. Martins, H. Baruah, J. Kramarczyk, G. Saluta, C. S. Day, G. L. Kucera and U. Bierbach: Design, synthesis and biological activity of a novel non-cisplatin-type platinum - acridine pharmacophore. J. Med. Chem ., 44:4492 (2001).