November 16, 2007

Phosphonates for Drug Design and Probing Enzyme Mechanisms

Dr. Charles McKenna
Professor of Chemistry & Pharmacology and Pharmaceutical Sciences

Phosphoric acid P(O)(OH)3 in its ionized forms (phosphates), esters (e.g. DNA) and
anhydrides (e.g. ATP, dGTP) is essential to life. Phosphonates are organic derivatives
of phosphates in which one P-O bond is replaced by a P-C bond, making possible
mimics of biologically important phosphates. Such phosphonate analogs may include
therapeutic drugs, such as the bisphosphonates (OH)2(O)P-CXY-P(O)(OH)2 which are
used to treat bone diseases and cancer, and the phosphonate-containing anti-viral
agents. Phosphonate analogs of nucleotides or deoxynucleotides have also been
synthesized to probe active site structure and mechanism in DNA polymerase beta, a
repair enzyme that is over-expressed in tumor cells and thus is a potential target for
anti-cancer drugs. This seminar will describe recent work from our laboratory on these
themes, illustrating how computer modeling, X-ray crystallography and organic
synthesis can be combined to further goals in drug design.