MEDI 309 |
| Small molecules that bind with strong affinity to specific DNA sequences, such as distamycin and its polyamide analogs, are important for the development of novel agents for specific gene regulation. In a side-by-side dimer binding motif, a stacked pyrrole (Py)/pyrrole pair recognizes an A•T or T•A base pair, an imidazole (Im)/Py pair binds to a G•C site. Polyamides can, thus, be tailor-made to target any DNA sequence. In an ongoing program aimed at developing gene-targeted compounds, polyamides were specifically designed to target the inverted CCAAT box-2 (ICB2) of the topoisomerase II alpha gene. Our primary objectives are the following: design of polyamides that bind reversibly and selectively to ICB2, have strong affinity for the target site, and exhibit slow rates of dissociation from the target ligand/DNA complexes. Polyamides that bind DNA in either the stacked side-by-side motif or hairpin motif were investigated. In addition, studies on the use of intercalating moieties, such as naphthalimide, to affect the rate of association and dissociation were conducted. The synthesis, biophysical properties of JS-I-93 (f-IPP-Nap), as well as its ability to inhibit the binding of NF-Y to ICB2 have been achieved. Furthermore, this compound was able to enter cells and move into the nucleus, interact with genomic DNA, and induce confluent cancer cells to express the topoisomerase II alpha gene. Results from these studies will be presented. |
|
Poster Session
7:00 PM-9:00 PM, Wednesday, August 22, 2007 BCEC -- Exhibit Hall - B2, Poster
Division of Medicinal Chemistry |