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Albany 2001

category image Biomolecular
Stereodynamics
SUNY at Albany
June 19-23, 2001

Combinatorial Libraries of Porphyrin Derivatives: Finding G-quadruplex: Interactive Agents With a High Specificity for Human Telomeric Repeats

A new class of compounds has recently been identified that bind to and stabilize the four-stranded (quadruplex) DNA found in eukaryotic telomeres; these have been referred to as G-quadruplex interactive agents, or QIAs. Recent interest has focused on their potential application to cancer chemotherapy. Increasing the stability of quadruplex regions is expected to inhibit the progression of telomerase, the enzyme which adds repetitive DNA sequences to the ends of our chromosomes. Telomerase is present in germ cells but is not typically found associated with normal somatic cells. About 90% of cancer cells, however, are known to exhibit telomerase activity (1). We are working to identify novel agents which bind to and stabilize DNA quadruplex structures with the hope of developing cancer treatments based on the inhibition of the telomerase enzyme. Recent efforts have concentrated on derivatives of porphyrin, a compound whose polycyclic structure is approximately the same size as the Hoogsteen base-paired G-tetrads that stabilize DNA quadruplex structure (2). A major drawback of the porphyrin compounds that have been studied to date is, despite their high affinity for quadruplex DNA, their relative lack of specificity for this structure over other forms of nucleic acid (3,4). We have been screening combinatorial libraries of porphyrin derivatives with the goal of finding compounds which possess a high selectivity for quadruplex DNA without compromising their high levels of affinity for these structures.

This research was supported by a grant from The City University of New York PSC-CUNY Research Award Program.

References and Footnotes
  1. Raymond, E., Sun, D., Chen, S.F., Windle, B., Von Hoff, D.D., Curr .Opin .Biotechnol., 7, 583-91 (1996).
  2. Gilbert, D.E., Feigon, J., Curr. Opin .Struct .Biol., 9, 305-14 (1999).
  3. Anantha, N.V., Azam, M., Sheardy, R.D., Biochemistry, 37, 2709-14 (1998).
  4. Ren, J., Chaires, J.B., Biochemistry, 38, 16067-75 (1999).

Jonathan Feig, Yosry Hussein and James S. Godde*

Department of Biology, The City University of New York, Brooklyn College, 2900 Bedford Ave., Rm 200NE, Brooklyn, NY 11210
*Phone: (718) 951-5723; Fax: (718) 951-4659; E-mail: jgodde@brooklyn.cuny.edu