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Albany 2001

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

Apoptosis, Cell Senescence And Telomere Shortening Induced By Specific Quadruplex Dna Ligands

The telomeric G-rich single-stranded DNA can adopt in vitro an intramolecular G-quadruplex structure, hypothesised to inhibit the catalytic reaction of telomerase. Specific ligands of G-quadruplex telomeric DNA structure are therefore potential new agents able to counteract the reactivation of telomerase in human tumors and may be proposed as new potential anticancer agents (1).

Based on a FRET assay (2), we identified three series of G4 ligands that also display a potent antitelomerase activity (3-5). Among these chemical series we selected a new library of quinoline-based inhibitors (5). SAR within these new series will be discussed in view of structural and physico-chemical requirements for G-quadruplex DNA binding and telomerase inhibition. These compounds exhibit selective and significant affinity for G-quadruplex DNA as well as nanomolar inhibition of telomerase in vitro.

We have further investigated the biological activity of several representative members. Long term treatment of tumor cells at sub-apoptotic dosage induced a delayed growth arrest that depends on the initial telomere length. This growth arrest is associated with telomere erosion and the appearance of phenotypic characteristics of senescent cells (large morphology, expression of beta-galactosidase activity).

Our data show that G-quadruplex interacting agents are able to impair telomerase function in a tumor cell and provide a basis for the development of new anticancer agents.

References and Footnotes

  1. Mergny, & Hélène, Nature Med. 4, 1366-1367 (1998).
  2. Mergny & Maurizot, Chem. Bio. Chem. 2, 124-132 (2001).
  3. Mergny et al., Proc. Natl. Acad. Sci. USA 98, in press (2001).
  4. Koeppel et al,.Nucleic Acids Res. 29, n°5, in press (2001).
  5. Riou et al,. in preparation (2001).

Mergny, J.L.(1) , Guittat, L.(1) ; Riou, J.F.(2); Teulade-Fichou, M.P.(3), Alberti, P.(1) , Hounsou, C.(3), François, J.C.(1) , Mailliet, P.(2); Laoui, A.(2); Lacroix, L.(1) , Vigneron, J.P.(3), Lehn, J.M.(3), Garestier, T.(1) and Hélène, C.(1)

(1)Muséum Nat. d?Histoire Naturelle, Lab./Biophysique, INSERM U 201, CNRS UMR 8646, 43, rue Cuvier, 75005 Paris, (2)Aventis Pharma S. A. - Centre de Recerches de Vitry-Alfortville, 13, Quai Jules Guesde - B. P. 14 - 94403 Vitry-sur-Seine, (3)Lab./Chimie