1. A new steroid derivative stabilizes g-quadruplexes and induces telomere uncapping in human tumor cells
Bertrand Brassart, et al. Mol Pharmacol. 2007 Sep;72(3):631-40. doi: 10.1124/mol.107.036574. Epub 2007 Jun 22.
Human telomeric DNA consists of tandem repeats of the sequence d(TTAGGG) with a 3' single-stranded extension (the G-overhang). The stabilization of G-quadruplexes in the human telomeric sequence by small-molecule ligands inhibits the activity of telomerase and results in telomere uncapping, leading to senescence or apoptosis of tumor cells. Therefore, the search for new and selective G-quadruplex ligands is of considerable interest because a selective ligand might provide a telomere-targeted therapeutic approach to treatment of cancer. We have screened a bank of derivatives from natural and synthetic origin using a temperature fluorescence assay and have identified two related compounds that induce G-quadruplex stabilization: malouetine and steroid FG. These steroid derivatives have nonplanar and nonaromatic structures, different from currently known G-quadruplex ligands. Malouetine is a natural product isolated from the leaves of Malouetia bequaaertiana E. Woodson and is known for its curarizing and DNA-binding properties. Steroid FG, a funtumine derivative substituted with a guanylhydrazone moiety, interacted selectively with the telomeric G-quadruplex in vitro. This derivative induced senescence and telomere shortening of HT1080 tumor cells at submicromolar concentrations, corresponding to the phenotypic inactivation of telomerase activity. In addition, steroid FG induced a rapid degradation of the telomeric G-overhang and the formation of anaphase bridges, characteristics of telomere uncapping. Finally, the expression of protection of telomere 1 (POT1) induced resistance to the growth effect of steroid FG. These results indicate that these steroid ligands represent a new class of telomere-targeted agents with potential as antitumor drugs.
2. Synthesis and biological evaluation of novel 4,5-bis(dialkylaminoalkyl)-substituted acridines as potent telomeric G-quadruplex ligands
Marie Laronze-Cochard, Young-Min Kim, Bertrand Brassart, Jean-François Riou, Jean-Yves Laronze, Janos Sapi Eur J Med Chem. 2009 Oct;44(10):3880-8. doi: 10.1016/j.ejmech.2009.04.021. Epub 2009 Apr 22.
Several 4,5-bis(dialkylaminoalkyl)-substituted acridines have been prepared starting from acridine and their telomeric G-quadruplex stabilizing properties were evaluated using FRET melting and TRAP (Telomerase Repeat Amplification Protocol Assay) experiments.
3. Synthesis and structural properties of oligonucleotides covalently linked to acridine and quindoline derivatives through a threoninol linker
Anna Aviñó, Stefania Mazzini, Rubén Ferreira, Ramon Eritja Bioorg Med Chem. 2010 Nov 1;18(21):7348-56. doi: 10.1016/j.bmc.2010.09.023. Epub 2010 Sep 16.
Oligonucleotide conjugates containing acridine and quindoline derivatives linked through a threoninol molecule were synthesized. We showed that these conjugates formed duplexes and quadruplexes with higher thermal stability than the corresponding unmodified oligonucleotides. When acridine is located in the middle of the sequence, DNA duplexes have a similar stability independently of the natural base present in front of acridine. Self-complementary oligonucleotides and thrombin binding aptamers (TBA) carrying the acridine and quindoline molecules are studied by NMR.
