This response is typical of the telomere deprotection occurring during cellular senescence Alpelisib or upon the loss of telomeric proteins [34–40]. The ability of G-quadruplex ligands

to uncap telomeres and to possess anti-tumor activity has been already described for other agents, [41–45] reinforcing the notion that these agents can act as inhibitors of a telomere-related process and therefore the rationale for the development of this class of inhibitors as anti-tumor agents must be found elsewhere other than in higher telomerase expression in cancer cells. Taken collectively our results clearly demonstrate that compounds 2 (but less efficiently 3) rapidly disrupt telomere architecture of cells, by delocalizing the telomeric protein POT1, resulting in a potent DNA damage response characterized by the formation of several telomeric foci. Furthermore, it is apparent that the 2-substitued Gemcitabine in vivo quinoacridinium salt 2 more closely mimics the overall pharmaceutical profile of the prototypic compound 1 than the regioisomer 3. Our recent synthetic work has therefore focused on the 2-substituted series and our efforts

to maximize on-target and minimize off-target properties will be reported separately. Conclusions Molecular modification of quinoacridinum salts 1 have shown to reduce undesired cardiotoxic effects while maintaining the on-target features as telomere targeting agents. This findings provide a strong rational for development of this class of compounds

as tools for a G-quadruplex targeted anti-cancer therapy. Electronic supplementary material Additional file 1: Cytotoxicity of 2 and 3 and SPR sensorgrams. (PDF 281 KB) References 1. Hanahan D, Weinberg RA: The hallmarks of cancer. Cell 2000, 100:57–70.PubMedCrossRef 2. Testorelli C: Telomerase and cancer. J Exp Clin Cancer Res 2003, 22:165–169.PubMed 3. Cech TR: Beginning to understand the end of the chromosome. Cell 2004, 116:273–279.PubMedCrossRef 4. Phan AT, Kuryavyi V, Patel DJ: DNA architecture: from G to Z. Curr Opin Struct Biol 2006, 16:288–298.PubMedCrossRef Tolmetin 5. Huppert JL, Subramanian S: Prevalence of quadruplexes in the human genome. Nucleic Acids Res 2005, 33:2908–2916.PubMedCrossRef 6. Garner TP, Williams HEL, Gluszyk KI, Roe S, KU55933 nmr Oldham NJ, Stevens MF, Moses JE, Searle MS: Selectivity of small molecule ligands for parallel and anti-parallel G-quadruplex structures. Org Biomol Chem 2009, 7:4194–4200.PubMedCrossRef 7. Akiyama M, Hideshima T, Munshi NC, Anderson KC: Telomerase inhibitors as anticancer therapy. Curr Med Chem Anticancer Agents 2002, 5:567–575.CrossRef 8. Lai XF, Shen CX, Wen Z, Qian YH, Yu CS, Wang JQ, Zhong PN, Wang HL: PinX1 regulation of telomerase activity and apoptosis in nasopharyngeal carcinoma cells. J Exp Clin Cancer Res 2012, 31:12.PubMedCrossRef 9. Yingying L, Junchao G, Dachuan J, Yanjing G, Mengbiao Y: Inhibition of telomerase activity by HDV ribozyme in cancers.