| Guanine-rich sequences of DNA are not only found at the ends of chromosomes as telomeric protein complexes, but also are present in a number of human genes, such as the c-myc oncogene and immunoglobin switch regions. Such sequences are able to form higher-order DNA structures, e.g. G-quadruplex. Stabilization of G-quadruplex can either inhibit telomerase activity, which has been found in 85-90% of human tumors but not in adjacent normal cells, or lead to repression of c-Myc, which is associated with many human and animal malignancies. Thus, the G-quadruplex structure has been a target for anti-cancer drug development.; Based on the fact that some previously prepared combilexin isoxazoles exhibited anti-tumor activity in the NCI (National Cancer Institute) 60-cell line screening protocol, a series of analogs were synthesized using nitrile oxide cycloaddition, Suzuki coupling, lateral metalation and Weinreb amidation. Computational modeling simulation showed this series of compounds capable of externally stacking with G-quadruplex. The TRAP (Telomeric Repeat Amplification Protocol) assay showed telomerase inhibition from compound 728558 and ESI-MS data suggested a potential interaction of compound 728559 with G-quadruplex. Compound 728559 also shows inhibition against colon cancer cell line HT29 and non-small cell lung cancer cell lines NCI H460, HOP-92 and HOP-62 cells with GI50 values as 7.08E-07, 6.04E-07, 6.3E-08 and 1.05E-08 M, respectively. These results imply a promising new approach to cancer therapy. |
