| Autor: |
Zagotto G; Department of Pharmaceutical Sciences, University of Padova, Via Marzolo 5, 35131 Padova, Italy., Sissi C, Lucatello L, Pivetta C, Cadamuro SA, Fox KR, Neidle S, Palumbo M |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2008 Sep 25; Vol. 51 (18), pp. 5566-74. |
| DOI: |
10.1021/jm800160v |
| Abstrakt: |
The telomerase-telomere complex is a prospective anticancer target. To inhibit enzyme activity by induction of G-quadruplex in human telomeres, we have synthesized a small library of 2,6- and 2,7-amino-acyl/ peptidyl anthraquinones with diverse connecting linkers, charge, lipophilicity and bulk. The test compounds modulated G-quadruplex stability to different extents and showed clear preference for quadruplex over duplex DNA. Telomerase inhibition correlated with G-quadruplex stabilization. A SAR analysis showed that type of linkage between the linker and the anthraquinone, together with the position of the side chains and the nature of the amino acid components play a major role both in stabilizing G-quadruplex and producing telomerase inhibition. Short-term cytotoxic activity was poor. However, after prolonged exposure to effective G-quadruplex binders, cells became senescent. These results are of help in the rational design of more efficient G-quadruplex stabilizers, possibly endowed with cancer cell-selective antiproliferative effects. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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