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Aminoacyl−Anthraquinone Conjugates as Telomerase Inhibitors: Synthesis, Biophysical and Biological Evaluation

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journal contribution
posted on 25.09.2008, 00:00 by Giuseppe Zagotto, Claudia Sissi, Lorena Lucatello, Claudia Pivetta, Sergio A. Cadamuro, Keith R. Fox, Stephen Neidle, Manlio Palumbo
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.