title: Aminoacyl-anthraquinone conjugates as telomerase inhibitors: synthesis, biophysical and biological evaluation.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Padova, Via Marzolo 5, 35131 Padova, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zagotto
authors.forename: Claudia
authors.initials: C
authors.lastname: Sissi
authors.forename: Lorena
authors.initials: L
authors.lastname: Lucatello
authors.forename: Claudia
authors.initials: C
authors.lastname: Pivetta
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Cadamuro
authors.forename: Keith R
authors.initials: KR
authors.lastname: Fox
authors.forename: Stephen
authors.initials: S
authors.lastname: Neidle
authors.forename: Manlio
authors.initials: M
authors.lastname: Palumbo