Tetrasubstituted naphthalene diimide ligands with selectivity for telomeric G-quadruplexes and cancer cells |
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Authors: | Hampel Sonja M Sidibe Assitan Gunaratnam Mekala Riou Jean-François Neidle Stephen |
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Affiliation: | CRUK Biomolecular Structure Group, The School of Pharmacy, University of London, London WC1N 1AX, UK. |
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Abstract: | A series of tetrasubstituted naphthalene diimide compounds with N-methylpiperazine end groups has been synthesized and evaluated as G-quadruplex ligands. They have high affinity and selectivity for telomeric G-quadruplex DNA over duplex DNA. CD studies show that they induce formation of a parallel G-quadruplex topology. They inhibit the binding of hPOT1 and topoisomerase IIIα to telomeric DNA and inhibit telomerase activity in MCF7 cells. The compounds have potent activity in a panel of cancer cell lines, with typical IC(50) values of ~0.1 μM, and up to 100-fold lower toxicity in a normal human fibroblast cell line. |
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