title: Tuning G-quadruplex vs double-stranded DNA recognition in regioisomeric lysyl-peptidyl-anthraquinone conjugates.
abstract: Anthraquinone is a versatile scaffold to provide effective DNA binders. This planar system can be easily conjugated to protonable side chains: the nature of the lateral groups and their positions around the tricyclic moiety largely affect the DNA recognition process in terms of binding affinity and mode, as well as sequence and structure of the target nucleic acid. Starting from an anthracenedione system symmetrically functionalized with N-terminal lysyl residues, we incremented the length of side chains by introducing a Gly, Ala, or Phe spacer, characterized by different flexibility, lipophilicity, and bulkiness. Moreover, 2,6, 2,7, 1,8, and 1,5 regioisomers were examined to yield a small bis(lysyl-peptidyl) anthracenedione library. By merging spectroscopic, enzymatic, and cellular results, we showed that the proper combination of a basic aminoacid (Lys) with a more hydrophobic residue (Phe) can provide selective G-quadruplex recognition, in particular when side chains are located at positions 2,6 or 2,7. In fact, while these derivatives effectively bind G-quadruplex structures, they behave at the same time as rather poor double-stranded DNA intercalators. As a result, the Lys-Phe substituted anthraquinones are poorly cytotoxic but still able to promote a senescence mechanism in cancer cells. This combination of chemical and biological properties foresees potentially valuable applications in anticancer medicinal chemistry.
authors: Department of Pharmaceutical Sciences, University of Padova, Padova, Italy.
authors: Giuseppe
authors: G
authors: Zagotto
authors: Antonio
authors: A
authors: Ricci
authors: Elena
authors: E
authors: Vasquez
authors: Andrea
authors: A
authors: Sandoli
authors: Silvia
authors: S
authors: Benedetti
authors: Manlio
authors: M
authors: Palumbo
authors: Claudia
authors: C
authors: Sissi
mesh_terms: D000880:Anthraquinones / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D054856:G-Quadruplexes; D006367:HeLa Cells; D006801:Humans; D007364:Intercalating Agents / Q000737:chemistry / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000880:Anthraquinones; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007364:Intercalating Agents; D009842:Oligopeptides; D004247:DNA; D019098:Telomerase