title: Rational design, synthesis, and DNA binding properties of novel sequence-selective peptidyl congeners of ametantrone.
abstract: Natural and synthetic compounds characterized by an anthraquinone nucleus represent an important class of anti-neoplastic agents, the mechanism of action of which is related to intercalation into DNA. Ametantrone (AM) is a synthetic 9,10-anthracenedione bearing two (hydroxyethylamino)ethylamino residues at positions 1 and 4; along with other anthraquinones and anthracyclines, it shares a polycyclic intercalating moiety and charged side chains that stabilize DNA binding. All these drugs elicit adverse side effects, which represent a challenge for antitumor chemotherapy. In the present work the structure of AM was augmented with appropriate groups that target well-defined base pairs in the major groove. These should endow AM with DNA sequence selectivity. We describe the rationale for the synthesis and the evaluation of activity of a new series of compounds in which the planar anthraquinone is conjugated at positions 1 and 4 through the side chains of AM or other bioisosteric linkers to appropriate dipeptides. The designed novel AM derivatives were shown to selectively stabilize two oligonucleotide duplexes that both have a palindromic GC-rich hexanucleotide core, but their stabilizing effects on a random DNA sequence was negligible. In the case of the most effective compound, the 1,4-bis-[Gly-(L-Lys)] derivative of AM, the experimental results confirm the predictions of earlier theoretical computations. In contrast, AM had equal stabilizing effects on all three sequences and showed no preferential binding. This novel peptide derivative can be classified as a strong binder regarding the sequences that it selectively targets, possibly opening the exploitation of less cytotoxic conjugates of AM to the targeted treatment of oncological and viral diseases.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Padova, Via Marzolo 5, 35131 Padova, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Gianoncelli
authors.forename: Serena
authors.initials: S
authors.lastname: Basili
authors.forename: Matteo
authors.initials: M
authors.lastname: Scalabrin
authors.forename: Alice
authors.initials: A
authors.lastname: Sosic
authors.forename: Stefano
authors.initials: S
authors.lastname: Moro
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zagotto
authors.forename: Manlio
authors.initials: M
authors.lastname: Palumbo
authors.forename: Nohad
authors.initials: N
authors.lastname: Gresh
authors.forename: Barbara
authors.initials: B
authors.lastname: Gatto
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D001483:Base Sequence; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry*; D004151:Dipeptides / Q000737:chemistry; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008942:Mitoxantrone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D056004:Molecular Dynamics Simulation
chemical_list: D000970:Antineoplastic Agents; D004151:Dipeptides; D004247:DNA; D008942:Mitoxantrone; C020182:ametantrone