title: Tri-, tetra- and heptacyclic perylene analogues as new potential antineoplastic agents based on DNA telomerase inhibition.
abstract: A recent approach in anticancer chemotherapy envisages telomerase as a potentially useful target. An attractive strategy deals with the development of compounds able to stabilize telomeric DNA in the G-quadruplex folded structure and, among them, a prominent position is found in the perylenes. With the aim to further investigate the role of drug structure, in view of possible pharmaceutical applications, we synthesized a series of compounds related to PIPER, a well-known perylene-based telomerase inhibitor. We modified the number of condensed aromatic rings and introduced different side chains to modulate drug protonation state and extent of self-aggregation. Effective telomerase inhibition was induced by heptacyclic analogues only, some showing a remarkably wide selectivity index with reference to inhibition of Taq polymerase. G-quadruplex stabilization was monitored by circular dichroism and melting experiments. Cell cytotoxicity measurements indicated a poor short-term cell killing ability for the best G-quartet binders. Besides the presence of a planar seven-condensed ring system, the introduction of a cyclic amine in the side chains critically affects the selectivity window.
authors.affiliation: Department of Pharmaceutical Sciences, University of Padova, Via Marzolo, 5-35131 Padova, Italy. claudia.sissi@unipd.it
authors.forename: Claudia
authors.initials: C
authors.lastname: Sissi
authors.forename: Lorena
authors.initials: L
authors.lastname: Lucatello
authors.forename: A
authors.initials: A
authors.lastname: Paul Krapcho
authors.forename: David J
authors.initials: DJ
authors.lastname: Maloney
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Boxer
authors.forename: Maria V
authors.initials: MV
authors.lastname: Camarasa
authors.forename: Gabriella
authors.initials: G
authors.lastname: Pezzoni
authors.forename: Ernesto
authors.initials: E
authors.lastname: Menta
authors.forename: Manlio
authors.initials: M
authors.lastname: Palumbo
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D010569:Perylene / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D012680:Sensitivity and Specificity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D019914:Taq Polymerase / Q000037:antagonists & inhibitors; D019098:Telomerase / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D010569:Perylene; D004247:DNA; D019914:Taq Polymerase; D019098:Telomerase