Shooting for selective druglike G-quadruplex binders: evidence for telomeric DNA damage and tumor cell death.
Targeting of DNA secondary structures, such as G-quadruplexes, is now considered an appealing opportunity for drug intervention in anticancer therapy. So far, efforts made in the discovery of chemotypes able to target G-quadruplexes mainly succeeded in the identification of a number of polyaromatic compounds featuring end-stacking binding properties. Against this general trend, we were persuaded that the G-quadruplex grooves can recognize molecular entities with better drug-like and selectivity properties. From this idea, a set of small molecules was identified and the structural features responsible for G-quadruplex recognition were delineated. These compounds were demonstrated to have enhanced affinity and selectivity for the G-quadruplex over the duplex structure. Their ability to induce selective DNA damage at telomeric level and to induction of apoptosis and senescence on tumor cells is herein experimentally proven.
Dipartimento di Scienze Ambientali,  Seconda Università di Napoli , 81100 Caserta, Italy.
Sandro
S
Cosconati
Angela
A
Rizzo
Roberta
R
Trotta
Bruno
B
Pagano
Sara
S
Iachettini
Stefano
S
De Tito
Ilaria
I
Lauri
Iolanda
I
Fotticchia
Mariateresa
M
Giustiniano
Luciana
L
Marinelli
Concetta
C
Giancola
Ettore
E
Novellino
Annamaria
A
Biroccio
Antonio
A
Randazzo
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D002478:Cells, Cultured; D016922:Cellular Senescence; D002942:Circular Dichroism; D004249:DNA Damage / Q000187:drug effects*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D054856:G-Quadruplexes / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D016615:Telomere / Q000737:chemistry / Q000187:drug effects*
D000970:Antineoplastic Agents