Rational design, synthesis, biophysical and antiproliferative evaluation of fluorenone derivatives with DNA G-quadruplex binding properties.
Molecular modeling studies carried out with experimental DNA models with the sequence d[AG(3)(T(2)AG(3))(3)] suggest that the introduction of a net positive charge onto the side chain of a series of fluorenone carboxamides can improve G-quadruplex binding. The terminal morpholino moiety was replaced with a novel N-methylmorpholinium cation starting from two 4-carboxamide compounds. A different substitution on the fluorenone ring was also investigated and submitted to the same quaternarization process. All compounds were analyzed for their DNA binding properties by competition dialysis methods. In vitro antiproliferative tests were carried out against two different tumor cell lines. Docking experiments were conducted by including all four known human repeat unit G-quadruplex DNA sequences (27 experimentally determined conformations) against the most active fluorenone derivatives. The results of theoretical, biophysical, and in vitro experiments indicate two novel derivatives as lead compounds for the development of a new generation of G-quadruplex ligands with greater potency and selectivity.
Dipartimento di Scienze Farmacobiologiche, Università degli Studi Magna Graecia di Catanzaro, Complesso Ninì Barbieri, 88021 Roccelletta di Borgia, CZ, Italy. alcaro@unicz.it
Stefano
S
Alcaro
Anna
A
Artese
James N
JN
Iley
Sotiris
S
Missailidis
Francesco
F
Ortuso
Lucia
L
Parrotta
Raffaele
R
Pasceri
Francesco
F
Paduano
Claudia
C
Sissi
Francesco
F
Trapasso
Maria Gabriella
MG
Vigorita
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D003198:Computer Simulation; D004247:DNA / Q000737:chemistry*; D030562:Databases, Protein; D015195:Drug Design; D005449:Fluorenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D054856:G-Quadruplexes; D006801:Humans; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D016615:Telomere / Q000378:metabolism
D000970:Antineoplastic Agents; D005449:Fluorenes; D004247:DNA