Macrocyclic naphthalene diimides as G-quadruplex binders.
The synthesis, biological and molecular modeling evaluation of a series of macrocyclic naphthalene diimides is reported. The present investigation expands on the study of structure-activity relationships of prototype compound 2 by constraining the molecule into a macrocyclic structure with the aim of improving its G-quadruplex binding activity and selectivity. The new derivatives, compounds 4-7 carry spermidine- and spermine-like linkers while in compound 8 the inner basic nitrogen atoms of spermine have been replaced with oxygen atoms. The design strategy has led to potent compounds stabilizing both human telomeric (F21T) and c-KIT2 quadruplex sequences, and high selectivity for quadruplex in comparison to duplex DNA. Antiproliferative effects of the new derivatives 4-8 have been evaluated in a panel of cancer cell lines and all the tested compounds showed activity in the low micromolar or sub-micromolar range of concentrations. In order to rationalize the molecular basis of the DNA G-quadruplex versus duplex recognition preference, docking and molecular dynamics studies have been performed. The computational results support the observation that the main driving force in the recognition is due to electrostatic factors.
Department of Pharmacy and Biotechnology, University of Bologna, via Belmeloro 6, 40126 Bologna, Italy; School of Pharmacy, University College London, London WC1N 1AX, UK.
Chiara
C
Marchetti
Department of Pharmacy and Biotechnology, University of Bologna, via Belmeloro 6, 40126 Bologna, Italy.
Anna
A
Minarini
Department for Life Quality Studies, University of Bologna, Rimini Campus, Corso d'Augusto 237, 47921 Rimini, Italy.
Vincenzo
V
Tumiatti
Dipartimento di Scienze della Salute, Università 'Magna Græcia' di Catanzaro, Viale Europa, 88100 Catanzaro, Italy.
Federica
F
Moraca
Dipartimento di Scienze della Salute, Università 'Magna Græcia' di Catanzaro, Viale Europa, 88100 Catanzaro, Italy.
Lucia
L
Parrotta
Dipartimento di Scienze della Salute, Università 'Magna Græcia' di Catanzaro, Viale Europa, 88100 Catanzaro, Italy.
Stefano
S
Alcaro
Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo 5, 35131 Padova, Italy.
Riccardo
R
Rigo
Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo 5, 35131 Padova, Italy.
Claudia
C
Sissi
School of Pharmacy, University College London, London WC1N 1AX, UK.
Mekala
M
Gunaratnam
School of Pharmacy, University College London, London WC1N 1AX, UK.
Stephan A
SA
Ohnmacht
School of Pharmacy, University College London, London WC1N 1AX, UK.
Stephen
S
Neidle
Department for Life Quality Studies, University of Bologna, Rimini Campus, Corso d'Augusto 237, 47921 Rimini, Italy. Electronic address: andrea.milelli3@unibo.it.
Andrea
A
Milelli
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015195:Drug Design; D054856:G-Quadruplexes; D006801:Humans; D007094:Imides / Q000138:chemical synthesis* / Q000494:pharmacology; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000494:pharmacology; D013095:Spermidine / Q000737:chemistry; D013096:Spermine / Q000737:chemistry; D055672:Static Electricity; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D007094:Imides; D009281:Naphthalenes; C542131:naphthalenediimide; D013096:Spermine; D013095:Spermidine
Docking; G-quadruplex; Naphthalene diimide; Telomeric DNA; c-KIT