TY - JOUR
T1 - Structure-activity relationships of novel substituted naphthalene diimides as anticancer agents
AU - Milelli, Andrea
AU - Tumiatti, Vincenzo
AU - Micco, Marialuisa
AU - Rosini, Michela
AU - Zuccari, Guendalina
AU - Raffaghello, Lizzia
AU - Bianchi, Giovanna
AU - Pistoia, Vito
AU - Fernando Díaz, J.
AU - Pera, Benet
AU - Trigili, Chiara
AU - Barasoain, Isabel
AU - Musetti, Caterina
AU - Toniolo, Marianna
AU - Sissi, Claudia
AU - Alcaro, Stefano
AU - Moraca, Federica
AU - Zini, Maddalena
AU - Stefanelli, Claudio
AU - Minarini, Anna
PY - 2012/11
Y1 - 2012/11
N2 - Novel 1,4,5,8-naphthalenetetracarboxylic diimide (NDI) derivatives were synthesized and evaluated for their antiproliferative activity on a wide number of different tumor cell lines. The prototypes of the present series were derivatives 1 and 2 characterized by interesting biological profiles as anticancer agents. The present investigation expands on the study of structure-activity relationships of prototypes 1 and 2, namely, the influence of the different substituents of the phenyl rings on the biological activity. Derivatives 3-22, characterized by a different substituent on the aromatic rings and/or a different chain length varying from two to three carbon units, were synthesized and evaluated for their cytostatic and cytotoxic activities. The most interesting compound was 20, characterized by a linker of three methylene units and a 2,3,4-trimethoxy substituent on the two aromatic rings. It displayed antiproliferative activity in the submicromolar range, especially against some different cell lines, the ability to inhibit Taq polymerase and telomerase, to trigger caspase activation by a possible oxidative mechanism, to downregulate ERK 2 protein and to inhibit ERKs phosphorylation, without acting directly on microtubules and tubuline. Its theoretical recognition against duplex and quadruplex DNA structures have been compared to experimental thermodynamic measurements and by molecular modeling investigation leading to putative binding modes. Taken together these findings contribute to define this compound as potential Multitarget-Directed Ligands interacting simultaneously with different biological targets.
AB - Novel 1,4,5,8-naphthalenetetracarboxylic diimide (NDI) derivatives were synthesized and evaluated for their antiproliferative activity on a wide number of different tumor cell lines. The prototypes of the present series were derivatives 1 and 2 characterized by interesting biological profiles as anticancer agents. The present investigation expands on the study of structure-activity relationships of prototypes 1 and 2, namely, the influence of the different substituents of the phenyl rings on the biological activity. Derivatives 3-22, characterized by a different substituent on the aromatic rings and/or a different chain length varying from two to three carbon units, were synthesized and evaluated for their cytostatic and cytotoxic activities. The most interesting compound was 20, characterized by a linker of three methylene units and a 2,3,4-trimethoxy substituent on the two aromatic rings. It displayed antiproliferative activity in the submicromolar range, especially against some different cell lines, the ability to inhibit Taq polymerase and telomerase, to trigger caspase activation by a possible oxidative mechanism, to downregulate ERK 2 protein and to inhibit ERKs phosphorylation, without acting directly on microtubules and tubuline. Its theoretical recognition against duplex and quadruplex DNA structures have been compared to experimental thermodynamic measurements and by molecular modeling investigation leading to putative binding modes. Taken together these findings contribute to define this compound as potential Multitarget-Directed Ligands interacting simultaneously with different biological targets.
KW - Anticancer
KW - Cytotoxicity
KW - Multitarget-directed ligands
KW - Naphthalene diimides
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U2 - 10.1016/j.ejmech.2012.06.045
DO - 10.1016/j.ejmech.2012.06.045
M3 - Article
C2 - 22819507
AN - SCOPUS:84870059174
VL - 57
SP - 417
EP - 428
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
ER -