Structure–activity relationships of novel substituted naphthalene diimides as anticancer agents

Abstract

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.

Screening of candidate G-quadruplex ligands for the human c-KIT promotorial region and their effects in multiple in-vitro models

“…To further optimize the promising outcome provided by these derivatives, we set up a library of “in house” available compounds that can be clustered into five different families according to their main scaffold: anthraquinone (AQ) [23], anthracene (AN) [24], phenantroline (Phen) [25-27], naphthalene diimide (NDI) [28] and heterocyclic diamidines (HAD) [29]. Interestingly, G4 recognition properties were previously reported for at least one member of each family.…”

Thermodynamics and kinetic studies in the binding interaction of cyclic naphthalene diimide derivatives with double stranded DNAs

“…6,7 Researchers have already reported that naphthalene diimide derivatives act as DNA-targeting anticancer agents, and such derivatives have shown potent activity against cancer cell lines and telomerase. 13,14 Depending on the substituents, naphthalene diimide derivatives have shown selectivity toward AT-or GC-rich regions of DNA. 4,6 We previously published our synthesis and evaluation of the binding of G-quadruplex and dsDNA with cNDI 1 and other cNDIs.…”

Preparation, characterization andin vitroevaluation of sterically stabilized liposome containing a naphthalenediimide derivative as anticancer agent

“…Hydrogenated soy phosphatidylcholine (HSPC), cholesterol (CHOL), 1,2 distearoylglycero-3-phosphatidylethanolamine-N-polyethylene glycol-2000 (DSPE-PEG) were from Avanti Polar Lipids, Inc. (Alabaster, AL (Milelli et al, 2012).…”

“…This compound, named AN169 and characterized by a side chain length of three methylene units and by two 2,3,4-trimethoxy benzyl groups (Figure 1), was further investigated to elucidate the molecular pathways involved in its growth inhibiting activity. The drug was not patented to let its use to the all the scientific community for better elucidate its mechanism of action (Milelli et al, 2012).…”