Design, synthesis, biophysical and biological studies of trisubstituted naphthalimides as G-quadruplex ligands

Peduto, Antonella; Pagano, Bruno; Petronzi, Carmen; Massa, António; Esposito, Veronica; Virgilio, Antonella; Paduano, Francesco; Trapasso, Francesco; Fiorito, Filomena; Florio, Salvatore; Giancola, Concetta; Galeone, Aldo; Filosa, Rosanna

doi:10.1016/j.bmc.2011.08.062

Cited by 35 publications

(14 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Some trisubstituted derivatives with the same naphthalimido aromatic nucleus of compound 2 have already been evaluated as telomeric G4 binders and telomerase inhibitors 34. Notably, compounds of this series are characterized by three substituents and side chains different from that of compound 2 (SI, Figure S5).…”

Section: Discussionmentioning

confidence: 99%

Looking for Efficient G‐Quadruplex Ligands: Evidence for Selective Stabilizing Properties and Telomere Damage by Drug‐Like Molecules

et al. 2015

Self Cite

View full text Add to dashboard Cite

There is currently significant interest in the development of G-quadruplex-interactive compounds, given the relationship between the ability to stabilize these non-canonical DNA structures and anticancer activity. In this study, a set of biophysical assays was applied to evaluate the binding of six drug-like ligands to DNA G-quadruplexes with different folding topologies. Interestingly, two of the investigated ligands showed selective G-quadruplex-stabilizing properties and biological activity. These compounds may represent useful leads for the development of more potent and selective ligands.

show abstract

Section: Discussionmentioning

confidence: 99%

Looking for Efficient G‐Quadruplex Ligands: Evidence for Selective Stabilizing Properties and Telomere Damage by Drug‐Like Molecules

et al. 2015

Self Cite

View full text Add to dashboard Cite

show abstract

“…Compounds I and II were prepared starting from commercially available 1,3-dimethoxybenzene (2a) and 1-hexyl-2,4-dimethoxybenzene (2b) that were easily prepared according to procedure described by Kikuchi and co-workers [12-14]. Condensation of cyclohexanone with 2a-b gave the tertiary alcohols 3a-b in 70% and 80% yields respectively.…”

Section: Methodsmentioning

confidence: 99%

“…As a part of our research program devoted to the preparation and evaluation of new antiproliferative agents, [12-14] the para-quinone of cannabinol HU-331 (1) was selected as biologically validated starting point for compound library development, in order to evaluate the structural requirements important for biological activity and in particular the role of the substituents linked to the quinone nucleus.…”

Section: Introductionmentioning

confidence: 99%

Cyclohexa-2,5-diene-1,4-dione-based antiproliferative agents: design, synthesis, and cytotoxic evaluation

Petronzi

Festa

Peduto

et al. 2013

J Exp Clin Cancer Res

Self Cite

View full text Add to dashboard Cite

BackgroundTumors are diseases characterized by uncontrolled cell growth and, in spite of the progress of medicine over the years, continue to represent a major threat to the health, requiring new therapies. Several synthetic compounds, such as those derived from natural sources, have been identified as anticancer drugs; among these compounds quinone represent the second largest class of anticancer agents in use. Several studies have shown that these act on tumor cells through several mechanisms. An important objective of this work is to develop quinoidscompounds showing antitumor activity, but with fewer side effects. The parachinone cannabinol HU-331, is a small molecule that with its core 4-hydroxy-1,4-benzoquinone, exhibits a potent and selective cytotoxic activity on different tumor cell lines. A series of derivatives 3-hydroxy-1,4-benzochinoni were thus developed through HU-331 chemical modifications. The purpose of the work is to test the ability of the compounds to induce proliferative inhibition and study the mechanisms of cell death.MethodsThe antitumor activities were evaluated in vitro by examining their cytotoxic effects against different human cancer cell lines. All cell lines tested were plated in 96-multiwell and treated with HU-100-V at different concentrations and cell viability was evaluated byMTT assay. Subsequently via flow cytometry (FACS) it was possible to assess apoptosis by the system of double labeling with PI and Annexin-V, and the effect of the compounds on ROS formation by measuring the dichlorofluorescein fluorescence.ResultsThe substitution by n-hexyl chain considerably enhanced the bioactivity of the compounds. In details, 2-hexyl-5-hydroxycyclohexa-2,5-diene-1,4-dione (V), 2,5-Dimethoxy-3-hexyl-2,5-cyclohexadiene-1,4-dione (XII) and 2-hydroxy-5-methoxy-3-hexyl-cyclohexa-2,5-diene-1,4-dione (XIII) showed most prominent cytotoxicity against almost human tumour cell lines. Compound V was further subjected to downstream apoptotic analysis, demostrating a time-dependent pro-apoptotic activity on human melanoma M14 cell line mediated by caspases activation and poly-(ADP-ribose)-polymerase (PARP) protein cleavage.ConclusionsThese findings indicate that 2-hexyl-5-idrossicicloesa-2,5-diene-1,4-dione can be a promising compound for the design of a new class of antineoplastic derivatives.Carmen Petronzi, Michela Festa, Antonella Peduto and Maria Castellano: equally contributed equally to this work.

show abstract

“…To confirm the implication of 5-LO in the pathogenesis of cancer, researchers have used several medications such as 5-LO inhibitors (zileuton, ZYflo, ABT-761), FLAP inhibitors (MK-886) or other related drugs (zafirlukast and montelukast) in inhibiting cell proliferation and inducing cell death in vitro and in vivo [11]. Our group has synthesized and characterized several agents such as quinone-based derivatives with anti-cancer and anti-inflammatory properties [12,13,14,15,16,17,18,19,20,21,22,23]. These studies on the development of quinone-based compounds with antitumor activity have led to investigate the natural compound embelin and its analogues known as inhibitors of 5-LO and able to suppress proliferation of GBM cells [24].…”

Section: Introductionmentioning

confidence: 99%

A Hydroquinone-Based Derivative Elicits Apoptosis and Autophagy via Activating a ROS-Dependent Unfolded Protein Response in Human Glioblastoma

Zappavigna

Cossu

Abate

et al. 2019

IJMS

Self Cite

View full text Add to dashboard Cite

5-Lipoxygenase (5-LO) has been reported to be highly expressed in brain tumors and to promote glioma cell proliferation. Therefore, we investigated the anticancer activity of the novel 5-LO inhibitor derivative 3-tridecyl-4,5-dimethoxybenzene-1,2-diol hydroquinone (EA-100C red) on glioblastoma (GBM) cell growth. Cell viability was evaluated by MTT assay. The effects of the compound on apoptosis, oxidative stress and autophagy were assessed by flow cytometry (FACS). The mode of action was confirmed by Taqman apoptosis array, Real Time qPCR, confocal microscopy analysis and the western blotting technique. Our results showed that EA-100C Red had a higher anti-proliferative effect on LN229 as compared to U87MG cells. The compound induced a significant increase of apoptosis and autophagy and up-regulated pro-apoptotic genes (Bcl3, BNIP3L, and NFKBIA) in both GBM cell lines. In this light, we studied the effects of EA-100C red on the expression of CHOP and XBP1, that are implicated in ER-stress-mediated cell death. In summary, our findings revealed that EA-100C red induced ER stress-mediated apoptosis associated to autophagy in GBM cells through CHOP and Beclin1 up-regulation and activation of caspases 3, 9, JNK and NF-kappaB pathway. On these bases, EA-100C red could represent a promising compound for anti-cancer treatment.

show abstract

Design, synthesis, biophysical and biological studies of trisubstituted naphthalimides as G-quadruplex ligands

Cited by 35 publications

References 49 publications

Looking for Efficient G‐Quadruplex Ligands: Evidence for Selective Stabilizing Properties and Telomere Damage by Drug‐Like Molecules

Looking for Efficient G‐Quadruplex Ligands: Evidence for Selective Stabilizing Properties and Telomere Damage by Drug‐Like Molecules

Cyclohexa-2,5-diene-1,4-dione-based antiproliferative agents: design, synthesis, and cytotoxic evaluation

A Hydroquinone-Based Derivative Elicits Apoptosis and Autophagy via Activating a ROS-Dependent Unfolded Protein Response in Human Glioblastoma

Contact Info

Product

Resources

About