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Disentangling the Structure-Activity Relationships of Naphthalene Diimides as Anticancer G-Quadruplex-Targeting Drugs.

ABSTRACT: In the context of developing efficient anticancer therapies aimed at eradicating any sort of tumors, G-quadruplexes represent excellent targets. Small molecules able to interact with G-quadruplexes can interfere with cell pathways specific of tumors and common to all cancers. Naphthalene diimides (NDIs) are among the most promising, putative anticancer G-quadruplex-targeting drugs, due to their ability to simultaneously target multiple G-quadruplexes and their strong, selective in vitro and in vivo anticancer activity. Here, all the available biophysical, biological, and structural data concerning NDIs targeting G-quadruplexes were systematically analyzed. Structure-activity correlations were obtained by analyzing biophysical data of their interactions with G-quadruplex targets and control duplex structures, in parallel to biological data concerning the antiproliferative activity of NDIs on cancer and normal cells. In addition, NDI binding modes to G-quadruplexes were discussed in consideration of the structures and properties of NDIs by in-depth analysis of the available structural models of G-quadruplex/NDI complexes.

SUBMITTER: Platella C

PROVIDER: S-EPMC8041303 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Trifunctionalized Naphthalene Diimides and Dimeric Analogues as G-Quadruplex-Targeting Anticancer Agents Selected by Affinity Chromatography.

Project description:A focused library of newly designed monomeric and dimeric naphthalene diimides (NDIs) was analyzed in its ability to recognize specific G-quadruplex (G4) structures discriminating duplex DNA. The best G4 ligands-according to an affinity chromatography-based screening method named G4-CPG-were tested on human cancer and healthy cells, inducing DNA damage at telomeres, and in parallel, showing selective antiproliferative activity on HeLa cancer cells with IC50 values in the low nanomolar range. CD and fluorescence spectroscopy studies allowed detailed investigation of the interaction in solution with different G4 and duplex DNA models of the most promising NDI of the series, as determined by combining the biophysical and biological assays' data.

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Project description:Five core-substituted naphthalene diimides bearing two dialkylamino groups were synthesized as potential visible light photoredox catalysts and characterized by methods of optical spectroscopy and electrochemistry in comparison with one unsubstituted naphthalene diimide as reference. The core-substituted naphthalene diimides differ by the alkyl groups at the imide nitrogens and at the nitrogens of the two substituents at the core in order to enhance their solubility in DMF and thereby enhance their photoredox catalytic potential. The 1-ethylpropyl group as rather short and branched alkyl substituent at the imide nitrogen and the n-propyl group as short and unbranched one at the core amines yielded the best solubilities. The electron-donating diaminoalkyl substituents together with the electron-deficient aromatic core of the naphthalene diimides increase the charge-transfer character of their photoexcited states and thus shift their absorption into the visible light (500-650 nm). The excited state reduction potential was estimated to be approximately +1.0 V (vs SCE) which is sufficient to photocatalyze typical organic reactions. The photoredox catalytic activity in the visible light range was tested by the ?-alkylation of 1-octanal as benchmark reaction. Irradiations were performed with LEDs in the visible light range between 520 nm and 640 nm. The irradiation by visible light together with the use of an organic dye instead of a transition metal complex as photoredox catalyst improve the sustainability and make photoredox catalysis "greener".

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Selectivity of Terpyridine Platinum Anticancer Drugs for G-quadruplex DNA.

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Project description:Targeting quadruplexes in cancer genes and pathways by a novel class of asymmetrically-substituted napththalene diimides (SOP1812) with potent cellular and antitumour activity in models for pancreatic cancer.

2020-06-04 | GSE151741 | GEO

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Structure-Activity Relationships of ENMs

Project description:Current nano-SARs are often based on univariate assessments and fail to provide tiered views on ENM-induced bio-effects. Here we pioneered a multi-hierarchical nano-SAR assessment for a representative ENM, Fe2O3, by metabolomics and proteomics analyses. The established nano-SAR profile allows visualizing the contributions of 7 basic properties of Fe2O3 to its diverse bio-effects. For instance, while surface reactivity is responsible for Fe2O3-induced cell migration, the inflammatory effects of Fe2O3 are determined by aspect ratio (nanorods) or surface reactivity (nanoplates). These nano-SARs were examined in THP-1 cells and animal lungs, which allowed us to decipher the detailed mechanisms including NLRP3 inflammasome pathway and monocyte chemoattractant protein-1 dependent signaling. This study provides new insights for nano-SARs, which may facilitate the tailored design of ENMs to endow them with desired bio-effects.

2019-11-12 | PXD010614 | Pride

G-quadruplex-binding molecule based on napththalene diimides showing potent activity on pancreatic cancer cells

Project description:Targeting quadruplexes in cancer genes and pathways by a set of napththalene diimides-based compounds in models for pancreatic cancer.

2023-10-31 | GSE234779 | GEO

Targeting of radioactive platinum-bisphosphonate anticancer drugs to bone of high metabolic activity.

Project description:Platinum-based chemotherapeutics exhibit excellent antitumor properties. However, these drugs cause severe side effects including toxicity, drug resistance, and lack of tumor selectivity. Tumor-targeted drug delivery has demonstrated great potential to overcome these drawbacks. Herein, we aimed to design radioactive bisphosphonate-functionalized platinum (195mPt-BP) complexes to confirm preferential accumulation of these Pt-based drugs in metabolically active bone. In vitro NMR studies revealed that release of Pt from Pt BP complexes increased with decreasing pH. Upon systemic administration to mice, Pt-BP exhibited a 4.5-fold higher affinity to bone compared to platinum complexes lacking the bone-seeking bisphosphonate moiety. These Pt-BP complexes formed less Pt-DNA adducts compared to bisphosphonate-free platinum complexes, indicating that in vivo release of Pt from Pt-BP complexes proceeded relatively slow. Subsequently, radioactive 195mPt-BP complexes were synthesized using 195mPt(NO3)2(en) as precursor and injected intravenously into mice. Specific accumulation of 195mPt-BP was observed at skeletal sites with high metabolic activity using micro-SPECT/CT imaging. Furthermore, laser ablation-ICP-MS imaging of proximal tibia sections confirmed that 195mPt BP co-localized with calcium in the trabeculae of mice tibia.

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Synthesis and anticancer activity evaluation of naphthalene-substituted triazole spirodienones.

Project description:Building on our previous work that discovered 1,2,4-triazole-spirodienone as a promising pharmacophore for anticancer activity, we have further diversified 1,2,4-triazole- spirodienone derivatives and synthesized a series of novel naphthalene-substituted triazole spirodienones to explore their antineoplastic activity. Of these, compound 6a possesses remarkable in vitro cytotoxic activity by arresting cell cycle and inducing apoptosis in MDA-MB-231 cells. Subsequently, acute toxicity assay showed that 6a at 20 mg/kg has no apparent toxicity to the major organ in mice. In addition, compound 6ain vivo suppressed breast cancer 4T1 tumor growth. Taken together, these results indicate that compound 6a may be a potential anticancer agent for further development.

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