Novel Ametantrone–Amsacrine Related Hybrids as Topoisomerase IIβ Poisons and Cytotoxic Agents

Zagotto, Giuseppe; Gianoncelli, Alessandra; Sissi, Claudia; Marzano, Cristina; Gandin, Valentina; Pasquale, Riccardo; Capranico, Giovanni; Ribaudo, Giovanni; Palumbo, Manlio

doi:10.1002/ardp.201400111

Cited by 8 publications

(8 citation statements)

References 37 publications

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“…In fact, DNA sequences containing core palindromic GC‐rich hexanucleotides were detected within several oncogenes in the human genome. Moreover, they have been identified in peculiar regions of HIV‐1 retrovirus genome …”

Section: Resultsmentioning

confidence: 99%

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Investigation of the molecular reactivity of bioactive oxiranylmethyloxy anthraquinones

Ribaudo

Ongaro

Zorzan

et al. 2019

Archiv der Pharmazie

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The design of a multitarget and multifunctional small molecule containing two functional groups reacting through different mechanisms represents an attractive goal for the medicinal chemist. The preparation of two bifunctional oxiranylmethyloxy anthraquinones, previously investigated as anticancer agents, is described here. These compounds combine a planar, DNA‐intercalating and pro‐oxidant anthraquinone scaffold and the alkylating epoxide functions which can covalently react with the nucleic acid. Their multilevel molecular reactivity was studied through a combination of analytical techniques: The DNA‐binding properties were investigated using a mass spectrometry‐based binding assay and by nuclear magnetic resonance, highlighting the formation of a covalent adduct with a nucleobase. Moreover, the contribution of the pro‐oxidant redox cycling was evaluated.

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Section: Resultsmentioning

confidence: 99%

“…Moreover, they have been identified in peculiar regions of HIV-1 retrovirus genome. [15][16][17] As depicted in Figure 1, it was possible to observe that compound 2 interacts with dsDNA forming 1:1 and 2:1 complex. The stability of the dsDNA-ligand complex was consequently investigated tuning the cone voltage parameter.…”

Section: Mass Spectrometry Binding Assaymentioning

confidence: 98%

Investigation of the molecular reactivity of bioactive oxiranylmethyloxy anthraquinones

Ribaudo

Ongaro

Zorzan

et al. 2019

Archiv der Pharmazie

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“…The compound was synthesized from trimellitic anhydride and hydroquinone by a Friedel Crafts reaction (AlCl 3 , NaCl, 150 °C, 7 h) followed by a mild air oxidation, according to a previously reported procedure 53,54 .…”

Section: Methodsmentioning

confidence: 99%

Pharmacophore-guided discovery of CDC25 inhibitors causing cell cycle arrest and tumor regression

Kabakci

Käppeli

Cantù

et al. 2019

Sci Rep

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CDC25 phosphatases play a key role in cell cycle transitions and are important targets for cancer therapy. Here, we set out to discover novel CDC25 inhibitors. Using a combination of computational methods, we defined a minimal common pharmacophore in established CDC25 inhibitors and performed virtual screening of a proprietary library. Based on the availability of crystal structures for CDC25A and CDC25B, we implemented a molecular docking strategy and carried out hit expansion/optimization. Enzymatic assays revealed that naphthoquinone scaffolds were the most promising CDC25 inhibitors among selected hits. At the molecular level, the compounds acted through a mixed-type mechanism of inhibition of phosphatase activity, involving reversible oxidation of cysteine residues. In 2D cell cultures, the compounds caused arrest of the cell cycle at the G1/S or at the G2/M transition. Mitotic markers analysis and time-lapse microscopy confirmed that CDK1 activity was impaired and that mitotic arrest was followed by death. Finally, the compounds induced differentiation, accompanied by decreased stemness properties, in intestinal crypt stem cell-derived Apc/K-Ras-mutant mouse organoids, and led to tumor regression and reduction of metastatic potential in zebrafish embryo xenografts used as in vivo model.

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“…Hybrid agents, designed as topo II inhibitors, have been obtained by combining the chemical features of known inhibitors (e.g., DNA intercalating agents such as ametantrone and amsacrine) in the attempt to optimize the interaction of the drug with the DNA-enzyme complex (1, Fig. 2) [10]. Although these studies may provide valuable information concerning the drug interaction in the enzyme-DNA ternary complex, the pharmacological activity of these hybrids was not investigated.…”

Section: Hybrid Compounds Incorporating Cytotoxic Agentsmentioning

confidence: 99%

Perspectives in the development of hybrid bifunctional antitumour agents

Musso

Dallavalle

Zunino

2015

Biochemical Pharmacology

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In spite of the development of a large number of novel target-specific antitumour agents, the single-agent therapy is in general not able to provide an effective durable control of the malignant process. The limited efficacy of the available agents (both conventional cytotoxic and novel target-specific) reflects not only the expression of defence mechanisms, but also the complexity of tumour cell alterations and the redundancy of survival pathways, thus resulting in tumour cell ability to survive under stress conditions. A well-established strategy to improve the efficacy of antitumour therapy is the rational design of drug combinations aimed at achieving synergistic effects and overcoming drug resistance. An alternative strategy could be the use of agents designed to inhibit simultaneously multiple cellular targets relevant to tumour growth/survival. Among these novel agents are hybrid bifunctional drugs, i.e. compounds resulting by conjugation of different drugs or containing the pharmocophores of different drugs. This strategy has been pursued using various conventional or target-specific agents (with DNA damaging agents and histone deacetylase inhibitors as the most exploited compounds). A critical overview of the most representative compounds is provided with emphasis on the HDAC inhibitor-based hybrid agents. In spite of some promising results, the actual pharmacological advantages of the hybrid agents remain to be defined. This commentary summarizes the recent advances in this field and highlights the pharmacological basis for a rational design of hybrid bifunctional agents.

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Novel Ametantrone–Amsacrine Related Hybrids as Topoisomerase IIβ Poisons and Cytotoxic Agents

Cited by 8 publications

References 37 publications

Investigation of the molecular reactivity of bioactive oxiranylmethyloxy anthraquinones

Investigation of the molecular reactivity of bioactive oxiranylmethyloxy anthraquinones

Pharmacophore-guided discovery of CDC25 inhibitors causing cell cycle arrest and tumor regression

Perspectives in the development of hybrid bifunctional antitumour agents

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