An aza-macrocycle containing maltolic side-arms (maltonis) as potential drug against human pediatric sarcomas

Guerzoni, Clara; Amatori, Stefano; Giorgi, Luca; Manara, Maria Cristina; Landuzzi, Lorena; Lollini, Pier‐Luigi; Tassoni, Aurora; Balducci, Mauro; Manfrini, Marco; Pratelli, Loredana; Serra, Massimo; Picci, Piero; Magnani, Mauro; Fusi, Vieri; Fanelli, Mirco; Scotlandi, Katia

doi:10.1186/1471-2407-14-137

Cited by 15 publications

(17 citation statements)

References 36 publications

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“…Free Malten was previously reported as exhibiting biological activity against neoplastic cells 10. 11 Here, the potential ability of all selected Malten metal complexes to interact with the DNA structure was evaluated by a cell‐free assay that exploits the use of circular plasmid DNA to reveal the possible induction of DNA structural changes. The Malten metal complexes considered were the mono‐nuclear [Cu(H −2 L )], the trinuclear [Ca{Cu(H −2 L )} 2 ] 2+ , [Sr{Cu(H −2 L )} 2 ] 2+ and [Gd{Cu(H −2 L )} 2 ] 3+ , and the tetranuclear [Ca{Cu(H −2 L )}] 2 4+ species.…”

Section: Resultsmentioning

confidence: 99%

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A Preorganized Metalloreceptor for Alkaline Earth Ions Showing Calcium Versus Magnesium Selectivity in Water: Biological Activity of Selected Metal Complexes

Amatori

Ambrosi

Fanelli

et al. 2014

Chemistry A European J

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The N,N'-bis[(3-hydroxy-4-pyron-2-yl)methyl]-N,N'-dimethylethylendiamine (Malten = L) forms the highly stable [CuH(-2)L] species in water, in which the converging maltol oxygen atoms form an electron-rich area able to host hard metal ions. When considering the alkaline earth series (AE), the [Cu(H(-2)L)] species binds all metal ions, with the exception of Mg(2+), exhibiting the relevant property to discriminate Ca(2+) versus Mg(2+) at physiological pH 7.4; the binding of the AE metal is visible to the naked eye. The stability constant values of the trinuclear [AE{Cu(H(-2)L)}2](2+) species formed reach the maximum for Ca(2+) (log K=7.7). Ca(2+) also forms a tetranuclear [Ca{Cu(H(-2)L)}]2(4+) species at a high Ca(2+) concentration. Tri- and tetranuclear calcium complexes show blue- and pink-colored crystals, respectively. [Cu(H(-2)L)] is the most active species in inducing DNA alterations. The DNA damages are compatible with its hydrolytic cleavages.

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Section: Resultsmentioning

confidence: 99%

“…Recently, we developed a class of molecules based on two 3‐hydroxy‐2‐methyl‐4‐pyrone units (Maltol, see below) linked to a polyamine scaffold that exhibited anti‐neoplastic activity in vitro10 and in vivo 11…”

Section: Introductionmentioning

confidence: 99%

A Preorganized Metalloreceptor for Alkaline Earth Ions Showing Calcium Versus Magnesium Selectivity in Water: Biological Activity of Selected Metal Complexes

Amatori

Ambrosi

Fanelli

et al. 2014

Chemistry A European J

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“…Expression levels of target genes were normalised to that of glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and the relative quantification analysis was based on the 2 -ΔΔCt method [34]. …”

Section: Methodsmentioning

confidence: 99%

Effects of Fifty-Hertz Electromagnetic Fields on Granulocytic Differentiation of ATRA-Treated Acute Promyelocytic Leukemia NB4 Cells

Provenzano

Amatori

Nasoni

et al. 2018

Cell Physiol Biochem

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Background/Aims: Life on Earth is constantly exposed to electromagnetic fields (EMFs) and the effects induced by EMFs on biological systems have been extensively studied producing different and sometimes contradictory results. Extremely low-frequency electromagnetic fields (ELF-EMFs) have shown to play a role in regulating cell proliferation and differentiation, although how EMFs influence these processes remains unclear. Human acute promyelocytic leukemia (APL) cells are characterized by the arrest of differentiation at the promyelocytic stage due to epigenetic perturbations induced by PML/RARα fusion protein (Promyelocytic Leukemia protein - PML/Retinoic Acid Receptor alpha - RARα). Therapeutic administration of all-trans retinoic acid (ATRA) re-establishes the leukemogenic mechanism re-inducing the normal differentiation processes. Methods: We studied the effects of ELF-EMFs (50 Hz, 2 mT) on the ATRA-mediated granulocytic differentiation process of APL NB4 cells (a cell line established from the bone marrow of a patient affected by the acute promyelocytic leukemia) by monitoring cellular proliferation and morphology, nitrob lue tetrazolium (NBT) reduction and the expression of differentiation surface markers. Finally, we investigated mechanisms focusing on reactive oxygen species (ROS) generation and related molecular pathways. Results: ELF-EMF exposure decreases cellular proliferation potential and helps ATRA-treated NB4 cells to mature. Furthermore, the analysis of ROS production and the consequent extracellular signal regulated kinases (ERK1/2) phosphorylation suggest that a changed intracellular oxidative balance may influence the biological effects of ELF-EMFs. Conclusions: These results indicate that the exposure to ELF-EMF promotes ATRA-induced granulocytic differentiation of APL cells.

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“…Thus, aimed both at discovering new drugs for treating cancer and at synthesizing ligands provided with marked binding properties towards metal ions, we recently developed a new class of maltol-based ligands by symmetrically coupling polyamines and maltol units, which exhibited antineoplastic activity in vitro [36][37][38][39] and in vivo [40]. The compounds show two (3-hydroxy-4-pyron-2-yl)methyl units separated by an aliphatic amine spacer, which could be either linear, as in the case of N,N -bis((3-hydroxy-4-pyron-2-yl)methyl)-N,N -dimethylethylendiamine (malten, Figure 1), or cyclic, as in the case of 4,10-bis[(3-hydroxy-4-pyron-2-yl)methyl]-1,7-dimethyl-1,4,7,10-tetraazacyclododecane (maltonis, Figure 1).…”

Section: Introductionmentioning

confidence: 99%

“…Maltonis is more effective than malten, and noteworthily, is effective on sarcoma (in vivo) and multidrug-and cisplatin-resistant cells (in vitro) while being ineffective on normal human mesenchymal stem cells. Its mechanism of action seems to involve the inhibition of cell proliferation and the involvement of a DNA damage response till induction of cell death [40].…”

Section: Introductionmentioning

confidence: 99%

Playing with Structural Parameters: Synthesis and Characterization of Two New Maltol-Based Ligands with Binding and Antineoplastic Properties

et al. 2020

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Two maltol-based ligands, N,N′-bis((3-hydroxy-4-pyron-2-yl)methyl)-1,4-piperazine (L1) and N,N′,N′-tris((3-hydroxy-4-pyron-2-yl)methyl)-N-methylethylendiamine (L2), were synthesized and characterized. L1 and L2, containing, respectively, two and three maltol units spaced by a diamine fragment, were designed to evaluate how biological and binding features are affected by structural modifications of the parent compound malten. The acid-base behavior and the binding properties towards transition, alkaline-earth (AE) and rare-earth (RE) cations in aqueous solution, studied by potentiometric, UV-Vis and NMR analysis, are reported along with biological studies on DNA and leukemia cells. Both ligands form stable complexes with Cu(II), Zn(II) and Co(II) that were studied as metallo-receptors for AE and RE at neutral pH. L1 complexes are more affected than L2 ones by hard cations, the L1-Cu(II) system being deeply affected by RE. The structural modifications altered the mechanism of action: L1 partially maintains the ability to induce structural alterations of DNA, while L2 provokes single strand (nicks) and to a lesser extent double strand breaks of DNA.

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An aza-macrocycle containing maltolic side-arms (maltonis) as potential drug against human pediatric sarcomas

Cited by 15 publications

References 36 publications

A Preorganized Metalloreceptor for Alkaline Earth Ions Showing Calcium Versus Magnesium Selectivity in Water: Biological Activity of Selected Metal Complexes

A Preorganized Metalloreceptor for Alkaline Earth Ions Showing Calcium Versus Magnesium Selectivity in Water: Biological Activity of Selected Metal Complexes

Effects of Fifty-Hertz Electromagnetic Fields on Granulocytic Differentiation of ATRA-Treated Acute Promyelocytic Leukemia NB4 Cells

Playing with Structural Parameters: Synthesis and Characterization of Two New Maltol-Based Ligands with Binding and Antineoplastic Properties

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