Synthesis, Basicity, Structural Characterization, and Biochemical Properties of Two [(3-Hydroxy-4-pyron-2-yl)methyl]amine Derivatives Showing Antineoplastic Features.

Abstract

The N,N'-bis[(3-hydroxy-4-pyron-2-yl)methyl]-N,N'-dimethylethylendiamine (malten) and 4,10-bis[(3-hydroxy-4-pyron-2-yl)methyl]-1,7-dimethyl-1,4,7,10-tetraazacyclododecane (maltonis) were synthesized and characterized. The acid-base behavior, structural characterizations, and biochemical studies in aqueous solution were reported. Each compound contains two 3-hydroxy-2-methyl-4-pyrone units (maltol) symmetrically spaced by a polyamine fragment, the 1,4-dimethylethylendiamine (malten), or the 1,7-dimethyl-1,4,7,10-tetraazacyclododecane (maltonis). They are present at physiological pH 7.4 in the form of differently charged species: neutral but in a zwitterion form for malten and monopositive with an internal separation of charges for maltonis. Malten and maltonis are both able to alter the chromatin structure inducing the covalent binding of genomic DNA with proteins, a feature consistent with the known antiproliferative activity exerted by this class of molecules. Solid-state results and MD simulations in water show that malten, because of its molecular topology, should be more prone than maltonis to act as a donor of H-bonds in intermolecular contacts, thus it should give a better noncovalent approach with the negatively charged DNA. Crystal structures of [H(2)malten](2+) and [H(2)maltonis](2+) cations were also reported.

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

“…With a larger population of long-survivors, scientific and patients’ associations are very sensitive to the need of therapy improvement in terms of reducing side effects and increasing quality of life, as well as potentiating efficacy of treatment in patients with metastatic disease. In this paper we explored the preclinical efficacy of two new-generation maltol-derived synthetic molecules named malten [N,N’-bis[(3-hydroxy-4-pyron-2-yl)methyl]-N, N’-dimethylethylendiamine] and maltonis [4(N),10 (N)–bis[(3-hydroxy-4-pyron-2-yl)methyl]-1, 7-dimethyl-1, 4, 7, 10 tetraazacyclododecane] [11,12]. Both chemical agents belong to the class of highly versatile molecules hydroxypyrones, that include compounds bearing anti-proliferative activities against a wide range of cancer cells, either alone or in combination with metals [13].…”

Crystal structure of the BaII-based CoII-containing one-dimensional coordination polymer poly[[aqua{μ4-2,2′-[(4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7-diyl)bis(methylidene)]bis(4-oxo-4H-pyran-3-olato)}perchloratocobaltbarium] perchlorate]

“…Ligand L1 {4,10-bis[(3-hydroxy-4-pyron-2-yl)methyl]-1,7-dimethyl-1,4,7,10-tetraazacyclododecane} is a Maltol-based macrocycle (Amatori et al, 2012) II heterodinuclear metal coordination compound of L1, where a one-dimensional wave-like infinite array of barium ions bridges the [Co(H -2 L1)] moieties through a barium-2 -oxygen motif. This is the first time that L1 has proven able to form a coordination polymer and, to our knowledge, this is the first example of a macrocyclic ligand forming a Ba II -based 1D-CP containing Co II ions surrounded by an N 4 O 2 donor set.…”

“…Ligand L1 {4,10-bis[(3-hydroxy-4-pyron-2-yl)methyl]-1,7-dimethyl-1,4,7,10-tetraazacyclododecane} is a Maltol-based macrocycle (Amatori et al, 2012) and is able to form discrete heteropolynuclear complexes. It has already proved to able form a Co II species (Benelli et al, 2013;Rossi et al, 2017).…”

“…Compound L1 was obtained following the synthetic procedure previously reported (Amatori et al, 2012).…”

“…Recently, the interest in alkaline-earth metal ion-based CPs has been growing due to their unusual advantages such as low toxicity, wide distribution and low cost, which are of benefit for applications in the field of materials science (Raja et al, 2014;Foo et al, 2012Foo et al, , 2013Xiao et al, 2012 earth metal-based CPs are less common compared to the reported transition metal and rare-earth metal CPs (Cai et al, 2017). Indeed, the study of alkaline-earth-metal systems is limited by challenges in the synthesis (Lian et al, 2016;Douvali et al, 2015;Mali et al, 2015;Chakraborty et al, 2014;Zhang, Huang et al, 2012;Liu, Tsao et al, 2010), the main reason being the variable coordination numbers (the most preferred coordination numbers are six for magnesium, six to eight for calcium, and six to twelve for strontium and barium), which lead to uncontrolled coordination geometries around the metal centre (Cai et al, 2016;Feng et al, 2015;Shi et al, 2015;Zheng et al, 2015;Jia et al, 2014;Zhang, Yuan et al, 2013;Smith et al, 2013;Zhai et al, 2013 Besides, the ability of a system to bind alkaline-earth metal ions in aqueous solution is highly desirable and can be achieved thanks to the presence of oxygenated ligands and the preorganization of the receptor, which satisfies the need for a high coordination number without specific coordination requirements.Ligand L1 {4,10-bis[(3-hydroxy-4-pyron-2-yl)methyl]-1,7-dimethyl-1,4,7,10-tetraazacyclododecane} is a Maltol-based macrocycle (Amatori et al, 2012) II heterodinuclear metal coordination compound of L1, where a one-dimensional wave-like infinite array of barium ions bridges the [Co(H -2 L1)] moieties through a barium-2 -oxygen motif. This is the first time that L1 has proven able to form a coordination polymer and, to our knowledge, this is the first example of a macrocyclic ligand forming a Ba II -based 1D-CP containing Co II ions surrounded by an N 4 O 2 donor set.…”