Abstract
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.
Highlights
Cancer has long been known and still is one of the most common diseases, despite the great technological and social development we have experienced in the last few decades
They show well-known coordination properties towards metal ions and/or anions [33,34,35]. Due to their protonable sites, polyamines allow one to obtain water-soluble compounds; that is a crucial point for both biological activity and guest coordination in aqueous solutions. 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]
N,N0,N0 -tris((3-hydroxy-4-pyron-2-yl)methyl)-N-methylethylendiamine following procedures analogous to those adopted for malten and maltonis [39], which are reported in Scheme 1
Summary
Cancer has long been known and still is one of the most common diseases, despite the great technological and social development we have experienced in the last few decades. The number of cancer survivors has grown, but even if this trend shows that progress is being made against the disease, much work remains [2]. The survival of patients is limited by the lack of specific therapies; the cytotoxicity of the drugs, and the resulting occurrence of severe side effects; and, not least, the resistance to currently used chemotherapics. In that light, finding new antineoplastic drugs with reduced toxicity and relevant clinical activity is currently a major therapeutic challenge. In the search for new molecules providing high and selective therapeutic anticancer efficacy, while being well tolerated by the human body, one important strategy is to look at natural sources
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