title: 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.
authors.affiliation: Molecular Pathology and Oncology Laboratory PaoLa, Department of Biomolecular Sciences, University of Urbino, via Arco d'Augusto 2, I-61032 Fano (PU), Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Amatori
authors.forename: Gianluca
authors.initials: G
authors.lastname: Ambrosi
authors.forename: Mirco
authors.initials: M
authors.lastname: Fanelli
authors.forename: Mauro
authors.initials: M
authors.lastname: Formica
authors.forename: Vieri
authors.initials: V
authors.lastname: Fusi
authors.forename: Luca
authors.initials: L
authors.lastname: Giorgi
authors.forename: Eleonora
authors.initials: E
authors.lastname: Macedi
authors.forename: Mauro
authors.initials: M
authors.lastname: Micheloni
authors.forename: Paola
authors.initials: P
authors.lastname: Paoli
authors.forename: Roberto
authors.initials: R
authors.lastname: Pontellini
authors.forename: Patrizia
authors.initials: P
authors.lastname: Rossi
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry / Q000187:drug effects / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D009363:Neoplasm Proteins / Q000737:chemistry; D011753:Pyrones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D020298:U937 Cells
chemical_list: C512308:1,7-dimethyl-1,4,7,10-tetraazacyclododecane; D000970:Antineoplastic Agents; D006571:Heterocyclic Compounds; D009363:Neoplasm Proteins; D011753:Pyrones; C008316:maltol; D004247:DNA