Synthesis, structure and biological activity of a new and efficient Cd(II)–uracil derivative complex system for cleavage of DNA

Abstract

The new complex formed by Cd(II) and the 1:2 Schiff-base-type ligand 2,6-bis[1-(4-amino-1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxopyrimidin-5-yl)imino]ethylpyridine (DAPDAAU) has been chemically and structurally characterized by X-ray diffraction: the ion Cd(II) is surrounded by six nitrogen atoms from two DAPDAAU ligands which coordinates each one in a tridentate fashion through the pyridine ring (N1) and both azomethine nitrogen atoms (N5). The interaction of the Cd(II) complex (compound I) with calf-thymus DNA as observed by circular dichroism spectroscopy suggests the initial unwinding of the DNA double helix strongly depends on increasing incubation times and metal-to-nucleic acid molar ratios. Electrophoretic experiments indicate that the cadmium complex induces cleavage of the plasmid pBR322 DNA to give ulterior nicking and shortening of this molecule, as a result of the complex binding to DNA, resulting in the conclusion that compound I behaves as a chemical nuclease. Cytotoxic activity of the Cd(II) complex against selected different human cancer cell lines is specific and increases with increasing concentration of the metal compound; this fact indicates the potential antitumor character of the complex. When the culture medium is supplemented with compound I, a remarkable inhibition of the growing cell is observed, important cell degeneration appears before 48 h and abundant precipitates are formed that correspond to cell residues and denatured proteins.

Synthesis, structure and cytotoxic activity evaluation of a dinuclear complex of Cd(II) with N′,N′2-bis[(1E)-1-(2-pyridyl)ethylidene]propanedihydrazide

“…Nevertheless, Cd(II) complexes with 2-formylpyridine and 3-acetylpyridine bis(thiocarbodiazones) showed a significant inhibitory activity on lymphomas and leukemias, as well as cytotoxic activity against the cisplatin-resistant ovarian tumor cell line A2780cisR, related to the ability to form interstrand cross-links [3]. Recently, a significant activity of the hexacoordinated Cd(II) complex with the condensation derivative of 2,6-diacetylpyridine and 5,6-diamino-1,3-dimethyluracil has been found [4].…”

“…Interstrand DNA cross-links formation was presumed as the mechanism of action [3]. Recently, a significant activity of the hexacoordinated Cd(II) complex with the condensation derivative of 2,6-diacetylpyridine and 5,6-diamino-1,3-dimethyluracil against the human cancer malignant melanoma (ADLD), cervix carcinoma (HeLa), colon adenocarcinoma (HT-29), neuroblastoma (SHSY5Y) and larynx carcinoma (Hep-2) cell lines has been found [4]. To the best of our knowledge, the results presented in this work are the first demonstration of the antitumor activity of a heptacoordinated Cd(II) complex.…”

“…The binuclear nature of the cation is related to the double NNO chelating functions possessed by the H 2 L molecules that display an approximate C 2 point group symmetry around the central methylene carbons. Thus, the complex is based on a Cd 2 (NNO) 4 coordination system, and a 12-membered (Cd-O-C-CH 2 -C-O-) 2 macrocycle is defined at the core of the binuclear cation (Cd1Á Á ÁCd2 = 7.102(2) Å ). An approximate twofold axis of symmetry is located at the center of this macrocycle, perpendicular to its mean plane.…”

A comparative study of DNA binding and cell cycle phase perturbation by the dinuclear complex of Cd(II) with the condensation product of 2‐acetylpyridine and malonic acid dihydrazide N′,N′2‐bis[(1E)‐1‐(2‐pyridyl)ethylidene]propanedihydrazide

“…However, several cadmium bis(thiosemicarbazones) have demonstrated remarkable cytotoxic activity against suspended lymphomas and leukemias and ovarian tumor cells [10]. The hexacoordinated Cd(II) complex with the condensation derivative of 2,6-diacetylpyridine and 5,6-diamino-1,3-dimethyluracil has induced a cleavage of plasmid DNA [11]. Recently, the dinuclear complex of Cd(II) with the condensation product of 2-acetylpyridine and malonic acid dihydrazide, N ,N 2 -bis[(1E)-1-(2-pyridyl)ethylidene]propanedihydrazide (H 2 L) has been synthesized, structurally characterized, and analyzed for its cytotoxic activity [6].…”

Enediyne compounds - new promises in anticancer therapy

“…Development of high-resolutions X-ray diffraction and nuclear magnetic resonance (NMR) techniques, together with thermodynamic studies and molecular modeling made a great contribution to disclosing the basic principles in DNA-drug interaction (2)(3)(4). The most striking finding that came out of it is that targets for drug's action are specific reactive, nucleophilic sites distributed on the surface of the double helix.…”