title: Structure, cytotoxicity, and DNA-cleavage properties of the complex [Cu(II)(pbt)Br2].
abstract: The reactions of the ligand 2-(2-pyridyl)benzthiazole (pbt) with CuBr 2 and ZnCl 2 in acetonitrile produce the complexes [Cu(pbt)Br 2] ( 1) and [Zn(pbt)Cl 2] ( 3), respectively. When complex 1 is dissolved in DMF, complex 2 is obtained as light-green crystals. The reaction of pbt with CuBr 2 in DMF also yields the complex [Cu(pbt)Br 2(dmf)] ( 2) (dmf = dimethylformamide). Complexes 1- 3 were characterized by X-ray crystallography. Complexes 1 and 3 have distorted tetrahedral coordination environments, and complex 2 is constituted of two slightly different copper centers, both exhibiting distorted trigonal bipyramidal geometries. Complexes 1 and 2 cleave phiX174 phage DNA, both in the presence and the absence of reductant. The free ligand pbt does not show any DNA-cleaving abilities. The poor solubility of complex 3 makes it not applicable for biological tests. The occurrence of DNA breaks in the presence of various radical scavengers suggests that no diffusible radicals are involved in the DNA cleavage by complex 1, as none of the scavengers inhibit the cleavage reaction. The DNA-cleavage products are not religated with the enzyme T4 DNA ligase, which is an additional proof that the cleavage is nonhydrolytic. Most probably the cleaving reaction involves reactive oxygen species, which could not be trapped, leading to an oxidative mechanism. An easy oxidation of Cu (II)(pbt)Br 2 to Cu (III) in DMF and the reduction of the same to Cu (I), under similar electrochemical conditions may lead to the in situ activation of molecular oxygen, resulting in the formation of metal solvated nondiffusible radicals able to prompt the oxidative cleavage of DNA. Complex 1 and the pure ligand exhibit remarkable cytotoxic effects against the cancer cell lines L1210 and A2780 and also against the corresponding cisplatin-resistant mutants of these cell lines.
authors.affiliation: Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.
authors.forename: Palanisamy Uma
authors.initials: PU
authors.lastname: Maheswari
authors.forename: Martijn
authors.initials: M
authors.lastname: van der Ster
authors.forename: Simon
authors.initials: S
authors.lastname: Smulders
authors.forename: Sharief
authors.initials: S
authors.lastname: Barends
authors.forename: Gilles P
authors.initials: GP
authors.lastname: van Wezel
authors.forename: Chiara
authors.initials: C
authors.lastname: Massera
authors.forename: Sudeshna
authors.initials: S
authors.lastname: Roy
authors.forename: Hans
authors.initials: H
authors.lastname: den Dulk
authors.forename: Patrick
authors.initials: P
authors.lastname: Gamez
authors.forename: Jan
authors.initials: J
authors.lastname: Reedijk
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003300:Copper / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004279:DNA, Viral / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy; D010084:Oxidation-Reduction; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D004279:DNA, Viral; D009942:Organometallic Compounds; D011725:Pyridines; D013844:Thiazoles; D003300:Copper