Structure, cytotoxicity, and DNA-cleavage properties of the complex [Cu(II)(pbt)Br2].
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.
Maheswari
Palanisamy Uma
PU
Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.
van der Ster
Martijn
M
Smulders
Simon
S
Barends
Sharief
S
van Wezel
Gilles P
GP
Massera
Chiara
C
Roy
Sudeshna
S
den Dulk
Hans
H
Gamez
Patrick
P
Reedijk
Jan
J
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
D004279:DNA, Viral; D009942:Organometallic Compounds; D011725:Pyridines; D013844:Thiazoles; D003300:Copper