title: DNA targeting polyaza macrobicyclic dizinc(II) complexes promoting high in vitro caspase dependent anti-proliferative activity against human carcinoma cancer cells.
abstract: A series of macrobicyclic dizinc(II) complexes [Zn(2)L(1-2)B](ClO(4))(4) (1-6) have been synthesized and characterized (L(1-2) are polyaza macrobicyclic binucleating ligands, and B is the N,N-donor heterocyclic base (viz. 2,2'-bipyridine (bipy) and 1,10-phenanthroline (phen)). The DNA and protein binding, DNA hydrolysis and anticancer activity of these complexes were investigated. The interactions of complexes 1-6 with calf thymus DNA were studied by spectroscopic techniques, including absorption, fluorescence and CD spectroscopy. The DNA binding constant values of the complexes were found to range from 2.80 × 10(5) to 5.25 × 10(5) M(-1), and the binding affinities are in the following order: 3 > 6 > 2 > 5 > 1 > 4. All the dizinc(II) complexes 1-6 are found to effectively promote the hydrolytic cleavage of plasmid pBR322 DNA under anaerobic and aerobic conditions. Kinetic data for DNA hydrolysis promoted by 3 and 6 under physiological conditions give observed rate constants (k(obs)) of 5.56 ± 0.1 and 5.12 ± 0.2 h(-1), respectively, showing a 10(7)-fold rate acceleration over the uncatalyzed reaction of dsDNA. Remarkably, the macrobicyclic dizinc(II) complexes 1-6 bind and cleave bovine serum albumin (BSA), and effectively promote the caspase-3 and caspase-9 dependent deaths of HeLa and BeWo cancer cells. The cytotoxicity of the complexes was further confirmed by lactate dehydrogenase enzyme levels in cancer cell lysate and content media.
authors.affiliation: Department of Inorganic Chemistry, University of Madras, Guindy Maraimalai Campus, Chennai-600 025, India.
authors.forename: Sellamuthu
authors.initials: S
authors.lastname: Anbu
authors.forename: Rajendran
authors.initials: R
authors.lastname: Ravishankaran
authors.forename: Anjali A
authors.initials: AA
authors.lastname: Karande
authors.forename: Muthusamy
authors.initials: M
authors.lastname: Kandaswamy
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D056831:Coordination Complexes / Q000737:chemistry / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism*; D053837:DNA Cleavage; D006367:HeLa Cells; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D012710:Serum Albumin, Bovine / Q000378:metabolism; D015032:Zinc / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D012710:Serum Albumin, Bovine; D004247:DNA; D007770:L-Lactate Dehydrogenase; D053148:Caspase 3; D053453:Caspase 9; D015032:Zinc