title: Diorganotin (IV) complexes with 4-nitro-N-phthaloyl-glycine: Synthesis, characterization, antitumor activity and DNA-binding studies.
abstract: Two novel diorganotin (IV) complexes, based on 4-nitro-N-phthaloyl-glycine (HL), namely {4-NO2C6H3(CO)2NCH2COO}2Sn(n-Bu)2 (1) and {4-NO2C6H3(CO)2NCH2COO}2SnMe2 (2), were synthesized and characterized by elemental analysis, FT-IR, (1)H- and (13)C-NMR spectroscopic techniques. In vitro antitumor activities of both complexes were evaluated by the 3-(4,5-dimethylthiazoly-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay against three human cancer cell lines: HepG-2 (human liver carcinoma), SGC-7901 (human gastric carcinoma) and LS174T (human colon carcinoma). Complex 1 exhibited strong antitumor activity with IC50 values of 1.51±0.41, 1.80±0.63, and 2.48±0.96 μM, respectively; while complex 2 had no obvious effects on the three selected cancer cell lines at high concentrations up to 100 μM. Complex 1-induced apoptosis was further confirmed by morphological observations and annexin V-FITC/PI staining flow cytometry analysis in HepG-2 cells. Cell cycle analysis revealed that complex 1 caused cell cycle arrest at G2/M phase. Molecular mechanism studies suggested that the apoptosis was mediated through the mitochondrial pathway with intracellular reactive oxygen species (ROS) promotion and mitochondrial membrane potential (MMP) disruption by finally activating effector caspase-3/9 to trigger cell apoptosis. Moreover, the interactions of both complexes with calf thymus DNA (CT-DNA) were investigated by using UV-Vis titration and fluorometric competition measurements. The DNA-binding constants Kb (intrinsic binding constant) and K(sv) (quenching constant) had been obtained in the order: 1>2, consisted with the antitumor activity results. Taken together, complex 1 exhibited excellent antitumor activity suggesting that it may be a potential candidate for further chemical optimization and cancer therapy.
authors.affiliation: School of Pharmaceutical Science, Shanxi Medical University, No 56, Xinjian Nan Road, Taiyuan 030001, Shanxi, People's Republic of China.
authors.forename: Chaoqun
authors.initials: C
authors.lastname: Yan
authors.affiliation: School of Pharmaceutical Science, Shanxi Medical University, No 56, Xinjian Nan Road, Taiyuan 030001, Shanxi, People's Republic of China.
authors.forename: Jiali
authors.initials: J
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Science, Shanxi Medical University, No 56, Xinjian Nan Road, Taiyuan 030001, Shanxi, People's Republic of China. Electronic address: ltaigang@163.com.
authors.forename: Taigang
authors.initials: T
authors.lastname: Liang
authors.affiliation: School of Pharmaceutical Science, Shanxi Medical University, No 56, Xinjian Nan Road, Taiyuan 030001, Shanxi, People's Republic of China. Electronic address: sxyxlqs@163.com.
authors.forename: Qingshan
authors.initials: Q
authors.lastname: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002417:Cattle; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D004273:DNA, Neoplasm / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004996:Ethidium / Q000378:metabolism; D005434:Flow Cytometry; D005998:Glycine / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009947:Organotin Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010797:Phthalimides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D066244:Proton Magnetic Resonance Spectroscopy; D017382:Reactive Oxygen Species / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D013056:Spectrophotometry, Ultraviolet; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D004273:DNA, Neoplasm; D009947:Organotin Compounds; D010797:Phthalimides; D017382:Reactive Oxygen Species; D004247:DNA; C427203:calf thymus DNA; D053148:Caspase 3; D053453:Caspase 9; D004996:Ethidium; D005998:Glycine
keywords: 4-nitro-N-phthaloyl-glycine; Apoptosis; DNA-binding; Organotin complex