title: Design, Synthesis, and Biological Features of Platinum(II) Complexes with Rigid Steric Hindrance.
abstract: A series of platinum(II) complexes, with N-monosubstituted 1R,2R-diaminocyclohexane bearing methoxy-substituted benzyl groups as carrier ligands, were designed and synthesized. The newly prepared compounds, with chloride anions as leaving groups, were found to be very active against the tested cancer cell lines, including a cisplatin-resistant cell line. Despite their efficacy against tumor cells, they also showed low toxicity to a human normal liver cell line. Among them, complex 1 had superior cytotoxic activity against A549, HCT-116, MCF-7, SGC7901, and SGC7901/CDDP cancer cell lines. The DNA binding assay is of further special interest, as an unusual monofunctional binding mode was found, due to the introduction of a rigid substituted aromatic ring in the 1R,2R-diaminocyclohexane framework as steric hindrance. The linkage of complex 1 with DNA was stable and insensitive to nucleophilic attack. Moreover, studies including cellular uptake, gel electrophoresis, apoptosis and cell cycle, and Western blot analysis have provided insight into the high potency of this compound.
authors.affiliation: Pharmaceutical Research Center and School of Chemistry and Chemical Engineering and ‡Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University , Nanjing 211189, China.
authors.forename: Zhimei
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Pharmaceutical Research Center and School of Chemistry and Chemical Engineering and ‡Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University , Nanjing 211189, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Yu
authors.affiliation: Pharmaceutical Research Center and School of Chemistry and Chemical Engineering and ‡Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University , Nanjing 211189, China.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Gou
authors.affiliation: Pharmaceutical Research Center and School of Chemistry and Chemical Engineering and ‡Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University , Nanjing 211189, China.
authors.forename: Feihong
authors.initials: F
authors.lastname: Chen
authors.affiliation: Pharmaceutical Research Center and School of Chemistry and Chemical Engineering and ‡Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University , Nanjing 211189, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Fang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004247:DNA / Q000737:chemistry; D018736:DNA Adducts / Q000737:chemistry; D004355:Drug Stability; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D005978:Glutathione / Q000737:chemistry; D006157:Guanosine Monophosphate / Q000737:chemistry; D006801:Humans; D008024:Ligands; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000077150:Oxaliplatin; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D018736:DNA Adducts; D008024:Ligands; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D006157:Guanosine Monophosphate; D004247:DNA; D005978:Glutathione; D002945:Cisplatin