title: Cytotoxicity of platinum (II) dinuclear complexes with 1-alkylthymine ligands against mouse sarcoma 180 cells.
abstract: We synthesized five platinum (II) dinuclear complexes containing 1-alkylated thymines. Two of the 1-alkylated thymine, 1-MeThy and 1-EtThy, complexes afforded good crystals. The X-ray structures of these complexes were determined. The 1-MeThy complexes has a head-to-head (H-H) arrangement, while the 1-EtThy complex has a head-to-tail (H-T) arrangement. The 1-MeThy complex (H-H) shows high electrophilicity against chloride anion (CI-) and high cytotoxicity against mouse sarcoma 180 (S-180) cells in vitro. The 1-EtThy complex (H-T) is inactive. The other 1-MeThy complex does not produce CDDP in the reaction with chloride ion and is inactive against the S-180 cell line. This complex is assumed to have an H-T arrangement. Similarly, two different 1-Pr(n)Thy complexes, one with high electrophilicity and cytotoxicity and the other without, must have an H-H and H-T arrangement, respectively. For comparison, we investigated six complexes, 1-methyluracil (1-MeUra) (H-H) dimer, alpha-pyridone (H-T) dimer, alpha-pyridone blue tetramer (PPB), 1-methylcytosine (1-MeCyt) (H-T) dimer, acetate dimer, and 1-MeUra monomer complexes. The alpha-pyridone (H-T), PPB, 1-MeCyt (H-T) dimer, and 1-MeUra monomer complexes are inert to chloride ion and inactive against mouse sarcoma S-180. The 1-MeUra (H-H) dimer and acetate dimer complexes show high electrophilicity and high cytotoxicity. Cellular accumulation of the platinum complexes phenomenally shows that all are incorporated to cancer cells to a lesser extent than CDDP. The relationships between the accumulation, the electrophilicity, and the interaction of these complexes with proteins are discussed.
authors.affiliation: Bimolecules Department, National Institute of Bioscience and Human-Technology, Ibaraki, Japan.
authors.forename: P
authors.initials: P
authors.lastname: Rekonen
authors.forename: Y
authors.initials: Y
authors.lastname: Dohta
authors.forename: M
authors.initials: M
authors.lastname: Kodaka
authors.forename: T
authors.initials: T
authors.lastname: Okada
authors.forename: K
authors.initials: K
authors.lastname: Okamoto
authors.forename: H
authors.initials: H
authors.lastname: Okuno
mesh_terms: D000478:Alkylation; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D051379:Mice; D008956:Models, Chemical; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012510:Sarcoma 180 / Q000188:drug therapy*; D013941:Thymine / Q000737:chemistry / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D013941:Thymine