title: Rational design of a cytotoxic dinuclear Cu2 complex that binds by molecular recognition at two neighboring phosphates of the DNA backbone.
abstract: The mechanism of the cytotoxic function of cisplatin and related anticancer drugs is based on their binding to the nucleobases of DNA. The development of new classes of anticancer drugs requires establishing other binding modes. Therefore, we performed a rational design for complexes that target two neighboring phosphates of the DNA backbone by molecular recognition resulting in a family of dinuclear complexes based on 2,7-disubstituted 1,8-naphthalenediol. This rigid backbone preorganizes the two metal ions for molecular recognition at the distance of two neighboring phosphates in DNA of 6-7 Å. Additionally, bulky chelating pendant arms in the 2,7-position impede nucleobase complexation by steric hindrance. We successfully synthesized the Cu(II)2 complex of the designed family of dinuclear complexes and studied its binding to dsDNA by independent ensemble and single-molecule methods like gel electrophoresis, precipitation, and titration experiments followed by UV-vis spectroscopy, atomic force microscopy (AFM), as well as optical tweezers (OT) and magnetic tweezers (MT) DNA stretching. The observed irreversible binding of our dinuclear Cu(II)2 complex to dsDNA leads to a blocking of DNA synthesis as studied by polymerase chain reactions and cytotoxicity for human cancer cells.
authors: Lehrstuhl für Anorganische Chemie I, Chemistry Department, ‡Lehrstuhl für Biochemie III, Chemistry Department, and §Experimentelle Biophysik, Physics Department, Bielefeld University , Universitätsstrasse 25, 33615 Bielefeld, Germany.
authors: Thomas
authors: T
authors: Jany
authors: Alexander
authors: A
authors: Moreth
authors: Claudia
authors: C
authors: Gruschka
authors: Andy
authors: A
authors: Sischka
authors: Andre
authors: A
authors: Spiering
authors: Mareike
authors: M
authors: Dieding
authors: Ying
authors: Y
authors: Wang
authors: Susan Haji
authors: SH
authors: Samo
authors: Anja
authors: A
authors: Stammler
authors: Hartmut
authors: H
authors: Bögge
authors: Gabriele
authors: G
authors: Fischer von Mollard
authors: Dario
authors: D
authors: Anselmetti
authors: Thorsten
authors: T
authors: Glaser
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D003300:Copper / Q000737:chemistry*; D004247:DNA / Q000096:biosynthesis / Q000737:chemistry* / Q000378:metabolism*; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D009281:Naphthalenes / Q000737:chemistry; D009690:Nucleic Acid Conformation; D009942:Organometallic Compounds / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D010710:Phosphates / Q000378:metabolism*
chemical_list: C518223:1,8-naphthalenediol; D000970:Antineoplastic Agents; D009281:Naphthalenes; D009942:Organometallic Compounds; D010710:Phosphates; D003300:Copper; D004247:DNA