Biochemistry III
 
 
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Uni von A-Z
Universität Bielefeld > Department of Chemistry > Research Groups > Prof. Dr. Gabriele Fischer von Mollard > Biochemistry III
  

Inorg. Chem. (2015) 54, 2679-2790

Rational design of a cytotoxic dinuclear Cu2 complex that binds by molecular recognition at two neighboring phosphates of the DNA backbone.

Jany, T., Moreth, A., Gruschka, C., Sischka, A., Spiering, A., Dieding, M., Wang, Y., Samo, SH., Stammler, A., Bögge, H., Fischer von Mollard, G., Anselmetti, D., Glaser, T.

 

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 CuII2 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 CuII2 complex to dsDNA leads to a blocking of DNA synthesis as studied by polymerase chain reactions and cytotoxicity for human cancer cells.