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Bis-intercalative dinuclear platinum(II) 6-phenyl-2,2′-bipyridine complexes exhibit enhanced DNA affinity but similar cytotoxicity compared to the mononuclear unit

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Abstract

The interactions between a series of platinum complexes, including (pyridyl)(6-phenyl-2,2′-bipyridine)platinum(II) hexafluorophosphate (1), three dinuclear bis[(6-phenyl-2,2′-bipyridine)platinum(II)] complexes (2–4), and (4-aminopyridine)(4,6-diphenyl-2,2′-bipyridine)platinum(II) perchlorate (5) with DNA have been investigated. All Pt(II) complexes, except 5, were demonstrated to be DNA intercalators, based on viscosity measurements. Absorption and fluorescence titration results indicated that the addition of a phenyl ring to the 6-phenyl-2,2′-bipyridine ligand dramatically reduced the DNA binding of the Pt(II) complex 5. The dinuclear complexes 2–4 exhibited multiple binding modes of mono/bisintercalation and groove binding, as revealed by viscosity and fluorescence titration measurements. While complexes 2–4 bound to DNA with significantly enhanced affinities as compared to 1, compounds 1 and 2–4 showed similar IC50 values against a panel of cancer cell lines. In addition, these complexes showed similar cellular uptakes. The results indicated that the cytotoxicity of these (6-phenyl-2,2′-bipyridine)platinum compounds may not be mediated through DNA binding but may involve interacting mechanisms with cellular components other than DNA.

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Abbreviations

AO:

acridine orange

ampy:

4-aminopyridine

bipy:

2,2′-bipyridine

bp:

base pair

CNN:

6-phenyl-2,2′-bipyridine

ctDNA:

calf thymus DNA

EB:

ethidium bromide

EI:

electron ionization

en:

ethylenediamine

FAB:

fast atomic bombardment

H33342:

Hoechst 33342

IC50 :

inhibitory concentration 50%

ICP-AES:

inductively coupled plasma–atomic emission spectroscopy

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-tetrazolium bromide

4-PhCNN:

4,6-diphenyl-2,2′-bipyridine

phen:

1,10-phenanthroline

terpy:

2,2′:6′,2″-terpyridine

Tris:

tris(hydroxymethyl)aminomethane

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Acknowledgements

This work was supported by the Hong Kong Research Grants Council (CityU 1189/01P, CityU project no. 9040652), and the Area of Excellence Scheme, University Grants Committee (Hong Kong).

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Authors and Affiliations

  1. Department of Biology and Chemistry, City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, Hong Kong, China

    Hing-Leung Chan & Mengsu Yang

  2. Department of Chemistry and Open Laboratory of Chemical Biology, The Institute of Molecular Technology for Drug Discovery and Synthesis, The University of Hong Kong, Pokfulam Road, Hong Kong, China

    Dik-Lung Ma & Chi-Ming Che

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  1. Hing-Leung Chan
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  2. Dik-Lung Ma
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  3. Mengsu Yang
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  4. Chi-Ming Che
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Correspondence to Mengsu Yang or Chi-Ming Che.

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Chan, HL., Ma, DL., Yang, M. et al. Bis-intercalative dinuclear platinum(II) 6-phenyl-2,2′-bipyridine complexes exhibit enhanced DNA affinity but similar cytotoxicity compared to the mononuclear unit. J Biol Inorg Chem 8, 761–769 (2003). https://doi.org/10.1007/s00775-003-0477-0

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