Potential adenine and minor groove binding platinum complexes.
This paper is a focused review of our recent efforts to produce multi-nuclear platinum anti-cancer complexes that preferentially target adenine residues in DNA. Multi-nuclear platinum complexes, like cisplatin, predominantly form covalent adducts with guanine bases; however, controlling the pre-covalent binding association of the metal complex may modify this preference. NMR experiments, using oligonucleotides, indicate that multi-nuclear complexes linked by flexible diaminoalkanes will pre-associate in the DNA minor groove at A/T rich regions. Despite this pre-covalent binding preference, these complexes still predominantly covalently bind guanine residues. However, using 4,4'-dipyrazolylmethane (dpzm) as a linking ligand produces a dinuclear platinum complex, trans-[[PtCl(NH(3))(2)](2)mu-dpzm](2+), that covalently binds DNA with a preference for adenine bases. In vitro transcription assays also demonstrate that the dpzm-based complex covalently binds within an A/T rich region of the 512 base-pair segment of DNA used for the study.
School of Physical, Environmental and Mathematical Sciences, University College, University of New South Wales, Australian Defence Force Academy, Northcott Drive, Campbell, ACT 2600, Australia. g.collins@adfa.edu.au
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Grant Collins
Nial J
NJ
Wheate
D000225:Adenine / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D004247:DNA / Q000737:chemistry* / Q000378:metabolism*; D008697:Methane / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism; D009690:Nucleic Acid Conformation; D017671:Platinum Compounds / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology / Q000633:toxicity; D011720:Pyrazoles / Q000737:chemistry*
C493313:4,4'-dipyrazolylmethane; D017671:Platinum Compounds; D011720:Pyrazoles; D004247:DNA; D000225:Adenine; D008697:Methane