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.
Grant Collins
J
J
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
Wheate
Nial J
NJ
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