An estrogen-platinum terpyridine conjugate: DNA and protein binding and cellular delivery.
A platinum metal complex in which terpyridine joins estradiol (via an ethynyl link) to a platinum with a labile ligand (chloride) has been designed, synthesised and its X-ray crystal structure determined. The aim of this work was to link a targeting motif (in this case estrogen) to a metal-based biomolecule recognition unit (the platinum moiety). The target molecule: 17alpha-[4'-ethynyl-2,2':6',2'-terpyridine]-17beta-estradiol platinum(II) chloride (PtEEtpy) has been shown to bind to both human and bovine serum albumin (SA) and to DNA. FTICR mass spectrometry shows that the bimolecular units are in each case linked through coordination to the platinum with displacement of the chloride ligand. Circular dichroism indicates that a termolecular entity involving PtEEtpy, SA and DNA is formed. A range of electrospray mass spectrometry experiments showed that the PtEEtpy complex breaks and forms coordination bonds relatively easily. A whole cell estrogen receptor assay in an estrogen receptor positive cell (MCF-7) confirms binding of both EEtpy and PtEEtpy to the estrogen receptor in cells. The work demonstrates the concept of linking a targeting moiety (in this case estrogen) to a DNA binding agent.
Hannon
Michael J
MJ
Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK. m.j.hannon@bham.ac.uk
Green
Philip S
PS
Fisher
Dianne M
DM
Derrick
Peter J
PJ
Beck
Jennifer L
JL
Watt
Stephen J
SJ
Ralph
Stephen F
SF
Sheil
Margaret M
MM
Barker
Philip R
PR
Alcock
Nathaniel W
NW
Price
Robert J
RJ
Sanders
Karen J
KJ
Pither
Richard
R
Davis
Julie
J
Rodger
Alison
A
D000818:Animals; D001483:Base Sequence; D001681:Biological Assay; D002417:Cattle; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry*; D006801:Humans; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism*; D012709:Serum Albumin / Q000737:chemistry*; D013057:Spectrum Analysis
C521296:17alpha-(4'-ethynyl-2,2':6',2'-terpyridine)-17beta-estradiol platinum(II) chloride; D009944:Organoplatinum Compounds; D011960:Receptors, Estrogen; D012709:Serum Albumin; D004247:DNA