A bifunctional platinum(II) antitumor agent that forms DNA adducts with affinity for the estrogen receptor.
A strategy is described for the re-design of DNA damaging platinum(II) complexes to afford elevated toxicity towards cancer cells expressing the estrogen receptor (ER). Two platinum-based toxicants are described in which a DNA damaging warhead, [Pt(en)Cl(2)] (en, ethylenediamine), is tethered to either of two functional groups. The first agent, [6-(2-amino-ethylamino)-hexyl]-carbamic acid 2-[6-(7alpha-estra-1,3,5,(10)-triene)-hexylamino]-ethyl ester platinum(II) dichloride ((Est-en)PtCl(2)), terminates in a ligand for the ER. The second agent is a control compound lacking the steroid; this compound, N-[6-(2-amino-ethylamino)-hexyl]-benzamide platinum(II) dichloride ((Bz-en)PtCl(2))), terminates in a benzamide moiety, which lacks affinity for the ER. Using a competitive binding assay, Est-en had 28% relative binding affinity (RBA) for the ER as compared to 17beta-estradiol. After covalent binding to a synthetic DNA duplex 16-mer, the compound retained its affinity for the ER; specificity of the binding event was demonstrated by the ability of free 17beta-estradiol as a competitor to disrupt the DNA adduct-ER complex. The (Est-en)PtCl(2) compound showed higher toxicity against the ER positive ovarian cancer cell line CAOV3 than did the control compound. (Est-en)PtCl(2) was also more toxic to the ER positive breast cancer line, MCF-7, than to an ER negative line, MDA-MB231.
Kim
Eunsuk
E
Department of Chemistry and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Rye
Peter T
PT
Essigmann
John M
JM
Croy
Robert G
RG
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D018736:DNA Adducts / Q000378:metabolism*; D004249:DNA Damage; D015195:Drug Design; D004958:Estradiol / Q000378:metabolism; D004963:Estrenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D005260:Female; D006801:Humans; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*
C538914:(6-(2-aminoethylamino)hexyl)carbamic acid 2-(6-(7-estra-1,3,5,(10)-triene)hexylamino)ethyl ester platinum(II) dichloride; D000970:Antineoplastic Agents; D018736:DNA Adducts; D004963:Estrenes; D009944:Organoplatinum Compounds; D011960:Receptors, Estrogen; D004958:Estradiol