title: Structure activity studies on leaving group derivatives of [meso-1,2-bis-(2,6-dichloro-4-hydroxyphenyl)ethylenediamine] platinum(II).
abstract: The spatial structures of leaving group derivatives of [meso-1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]platinum(II) (meso-1-PtL2; L2 = SO4, Cl2, I2, CBDC (cyclobutane-1,1-dicarboxylate)) were investigated by NMR methods and correlated with their reactivity against nucleophiles, their estrogenic potency, and their activity on the hormone dependent MCF-7 mammary carcinoma cell line. It was demonstrated that beside the non-leaving group meso-1 the PtL2 moiety of meso-PtL2 complexes is important for the estrogen receptor binding. Among the tested complexes meso-1-PtI2 possesses the highest affinity for the estrogen receptor (RBA = 2.6) and represents a strong estrogen on the MCF-7-2a cell line. The use of CBDC as leaving group decreases the effects. Meso-1-PtCBDC shows an RBA of 0.06 and has only half of the estrogenic activity. Both complexes are sufficiently stable under physiological conditions, so a transformation into the dichloroplatinum(II) complex prior to the binding to the estrogen receptor can be excluded. Due to their high stability meso-1-PtI2 and meso-1-PtCBDC were only marginally active on the human estrogen receptor positive MCF-7 cell line, while meso-1-PtSO4 and meso-1-PtCl2 reduced the cell growth to T/Cmax = 45% and 25%, respectively.
authors.affiliation: Institut für Pharmazie I, Freien Universität Berlin, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Gust
authors.forename: R
authors.initials: R
authors.lastname: Keilitz
authors.forename: R
authors.initials: R
authors.lastname: Krauser
authors.forename: K
authors.initials: K
authors.lastname: Schmidt
authors.forename: B
authors.initials: B
authors.lastname: Schnurr
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy*; D051379:Mice; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy*; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use*; D011960:Receptors, Estrogen / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D011960:Receptors, Estrogen