Mammary tumor inhibiting [1,2-bis(2,6-dihalo-3-hydroxyphenyl)ethylenediamine]platinum(II) complexes, III: Relationship between structure and estrogenic activity of the diamine ligands, their sulfatoplatinum(II) and diiodoplatinum(II) complexes.

1,2-Bis(2,6-dihalo-3-hydroxyphenyl)ethylenediamines with 2,6-Cl2, 2-F-6-Cl, 2-Cl,6-F, and 2,6-F2 substituents (meso-1 to meso-4, D,L-1 and D,L-4) and their sulfatoplatinum(II) complexes were tested in the immature mouse uterine weight test. The only complex with marked estrogenic properties proved to be meso-1-PtSO4. Surprisingly its diamine ligand meso-1 was only marginally active. 1H-NMR spectroscopic studies on the 1,2-diphenylethylenediamine ligand reveal that the 2,6-standing Cl-atoms in meso-1 (antiperiplanar phenyl residues) hinder the rotation of the aromatic rings, which results in very stable conformers with different O-O distances owing to the unsymmetric arrangement of the ring substituents. On transformation into the Pt(II) complex the conformations of meso-1 change (synclinal phenyl residues) and a delta and lambda interconversion takes place already at physiological temp. (37 degrees C). This process is accompanied by a rotation of phenyl rings, which is supposed to allow an optimal fit for the formation of hydrogen bridges to the estrogen receptor, resulting in a marked estrogenic activity. The other ligands and complexes are inactive presumably due to a diminished hydrophobic interaction with the estrogen receptor, resulting from their R,R/S,S-configuration or the reduced number of Cl-atoms.