Platinum(II) and technetium(I) complexes anchored to ethynylestradiol:: a way to drug targeting and delivery

Starting from ethynylestradiol (1), or, more precisely, from its 3,17beta-bis-(triethylsilyloxy) derivative 2, two new ligands containing the ethylenediamino motif were synthesised by a Mannich aminomethylation, namely N-methyl-N-(prop-2-ynyl-3-(17beta-testradiolyl))-N',N'-dimethylethylenediamine (3) and N-(prop-2-ynyl-3-(17alpha-estradiolyl))-N'-methylpiperazine (4). The corresponding platinum(II)-malonato complexes (7 and 8) were prepared through the PtI2 intermediates (namely 5 and 6) by Dhara's method. The structures of the two platinum complexes were energy-minimised by molecular mechanics employing the Amber force field. Both ligands were joined to the [Tc-99m(CO)(3)Cl] moiety, Tc-99m being the chief gamma-emitter employed in nuclear medicine. Unfortunately, piperazine ligand 4 afforded complexes that were unstable under physiological conditions. The RBA values for both ligands and complexes derived from 3, measured for the two forms of estrogen receptor, were less than 1%. Such a poor degree of ligand recognition may be due to the partial protonation of the amino groups at physiological pH, making the carrier quite hydrophilic, therefore unsuitable for entering the hydrophobic pocket of estrogen receptors. (C) 2003 Elsevier B.V. All rights reserved.