| Abstract
| - N-Ethyl and N,N‘-diethyl derivatives (erythro- and threo-2-PtCl2; meso- and d,l-3-PtCl2) of[meso- and [d,l-1,2-bis(2,6-difluoro-3-hydroxyphenyl)ethylenediamine]dichloroplatinum(II) (meso- and d,l-1-PtCl2) were synthesized and tested for cytotoxicity on the estrogen receptor-positive (ER+) human MCF-7 breast cancer cell line. In this test, only d,l-1-PtCl2 and threo-2-PtCl2 showed strong cytotoxic properties. This revealed the existence of at least one NH2fragment as a prerequisite for antitumor activity. Furthermore, studies on the three-dimensionalstructure of the new compounds demonstrated that the aryl and alkyl residues at the five-membered chelate ring have to be arranged in equatorial positions for the triggering of cytotoxiceffects, very likely due to the reaction with d(GpG) sequences in DNA resulting in GG−N7,N7chelates. A contribution of the ER-mediated processes(a) hindrance of the cellular processingof Pt-modified DNA by overexpression of high mobility group domain proteins and (b)interruption of the vicious circle of mutual growth stimulation of breast cancer cells andgranulocytes/macrophages by reduction of the formation of key cytokinesto the anti-breastcancer activity of threo-2-PtCl2 is unlikely, since we did not observe transcription activationin the test on ER+ MCF-7 breast cancer cells stably transfected with luciferase reporter plasmidEREwtcluc.
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