[N-ethyl- and [N,N'-diethyl-1,2-bis(2,6-difluoro-3-hydroxyphenyl)-ethylenediamine]dichloroplatinum(II): structure and cytotoxic/estrogenic activity in breast cancer cells.
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 NH2 fragment as a prerequisite for antitumor activity. Furthermore, studies on the three-dimensional structure 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 cytotoxic effects, very likely due to the reaction with d(GpG) sequences in DNA resulting in GG-N7,N7 chelates. A contribution of the ER-mediated processes--(a) hindrance of the cellular processing of 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 and granulocytes/macrophages by reduction of the formation of key cytokines--to the anti-breast cancer activity of threo-2-PtCl2 is unlikely, since we did not observe transcription activation in the test on ER+ MCF-7 breast cancer cells stably transfected with luciferase reporter plasmid ERE(wtc)luc.
Gust
Ronald
R
Institute of Pharmacy, Free University of Berlin, D-14195 Berlin (Dahlem), Germany. rgust@zedat.fu-berlin.de
Niebler
Karlheinz
K
Schönenberger
Helmut
H
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D004965:Estrogen Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases / Q000235:genetics; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D009376:Neoplasms, Hormone-Dependent; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects
C507021:(N,N'-diethyl-1,2-bis(2,6-difluoro-3-hydroxyphenyl)ethylenediamine)dichloroplatinum(II); C507020:(N-ethyl-1,2-bis(2,6-difluoro-3-hydroxyphenyl)ethylenediamine)dichloroplatinum(II); D000970:Antineoplastic Agents; D002614:Chelating Agents; D004965:Estrogen Antagonists; D009944:Organoplatinum Compounds; D008156:Luciferases