[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

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 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.

Searching for the Magic Bullet: Anticancer Platinum Drugs Which Can Be Accumulated or Activated in the Tumor Tissue

“…Optimization of the alkyl substituents on the nitrogens afforded ligands with relatively high RBA values (up to 20.88%) in the competitive (to estradiol) calf uterus estrogen receptor binding assay but coordination to platinum(II) reduced the affinity to the ER drastically (RBA values 0.1 to 0.5%) [43]. Surprisingly, this did not lead to substantial changes in the estrogenic potency of the substances in the mouse uterine weight test.…”

“…As shown exemplarily for the meso derivative the in-vivo effect in the animals is based on a reduction of the endogenous estrogen level caused by an interference with the ovarian steroid biosynthesis. N-ethylated derivatives of these compounds did not display strong estrogenic properties indicating that variation of the type and position of the ring substituents is the better choice for optimization of the pharmacological properties [51]. Comparative studies with cisplatin indicated that the minor antiproliferative invitro activity is probably not due to a rapid inactivation of the compounds by bionucleophiles but rather to an insufficient accumulation in the cultured tumor cells and a steric hindrance of its 2,6-standing fluorine atoms during the interaction with the DNA [50].…”

Platinum Group Antitumor Chemistry: Design and development of New Anticancer Drugs Complementary to Cisplatin

“…Ligands such as estrogen analogues [142], amino acids [143], tryptamine [143], berenil [144], sugars [145], and ferrocene [146] have also been utilized for specific targeting. Recently, novel platinum complexes containing Cantharidinbased bioactive ligands [147] Fig.…”

Metallodrug Conjugates with Steroids and Selective Estrogen Receptor Modulators (SERM)

“…Apart from its decreasing the endogenous level of testosterone to values comparable with those after orchiectomy it does not possess sufficient Ptbased cytotoxicity or ER-mediated antitumour activity like meso-26. Partly in continuation of these studies, Gust et al investigated the stereochemical implications and preconditions for the antitumoural activity of compounds 27 in ER + human MCF-7 breast cancer cells [71]. When they tried to increase the estrogenic and cytotoxic activities of meso-27 and D,L-27 by ethylation of the N-atom(s) they found that these two kinds of activity require different substituent patterns of the aromatic rings and different spatial structures of the five-membered chelate rings.…”

“…(16). Estrogenic and non-estrogenic [1,2-diphenylethylenediamine]platinum(II) complexes 26 and 27 and their effects in tumour cells[67][68][69][70][71].…”