The synthesis of new platinum(II) complexes linked to non-steroidal estrogens

Wheeler, P.; Bérubé, Gervais

doi:10.1016/s0020-1693(00)84987-7

Cited by 6 publications

(1 citation statement)

References 15 publications

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“…This structural analogy should confer upon the new platinum(I1) complexes both antiestrogenic and cytotoxic activity. W e wish to report the details of our initial effort towards the synthesis of such derivatives (10) as well as their in vitro biological activity on MCF-7 (ER+) and MDA-MD-23 1 (ER-) human breast cancer cell lines.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and preliminary in vitro biological activity of non-steroidal cytotoxic estrogens designed for the treatment of breast cancer

Bérubé¹,

Wheeler²,

Ford³

et al. 1993

Can. J. Chem.

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The development of resistance to endocrine therapy as well as chemotherapy is presently a major problem in the treatment of breast cancer. To minimize this obstacle, new, more selective and potent, chemotherapeutic agents should be designed. One way to improve selectivity is to link a cytotoxic moiety to a molecule possessing an affinity to the estrogen receptor (ER). The latter would be used to direct the cytotoxic portion of the molecule towards the target cells. Our initial approach led us to the synthesis of new triphenylethylene–platinum(II) complexes 1a–c. The commercially available desoxyanisoin (10) was efficiently transformed in seven steps into the platinum(II) complexes 1a–c with an overall yield exceeding 30%. The biological activity of compounds 1a–c was evaluated in vitro on ER+ and ER− human breast tumor cell lines: MCF-7 and MDA-MD-231.

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Section: Introductionmentioning

confidence: 99%

Synthesis and preliminary in vitro biological activity of non-steroidal cytotoxic estrogens designed for the treatment of breast cancer

Bérubé¹,

Wheeler²,

Ford³

et al. 1993

Can. J. Chem.

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ChemInform Abstract: The Synthesis of New Platinum(II) Complexes Linked to Non‐Steroidal Estrogens.

Wheeler

Bérubé

1993

ChemInform

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Chemical stability, biological activity and cellular uptake of a cisplatin analogue having a 1,2-diarylethyleneamine ligand in cultures of human breast cancer cells

Otto

Kratochwil

Eggers

et al. 1995

J Cancer Res Clin Oncol

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The platinum(II) complex PtCl2(meso-6), which has the estrogenic ligand meso-1,2-bis(2,6-dichloro-4- hydroxyphenyl)ethylenediamine (meso-6), has been reported to be an effective antitumor drug for estrogen-receptor(ER)-positive tumors in animal experiments. The goal of this study was to investigate whether the observed biological effects could be ascribed to the intact PtCl2(meso-6). Cultures of the ER-positive human breast cancer cell line MCF-7 were used as the in vitro test system. In culture medium containing 10% fetal calf serum, PtCl2(meso-6) had a half-life of about 2 h, as determined by HPLC analysis, and no PtCl2(meso-6) was detectable after 10 h. The Pt complex bound irreversibly to serum protein. After 30 min, the diamine ligand was found released, with a maximum conversion of about 35% at 24 h. At this time the culture medium still had estrogenic activity, i.e. it induced ER processing in the MCF-7 cells. This indicates that the estrogenic effect was elicited by the released diamine ligand. In contrast, the growth-inhibitory activity of the medium preincubated with PtCl2(meso-6) was lost at a rate similar to the rate of loss of PtCl2(meso-6) from the medium. This accords with the platinum complex being the main cytotoxic entity. When MCF-7 cells were incubated with PtCl2([3H]meso-6), no free Pt complex could be identified in cellular extracts, and most of the cell-associated radioactivity coeluted with meso-6 in HPLC analysis. After 12 h, only 1.4% of the total cellular platinum was bound to DNA, but no tritium label could be detected. In conclusion, diamine ligand is released from the Pt(II) complex and can account for the estrogenic effects so far ascribed to PtCl2(meso-6).

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The synthesis of new platinum(II) complexes linked to non-steroidal estrogens

Cited by 6 publications

References 15 publications

Synthesis and preliminary in vitro biological activity of non-steroidal cytotoxic estrogens designed for the treatment of breast cancer

Synthesis and preliminary in vitro biological activity of non-steroidal cytotoxic estrogens designed for the treatment of breast cancer

ChemInform Abstract: The Synthesis of New Platinum(II) Complexes Linked to Non‐Steroidal Estrogens.

Chemical stability, biological activity and cellular uptake of a cisplatin analogue having a 1,2-diarylethyleneamine ligand in cultures of human breast cancer cells

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