Breast cancer inhibiting diastereomeric diacetato[1,2-bis(4-fluorophenyl)ethylenediamine]platinum(II) derivatives: synthesis and studies on the relationship between reactivity and antitumor activity

Self Cite

The synthesis of the diastereomeric [1,2‐bis(4‐fluorophenyl)‐ethylenediamine][dicarboxylato]platinum(II) complexes, rac‐ and meso‐4F‐Pt(X) [X: oxalato (Ox), malonato (Mal), hydroxymalonato (OHMal), phenylmalonato (PhMal), tetrahydro‐4H‐pyran‐4,4‐dicarboxylato (Thpdc)], the evaluation of their structure, water solubility, resistance against attack by nucleophiles, and growth inhibiting properties on the human MCF‐7 breast cancer cell line are described [parent compounds: rac‐4F‐Pt(CBDC) and meso‐4F‐Pt(CBDC); reference complexes: carboplatin, cisplatin, rac‐ and meso‐4F‐PtCl2]. The most active 4F‐Pt(X) complexes, rac‐4F‐Pt(Mal), rac‐4F‐Pt(OHMal) and rac‐4F‐Pt(Thpdc), equal the parent compound rac‐4F‐Pt(CBDC) as well as cisplatin and surpass carboplatin in their effect on the MCF‐7 breast cancer cell line. Their water solubility, which is of importance for an application in the cancer chemotherapy, is higher than that of rac‐4F‐Pt(CBDC), especially in the case of rac‐4F‐Pt(OHMal) and rac‐4F‐Pt(Thpdc). In comparison to the dichloroplatinum(II) analogue (4F‐PtCl2) the stability of the three compounds in the presence of the strong nucleophile iodide is markedly enhanced, which means a reduction of the protein bound drug fraction in the blood and tissue compartments accompanied by an increase of the active, free drug level. The found physio‐chemical properties of these compounds meet the requirements for the transferability of their promising breast cancer inhibiting effects detected in cell culture experiments to in vitro conditions.

Section: Physiochemical and Biological Properties Water Solubilitymentioning

confidence: 99%

Section: Stability Studiesmentioning

confidence: 99%

Section: Stability Studiesmentioning

confidence: 99%

Section: Stability Studiesmentioning

confidence: 99%

See 2 more Smart Citations

Synthesis and Antitumor Activity of [1,2-Bis(4-fluorophenyl)ethylenediamine][dicarboxylato]platinum(II) Complexes

Gust

Krauser

Schmid

et al. 1998

Self Cite

“…The rate constants were computed according to the kinetic scheme described in ref. [30] by methods of the formal reaction kinetics.…”

Section: Hplc Analyses Of the Product Mixturesmentioning

confidence: 99%

Structure Activity Studies on Leaving Group Derivatives of [meso-1,2-Bis-(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]-platinum(II)

Gust¹,

Keilitz

Krauser

et al. 1999

Self Cite

The spatial structures of leaving group derivatives of [meso‐1,2‐bis(2,6‐dichloro‐4‐hydroxyphenyl)ethylenediamine]platinum(II) (meso‐1‐PtL2; L2 = SO4, Cl2, I2, CBDC (cyclobutane‐1,1‐dicarboxylate)) were investigated by NMR methods and correlated with their reactivity against nucleophiles, their estrogenic potency, and their activity on the hormone dependent MCF‐7 mammary carcinoma cell line. It was demonstrated that beside the non‐leaving group meso‐1 the PtL2 moiety of meso‐PtL2 complexes is important for the estrogen receptor binding. Among the tested complexes meso‐1‐PtI2 possesses the highest affinity for the estrogen receptor (RBA = 2.6) and represents a strong estrogen on the MCF‐7‐2a cell line. The use of CBDC as leaving group decreases the effects. Meso‐1‐PtCBDC shows an RBA of 0.06 and has only half of the estrogenic activity. Both complexes are sufficiently stable under physiological conditions, so a transformation into the dichloroplatinum( II) complex prior to the binding to the estrogen receptor can be excluded. Due to their high stability meso‐1‐PtI2 and meso‐1‐ PtCBDC were only marginally active on the human estrogen receptor positive MCF‐7 cell line, while meso‐1‐PtSO4 and meso‐1‐PtCl2 reduced the cell growth to T/Cmax = 45% and 25%, respectively.

[meso-1,2-Bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]sulfato-platinum(II) — Pharmacokinetic Studies

Bernhardt¹,

Koch²,

Spruß³

et al. 1999

Self Cite

The maximally attainable level of the non‐plasma protein bound fraction of a single 10.0 μmol/kg i.p. dose of [meso‐1,2‐bis(2,6‐di‐chloro‐4‐hydroxyphenyl)ethylenediamine]sulfatoplatinum(II), a drug active on the murine, hormone‐sensitive MXT‐M‐3.2 breast cancer, lies markedly below the concentration causing a significant cytotoxic effect on a cell line derived from this tumor. This result confirms our opinion that the strong in vivo activity of this drug on hormone‐sensitive breast cancers is mediated by its estrogenic potency by analogy with high dosed steroidal and non‐steroidal estrogens. A specific cytotoxic effect utilizing the estrogen receptor as carrier, as formerly postulated, is unlikely.