Aqua[1-(2,6-dichloro-4-hydroxyphenyl)-2-phenylethylenediamine](sulfato)platinum(II) complexes with variable substituents in the 2-phenyl ring. 1. Synthesis and antitumor and estrogenic properties

Abstract

Erythro- and threo-configurated aqua[1-(2,6-dichloro-4-hydroxyphenyl)-2- phenylethylenediamine](sulfato)platinum(II) complexes with variable substituents in the 2-phenyl ring (2-PtSO4 to 9-PtSO4: H, 4-F, 3-OH, 4-OH, 2,6-F2, 2,6-Cl2, 2-F/4-OH, 2-Cl/4-OH) were synthesized and tested for estrogenic and antitumor activities. The ligands were obtained by a three-step reaction. The stilbenes were reacted with a mixture of IN3 and NaN3 to yield the respective 1,2-diazido-1,2-diphenylethanes. The subsequent reduction with LiAlH4 led to the corresponding 1,2-diphenyl-ethylenediamines. The (sulfato)platinum(II) complexes were synthesized by reaction of Ag2SO4 with the diiodo complexes, which had been obtained by coordination of the diamines with K2PtI4. Two complexes, erythro-8-PtSO4 and erythro-9-PtSO4, possess antitumor and estrogenic effects and are therefore of interest for the therapy of breast cancer.

Synthesis and Cytotoxicity of Enantiomerically Pure [1,2‐Diamino‐1‐(4‐fluorophenyl)‐3‐methylbutane]platinum(II) Complexes

“…This indicated a preference for the conformer with an axially oriented aromatic ring. [15] Antitumor activity (Figure 1). LNCaP/FGC cells were somewhat more resistant against cisplatin (maximal T/C corr = 20 % at 5 mm; Figure 1).…”

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

“…In the 1 H-NMR-spectra, the benzylic protons appear as a singlet resonance broadened by the coupling to platinum ( 3 J H-Pt ≈ 55 Hz). The chemical shift of C-H benzylic (see C-H b in Table 1: δ = 5.21) as well as the H-195 Pt coupling remained unchanged at a temperature between 263 and 313 K and indicate an interconversion of the chelate ring [7] .…”

“…For the change of the ER conformation and the subsequent dimerization, an interaction with a second pharmacophoric anchor is essential. This should be accomplished by the aromatic ring at C-2, since its substituent pattern determines the hormonal activity [7] . It should be located in in the proximity of the E2-binding cavity near the C-11 position of E2.…”

“…Since high estrogenic potency requires a binding to the ER, the low RBA values of the complexes make an interaction analogous to E2 unlikely, we assume a binding mode different from E2 or hexestrol. In structure activity studies we investigated the essential pharmacophors for the hormonal activity [7,8] .…”

Relationship Between Anticancer Activity and Stereochemistry of Saldach Ligands and their Iron(III) Complexes

“…The flexibility of the build five-membered iron ethylenediamine chelate is marginal and allows only an interconversion between a d-and a kform as it is well known from platinum(II) complexes. [3,[13][14][15] A further dynamic process which is independent on the coordination to iron suffers from the cyclohexane ring: It changes between chair-chair or chair-boat conformations (see Fig. 4).…”