Platinum(IV) Complexes Featuring One or Two Axial Ferrocene Bearing Ligands – Synthesis, Characterization, and Cytotoxicity

Abstract

Ferrocenyl compounds show interesting antiproliferative properties. Consequently, ferrocene bearing moieties were prepared and coupled for the first time to anticancer platinum(IV) complexes. The compounds, featuring either one or two axially coordinated ferrocene-containing ligands, were fully characterized by ESI-MS and multinuclear ( 1 H, 13 C, 15 N, and 195 Pt) one-and two-dimensional NMR spectroscopy. 484Their cytotoxicity was investigated in three human cancer cell lines deriving from ovarian carcinoma (CH1), colon carcinoma (SW480), and non-small-cell lung carcinoma (A549) by means of the colorimetric MTT assay. Promising IC 50 values in the low micromolar range in CH1 and SW480 human cancer cells were found. www.eurjic.org FULL PAPER Scheme 1. Synthesis of ferrocene precursors L2-L6 and NMR numbering scheme. Scheme 2. Synthesis of complexes 3-5 and NMR numbering scheme. 486 www.eurjic.org FULL PAPER Scheme 3. Synthesis of platinum(IV) complexes 11-15 and NMR numbering scheme.As described in the literature, [16] novel Pt IV complexes with the Cl 2 N 2 O 2 coordination sphere show 195 Pt resonances in the region around 2656 ppm, whereas resonances for oxaliplatin-type platinum(IV) complexes appear in the region of 3230 ppm. As anticipated, the 195 Pt resonances are comparable for oxaliplatin-based Pt IV complexes 13, 14, and 15 with one acetato and one derivatized carboxylato ligand in the axial position to those for their biscarboxylated analogues. ESI-MS spectra were measured in the positive as well as in the negative mode. The highest peak observed in each spectrum in the positive mode is [M + Na] + , which is also in accordance with the calculated values.

Influence of the Number of Axial Bexarotene Ligands on the Cytotoxicity of Pt(IV) Analogs of Oxaliplatin

“…For complexes 3 and 4 , the resonance at 3228 ppm and 3233 ppm, respectively, indicates a Pt(IV)N 2 O 4 coordination sphere ( Figure 2 ). As reported earlier, the nature of carboxylates in the axial position has no dramatic influence on the resonance in 195 Pt spectra [ 25 , 36 , 37 ].…”

“…Complex 4 was notably more active than parent bexarotene and exhibited high sensitivity against breast cancer cells: the IC 50 value in the MCF7 cell line was in the submicromolar range, providing a promising basis for further investigation ( Table 1 ). Such a specificity (complex 4 is active, but 3 is not) is unexpected but rarely reported in the literature for Pt(IV) complexes with different ligands [ 37 , 38 ], although it is not a general rule. Recently we presented a similar design with lonidamine as biologically active component and no such specificity was observed [ 25 ].…”

“…195 Pt NMR spectroscopy is a known method for monitoring the coordination sphere of the Pt(IV) center [ 34 , 37 ]. For complexes 3 and 4 , the resonance at 3228 ppm and 3233 ppm, respectively, indicates a Pt(IV)N 2 O 4 coordination sphere ( Figure 2 ).…”

Synthesis, Characterization, Cytotoxicity, and Time‐Dependent NMR Spectroscopic Studies of (SP‐4‐3)‐Oxalato[(1R,2R,4R/1S,2S,4S)‐(4‐trifluoromethyl‐cyclohexane‐1,2‐diamine)]platinum(II)

“…As in the case of related compounds, CH1(PA-1) is the most sensitive, the P-glycoprotein-expressing SW480 cells intermediate and the highly multidrug-resistant A549 cells the least sensitive of these cell lines. [19] [20] 0.18 ± 0.01 0.29 ± 0.05 0.98 ± 0.21 1S,2S-enantiomer of oxaliplatin [9] 1.03 ± 0.04 1.3 ± 0.3 -KP1537 [9] 0.28 ± 0.09 0.67 ± 0.31 - Figure 9. In part, the higher IC 50 values are a consequence of testing an enantiomeric mixture (1R,2R,4R/1S,2S,4S) instead of the pure (1R,2R,4R)-enantiomer of 8a, which can be inferred from the comparison of cytotoxicity data of oxaliplatin and its (1S,2S)enantiomer (Table 1), with the differences being due to the chiral differentiation of DNA adducts and DNA binding proteins.…”

Bis‐ and Tris(carboxylato)platinum(IV) Complexes with Mixed Am(m)ine Ligands in the trans Position Exhibiting Exceptionally High Cytotoxicity

“…0.051 Ϯ 0.012 4.9 Ϯ 1.4 0.52 Ϯ 0.14 Cisplatin [43] 0.077 Ϯ 0.006 [44] Compounds 4e and 4h displayed an exceptionally high antiproliferative potential in CH1(PA-1) cells with an IC 50 value of 0.016 μm, being more active than clinically administered cisplatin (0.077 μm) or oxaliplatin (0.18 μm). Furthermore, both complexes, 4e and 4h, showed a cytotoxic potency comparable to oxaliplatin for the intrinsically cisplatin-resistant cell line SW480.…”