Structure‐activity relations of Pd(II) and Pt(II) thiosemicarbazone complexes on different human glioblastoma cell lines

Abstract

Ten thiosemicarbazone ligands obtained by condensation of pyridine-2-carbaldehyde, quinoline-2-carbaldehyde, 2-acetylpyridine, 2-acetylquinoline, or corresponding 2-pyridyl ketones with thiosemicarbazides RNHC(S)NHNH 2 and R=CH 3 , C 6 H 5 were prepared in good yield. The reaction of [PdCl 2 (cod)] with cod = 1,5-cyclooctadiene or K 2 [PtCl 4 ] resulted in a total of 17 Pd(II) and Pt(II) complexes isolated in excellent purity, as demonstrated by 1 H, 13 C, and, where applicable, 195 Pt NMR spectroscopy combined with CHNS analysis. The cytotoxicity of the title compounds was studied on four human glioblastoma cell lines (GaMG, U87, U138, and U343). The most active compound, with a Pd(II) metal centre, a 2-quinolinyl ring, and methyl groups on both the proximal C and distal N atoms exhibited an EC 50 value of 2.1 μM on the GaMG cell lines, thus being slightly more active than cisplatin (EC 50 3.4 μM) and significantly more potent than temozolomide (EC 50 67.1 μM). Surprisingly, the EC 50 values were inversely correlated with the lipophilicity, as determined with the "shake-flask method", and decreased with the length of the alkyl substituents (C 1 > C 8 > C 10 ). Correlation with the different structural motifs showed that for the most promising anticancer activity, a maximum of two aromatic rings (either quinolinyl or pyridyl plus phenyl) combined with one methyl group are favoured and the Pd(II) complexes are slightly more potent than their Pt(II) analogues.

Role of the auxiliary ligand in determining the genotoxicity and mode of cell death of thiosemicarbazone Pd(ii) complexes

“…A different procedure from what has been reported in the literature was used to synthesize the chloro complex. 27 A flat-bottomed flask charged with Na 2 [PdCl 4 ] (147 mg, 0.5 mmol) and thiosemicarbazone ligand 2 (137 mg, 0.5 mmol) in methanol (30 mL) was heated to reflux for 3 h. After filtering, hot methanol and diethyl ether were used to wash the precipitate, which was Scheme 1 Synthesis of the thiosemicarbazone ligand 2 and the Pd(II) complexes (3)(4)(5)(6)(7)(8).…”

“…26 When tested against the human glioblastoma cell line GaMG, the Pd (II) complex of 2 and its C-methyl analogue showed EC 50 values of 2.1 and 18.0 μM, while cisplatin and temozolomide showed EC 50 values of 3.4 and 57.01 μM. 27 Topoisomerase IIa was inhibited in vitro by 2 and its Cu(II) complex, whereas the Ni(II) complex was inert. 24 Herein, a series of Pd(II) complexes with N,N,S-tridentate thiosemicarbazone of the general formula [Pd(X)(N,N,S)] (X = Cl, Br, I, NCS and S-tetrazole) (Scheme 1) was tested against four malignant cell lines for their antiproliferative properties and the outcomes were compared to those seen in normal mouse splenocytes.…”

“…26 When tested against the human glioblastoma cell line GaMG, the Pd( ii ) complex of 2 and its C -methyl analogue showed EC 50 values of 2.1 and 18.0 μM, while cisplatin and temozolomide showed EC 50 values of 3.4 and 57.01 μM. 27 Topoisomerase IIa was inhibited in vitro by 2 and its Cu( ii ) complex, whereas the Ni( ii ) complex was inert. 24…”