Biological evaluation of novel Pt(II) and Pd(II) complexes with pyrazole-containing ligands

The new platinum (II) and palladium (II) complexes (2-4) with ligands 5-(2-hydroxyphenyl)-1,3-dimethyl-4-(dimethoxy)phosphonyl-1H]-pyrazole (1a) and 5-(2-hydroxyphenyl)-1,3-dimethyl-4-methoxycarbonyl-1H]-2-pyrazole (1b) were screened in a search for novel anticancer agents. Thus, alkylating activity, cytotoxicity, ability for induction of apoptosis and binding to DNA were tested. The cis-[Pt(1b)(2)Cl-2] complex (3b) was the most potent alkylating agent in a Preussmann test, in comparison with the other test compounds and cisplatin. The highest cytotoxicity against the HL-60 and NALM-6 leukemia cell lines was observed for complexes 3b and 4b (trans-[Pd(1b)(2)Cl-2]), although the extent of the effect was lower relative to cis-platin. Moreover, both complexes were remarkably less toxic to human umbilical vein endothelial cells (HUVECs) with IC50 values of 3b 14 and 20 times higher than that ones for HL-60 and NALM-6 cells, respectively. Complexes 3b and 4b induced caspase-3 activity. Apoptosis occurred in a strictly dose-dependent manner and required only low concentrations of 4b. However, compounds 3b and 4b showed lower binding affinity to double-stranded DNA than cis-platin. (C) 2004 Elsevier B.V. All rights reserved.