Antiproliferative activity of mixed-ligand Cu(II) complexes with pendant octaazamacrocycle in vitro

Abstract

Four cationic mixed-ligand complexes of Cu (II) with N, N', N'', N''' -tetrakis (2-pyridylmethyl) -1,4,8,11 -tetraazacyclotetradecane (tpmc) and aliphatic dicarboxylic acids: succinic, glutaric , adipic and sebacic were investigated in vitro on the human cervix adenocarcinoma (HeLa), human malignant melanoma (Fem-x), oestrogen-receptor-positive human breast cancer (MCF-7) cells and the human acute monocyte leukemia cell line (THP1), while free ligands, Cu(II) salt and solvent (used as a controls) were inactive on the same conditions. The metabolic activity of the cells was determined by tetrazolium MTS test. All complexes showed cytotoxicity toward the used cell lines, while free ligands, Cu(II) salt and solvent (used as a controls) were inactive on the same conditions. Increasing the number of - CH2- groups in homologous serie of aliphatic dicarboxylate ligands leads to the increasing cytotoxic activity of the complex. The highest cytotoxic effect of azamacrocycle Cu(II) complexes with glutarate, adipate, sebacinate ligand showed on the cell line MCF-7 and the worst on HeLa cells. A significant effect of sebacinate Cu(II)complex to all tested tumor cell lines applied in concentrations of 100 and 200 μM and up to HeLa cells.

Četiri katjonska mešovito-ligandna kompleksa Cu(II) sa N,N',N'N''-tetrakis(2- piridilmetil)-1,4,8,11-tetraaza-ciklotetradekanom i alifatičnim dikarboksilatima: ćilibarnom, glutarnom, adipinskom i sebacinskom kiselinom su ispitivani na humanim malignim ćelijskim linijama: cervikalnog adenokarcinoma (HeLa), melanoma (Fem-X), estrogen pozitivnog karcinoma dojke (MCF-7) i akutne monocitne leukemjie (THP1). Uporedo su testirani i sami ligandi, proste soli i rastvarači. Metabolička aktivnost ćelija je određena MTS testom. Svi ispitivani kompleksi su pokazali citotoksični efekat prema testiranim ćelijskim linijama, dok su slobodni ligandi, Cu(II) so i rastvarač (koji su korišćeni kao kontrolni) pod istim uslovima, bili neaktivni. Sa povećanjem broja -CH2- grupa homologog niza alifatičnih dikarboksilato liganada dolazi i do povećane citotoksičnosti kompleksa. Najveći citotoksični efekat su pokazali makrociklični Cu(II) kompleksi sa glutarato, adipato i sebacinato ligandima prema MCF-7, a najslabiji prema HeLa ćelijama. Najveći antiproliferativni efekat pokazuje kompleks sa sebacinato ligandom prema svim testiranim linijama tumorskih ćelija u primenjenim koncentracijama od 100 i 200 μM, a najviše prema HeLa ćelijama.