Oxa-aza crown ethers as ligands for mixed-ligand cisplatin derivatives and dinuclear platinum anticancer drugs

摘要

In the search for novel platinum anticancer drugs, cisplatin derivatives and dinuclear platinum complexes containing oxa-aza crown ether and oxa-diaza crown ether ligands have been prepared. The cisplatin derivatives cis-[PtCl_2(NH)_3(1,4,7,10,13-pentaoxa-16-azacyclooctadecane-N)] (AO18) and cis-[PtCl_2(NH_3)(1,4,7,10-tetraoxa-13-azacyclopentadecane-N)] (AO15), and the dinuclear cationic platinum complexes [{trans-PtCl(NH_3)_2}_2(mu-1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-N,N')](NO_3)_2 (DAO18) and [{trans-PtCl(NH_3)_2}_2(mu-1,4,10-trioxa-7,13-diazacyclopentadecane-N,N')](NO_3)_2 (DAO15) were investigated for their cytotoxic properties, cellular uptake and intracellular DNA binding in A2780 human ovarian cancer. The cisplatin derivative AO15 shows the highest cytotoxic activity, whereas the cationic dinuclear complexes DAO18 and DAO15 display a disappointing lack of biological activity at concentrations up to 100 muM. In the intracallular DNA platination experiments, the fifteen-membered rings were found to have a threefold higher intracellular DNA binding compared to their 1eight-emebered analogues for the neutral cisplatin derivatives as well as for the cationic dinuclear complexes. The crown ether complex with the most effective binding to DNA, AO15, also shows that highest cytotoxicity against A2780 cancer cells. It is remarkable that, although AO15 binds more effectively to DNA than cisplatin, its cytotoxic effect is much lower.