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Oxa‐aza Crown Ethers as Ligands for Mixed‐Ligand Cisplatin Derivatives and Dinuclear Platinum Anticancer Drugs
Author(s) -
Jansen Bart A. J.,
Wielaard Peter,
den Dulk Hans,
Brouwer Jaap,
Reedijk Jan
Publication year - 2002
Publication title -
european journal of inorganic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.667
H-Index - 136
eISSN - 1099-0682
pISSN - 1434-1948
DOI - 10.1002/1099-0682(200209)2002:9<2375::aid-ejic2375>3.0.co;2-b
Subject(s) - chemistry , cisplatin , platinum , cytotoxicity , cationic polymerization , stereochemistry , ligand (biochemistry) , ether , dna , medicinal chemistry , in vitro , biochemistry , organic chemistry , chemotherapy , receptor , medicine , surgery , catalysis
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 (μ‐1,4,10,13‐tetraoxa‐7,16‐diazacyclooctadecane‐ N , N′ )](NO 3 ) 2 ( DAO18 ) and [{ trans ‐PtCl(NH 3 ) 2 } 2 (μ‐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 μ M . In the intracallular DNA platination experiments, the fifteen‐membered rings were found to have a threefold higher intracellular DNA binding compared to their 1eight‐membered 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 the 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. (© Wiley‐VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)