In continuation of our search for higher generation platinum drugs, we examined a series of complexes, well soluble in water, weakly reactive with glutathione and resistant against hydrolysis. Such properties are expecteded to result in lower toxicity of these compounds.

There was obtained a group of dicarboxylatoplatinum(II) complexes of general formulae:[Pt(A)2(X2)] or [Pt(A2)(X2)], where A = monodentate (or A2 - bidentate) amine and X2= dicarboxylate dianion.

As amine neutral ligands there were used: ethylenediamine, 1-ethylimidazole, 1-propylimidazole. In this way we synthesized two kinds of complexes, "classical" having NH2 donor group, and "non-classical" having tertiary donor nitrogen atom. Considering our earlier studies [1], we expected that new "non-classical" cisplatin analogs may be the source of drugs overcoming the resistance of cancer cells.

As anionic ligands there were introduced dianions originating from acids which differ significantly in their hydrophobic properties: (L-,D-, or DL-) malato-, 2-oxo-glutarato- and 2-etoxyglutarato- ligands should cause the modification of pharmacokinetic properties of complexes and thus deliver the broader and more varied samples for testing.

The antiproliferative effects were determined by SRB and MTT assays [2] against human neoplastic cell lines such as: A549 (nono-small cell lung carcinoma), SW707 (rectal adenocarcinoma), HCV29T (uroepithelial cancer), T47D (breast cancer). On the base of results obtained from in vitro studies there were pre-selected five malatoplatinum complexes for in vivo toxicity evaluation. Toxicity (subacute toxicity, three-week observation) was measured as lethal dose [LD50] and as mouse mortality [%] in dependence on dose of platinum compound. It was shown that four compounds revealed lethal toxicity similar to carboplatin (referential drug), whereas the one, bis(1-ethylimidazole)L-malatoplatinum(II), was six times less toxic than carboplatin.

Concluding, the new synthesized dicarboxylatoplatinum(II) complexes seem to be very promising group of potentially antitumor active carboplatin analogs, in particular with regard on its unusually low toxicity and "non-classical" chemical character among platinum drugs.

References: [1] . I. Grądzka, I. Buraczewska, J. Kuduk-Jaworska, A. Romaniewska, I. Szumiel. Chem.-Biol. Interact. 146, 165-177 (2003).[2] Skehan P, Storeng R, Scudiero D, Monks A, McMahon J, Vistica D, Warren JT, Bokesch H, Kenney S, Boyol MR: J Natl Cancer Inst 82: 1107-1112, 1990.

Acknowledgement: Authors thank for financial support by KBN-Pr UE/DIE 621/2004

^1* correspondence author (JKJ) e-mail: wchuwr.chem.uni.wroc.pl

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