From the Modelization of DNA Platination to the Conception of New Drugs
Much effort is devoted to the search for analogues of the anticancer drug cis-diamminedichloroplatinum (II) (cisplatin or cis-DDP) which would be less toxic, would affect a larger range of tumors and would not elicit cross-resistance with cisplatin1,2. DNA is considered as one of the main cellular targets of platinum drugs, at the origin of their antitumor activity3. DNA platination by cis-DDP is under kinetic control4,5. It is therefore of interest to try to alter the various kinetic parameters of DNA platination by chemical modification of cisplatin. If DNA is the actual cellular target of cisplatin, increasing the ratio of the rate of DNA platination vs. that of protein platination could lead to more selective drugs. To do so, we studied ethylenediamine (en) dichloro complexes with various substituents on the en ligand. We first investigated cationic ammonium substituents, then neutral hydrogen bond-donor carbamates and finally bulky hydrophobic bi- and tricycloalkyl substituents. For typical examples of these complexes, compared to cis-DDP, we discuss their kinetics of reaction with DNA, assessed by fluorescence, their cytotoxicity in vitro and antitumor activity in vivo, and for the last group, the interaction of the platinated DNA with the UvrAB proteins.
KeywordsPlatinum Complex Filter Binding Assay Metal Coordination Compound Platinum Coordination pSP65 Plasmid
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