Ditercallnium : 2 , 2 ' -[ 4 , 4 ' -b i p i p e ~~e -l . l ' -b ~ (ethane-l.2-dfyl)l bis (10-methoq-7Hpyrido[4.3-c] carbazolium) tetramethanesulfonate (NSC 366241 1 is a potent
antitumor DNA bis-intercalator characterized by a new mechanism of action. In order to elucidate its biological action at the cellular level and its phannacoldnetic and metabolic properties, radiolabelled ditercalhium was prepared. In the present paper, we report the synthesis of the 1 l-bromo-10-methoxy-irH-pyrIdo I4.3-cl carbazole presursor and its reductive trltiation by exchange with 13H]2. The pyrido[4.3-c]carbazole ring labelled in position 11 is then condensed either with the 1,l' bis (2-chlorcethy1)-4.4'-bipiperldine chain to provide tritiated ditercalMum or with the 1-(2-chloroethylJ piperldine chain to yield its monomeric analog.
&?v wordg : tritiated ditercallnium. DNA bis-intercalator, antitumor drug.
INTRODUcTIolv
Ditercallnium (NSC 366241) is a highly potent antitumor DNA bls-intercalator developped in our laboratory (1-2). Several biochemical studies have evidenced that ditercalinium elicits its cytotoxicity through a new mechanism of action largely dlfferent from that of other DNA intercalating antitumor agents (3-6). Ditercallnium induces a delayed cytotoxkity in sensitive L 1210 cells and arrests the cell growth almost randomly at any phase of the cell cycle (3). On the other hand, this bifunctional intercalator does not produce any protein-associated DNA breaks such as those obtained with most of the other antitumor intercalating agents such as mAMSA (7).
However ditercalinium inhibits the formation of linear DNA's in presence of mAMSA (4).
Moreover ditercallnium provokes the formation of high molecular weight DNA constituted by catenanes or aggregates (4). Electronic microscopy studies of L1210 cells treated with 0362 -4803/88/101143 -055O5.oO 0 1988 by John Wiley & Sons, Ltd.