SYNTHESIS AND CYTOTOXICITY STUDIES OF NEW ANALOGS OF POLYAMINES

In order to regulate simultaneously the biosynthesis and the transport of natural polyamines, the synthesis of a series of N-methylated anal ogues of N,N'-Bis(benzyl)-alkanediamines (propanediamine and butanedia mine) was achieved and the cytotoxicity of these compounds on the P388 D1 cell line was determined. Experiments were conducted in a growth cu lture medium 20 mu M of 2-mercaptoethanol or 0.1 mM of aminoguanidine. Their cytotoxic effects were compared to those obtained under the sam e conditions with natural polyamines known as toxic compounds at high concentrations. The IC50 of each compound was found very similar for a ll experimental conditions (IC50 similar to 150 mu M) at the opposite of spermidine and spermine which were less toxic (IC50 > 500 mu M) whe n cells were grown in the presence of aminoguanidine (a specific inhib itor of fetal calf serum's PAO). THe DL-difluoromethylomithine (DEMO) and MDL 72527DA, two well known inhibitors of ornithine decarboxylase (ODC) and Polyamine Oxidase (PAO) respectively, had no toxicity on the P388D1 cells compared to our compounds. Our most toxic compound was - Bis(benzyl)-N-1,N-4-bis(methyl)-1,4-butanediamine (6) with an IC50 of 127 +/- 3 mu M (in culture medium alone). The synthesis of the beta-am inothioether derivative of N-benzylputrescine (11) and the beta-aminot hiol derivative of N-benzylspermidine (13) were also related. The Comp ound 11 was tested against the P388D1 cells, and did not show any cyto toxic effect. The N-methyl derivatives should give the advantage to be used at low concentrations than those used to test the DFMO.