Synthesis of Arylamino-1,3,5-triazines Functionalized with Alkylatin 2-chloroethylamine Fragments and Studies of their Cytotoxicity on the Breast Cancer MCF-7 Cell Line.

Abstract

Dual action alkyl(aryl)amino-1,3,5-triazines functionalized with nitrogen mustards were obtained by treating 2-alkyl(aryl) amino-4-chloro-6-methoxy-1,3,5-triazines with amines or amino acid methyl esters, followed by reactions with 1,4-diazabicyclo[2.2.2]octane (DABCO) and rearrangement with an opening diazabicyclic fragment, leading to the formation of 2-chloroethylamino moiety. In vitro antitumor activity was tested in the standard human breast cancer MCF-7 and MDA-MB-231cell lines using flow cytometry, based on the detection of apoptosis through qualitative analysis of morphological changes, DNA fragmentation, DNA loss and membrane changes. For all the compounds studied, induced apoptosis was substantially stronger than necrosis at concentrations of both 5 μM and 50 μM, and in some cases there was no increase in necrotic cell death for the estrogen dependent MCF-7 cell line. The most active compounds were derivatives of triazine substituted with phenylamine (IC50 = 12.30 μM) and/or p-tolylamine fragments (IC50 = 7.40 μM).