α-N-Heterocyclic thiosemicarbazones induce ER stress-mediated CHOP activation

Background Blocking of DNA synthesis through inhibition of ribonucleotide reductase has been proposed to be the main mechanism of anti-neoplastic action for a-N-heterocyclic thiosemicarbazones. Currently the best-studied agent of this class of compounds is triapine (3-amino-2-carboxaldehyde thiosemicarbazone), which has been tested in several phase I and II clinical trials. We synthesized triapine (HL) and the corresponding terminally Ndimethylated derivative, 3-aminopyridine-2-carbaldehyde N,N-dimethylthiosemicarbazone (HL). Previously, we have shown that dimethylation of the terminal amino group leads to significant amplification of the activity in cytotoxicity assays. Previously, we also discovered intrinsic fluorescence properties for both compounds. Here we present a study of intracellular distribution of the compounds and a possible new mechanism of action for a-N-heterocyclic thiosemicarbazones by induction of endoplasmic reticulum (ER) stress.