Synthesis of novel DNA cross-linking antitumour agents based on polyazamacrocycles Original Research Article

We are seeking to develop more effective alkylating agents as antitumour agents. In previous work conformationally restricted nitrogen mustards were synthesised containing piperidine or pyrrolidine rings. The free bases were designed to be bifunctional alkylating agents via aziridinium ion formation and the effects of varying the distances between the two alkylating sites were studied. Some efficient cross-linkers of naked DNA were prepared but few of these compounds exhibited significant cytotoxicity in human tumour cells in vitro. We have extended this work by making tri- and tetra-azamacrocyclic compounds containing two to four potential alkylating sites. Most of these compounds were powerful DNA alkylating agents and showed cytotoxicity (IC50 values 6–100 μM) comparable with chlorambucil (45 μM) and melphalan (8.5 μM). In particular the cyclen derivative 2a was more than 104 times more effective at cross-linking DNA (2a XL50 ≪ 10 nM) than chlorambucil (XL50 100 μM), and showed significant cytotoxicity in human tumour cells in vitro.