Synthesis and Structure-Activity Relationships of Bis-3-chloropiperidines as Bifunctional DNA Alkylating Agents

Bifunctional alkylating agents such as chlorambucil and melphalan represent an important class of clinical cancer chemotherapeutics. The antitumor antibiotics azinomycin A and B have the ability to alkylate and cross-link DNA. However, their poor chemical stability suggests that these natural products are unlikely to progress as therapeutic candidates. Yet they can act as lead structures from which to develop potentially useful new molecules.1 Due to our interest in developing more effective bifunctional alkylating agents, we designed novel bis-3-chloropiperidines based upon the azinomycins backbone (fig.1). The nitrogen mustard moiety is more stable and the alkylating functions generated via intermediate aziridinium ions are positioned in a similar distance as has been observed for the azinomycins.2,3 Accordingly, we synthesised a series of derivatives and evaluated the alkylating properties towards nucleic acids to assess their molecular mechanism of action and elaborate SAR useful to direct the synthesis of new molecules. The biochemical results as well as the synthetic approach to bis-3- chloropiperidines will be presented.