Appended aromatic moieties in flexible bis-3-chloropiperidines confer tropism against pancreatic cancer cells.

Nitrogen mustards (NMs) are an old but still largely diffused class of anticancer drugs. However, spreading mechanisms of resistance undermines their efficacy and therapeutic applicability. To expand their antitumor value, we engaged in the development of bis-3-chloropiperidines (B-CePs), a new class of mustard-based alkylating agents and we recently reported the striking selectivity for BxPC-3 pancreatic tumor cells by B-CePs bearing aromatic moieties embedded in the linker. In the present study, we demonstrate that such tropism is shared by bis-3-chloropiperidines bearing appended aromatic groups in flexible linkers, whereas esters substituted by aliphatic groups or by efficient DNA interacting groups are potent but non-selective cytotoxic agents. Besides, we describe how the critical balance between water stability and DNA reactivity can affect the properties of bis-3-chloropiperidines. Together, these findings support the exploitation of B-CePs as potential antitumor clinical candidates.