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 undermine their efficacy and therapeutic applicability. To expand their antitumour value, we developed bis-3-chloropiperidines (B-CePs), a new class of mustard-based alkylating agent, and we recently reported the striking selectivity for BxPC-3 pancreatic tumour cells of B-CePs bearing aromatic moieties embedded in the linker. In this 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 nonselective 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 antitumour clinical candidates.

Automated summary

The study showed that the new class of nitrogen mustard-based alkylating agent, B-CePs, demonstrated a remarkable selectivity for BxPC-3 pancreatic tumor cells when bearing aromatic moieties embedded in the linker. However, bis-3-chloropiperidines with esters substituted by aliphatic groups or by efficient DNA-interacting groups were potent but nonselective cytotoxic agents. The critical balance between water stability and DNA reactivity was also found to affect the properties of bis-3-chloropiperidines.