Appended Aromatic Moieties in Flexible Bis‐3‐chloropiperidines Confer Tropism against Pancreatic Cancer Cells. (3rd December 2020)

• Record Type: Journal Article
• Authors: Carraro, Caterina; Helbing, Tim; Francke, Alexander; Zuravka, Ivonne; Sosic, Alice; De Franco, Michele; Gandin, Valentina; Gatto, Barbara; Göttlich, D. Richard
• Is Part Of: ChemMedChem. Volume 16:Number 5(2021)
• Page Start: 860
• Page End: 868
• Publication Date: 2020-12-03
• Subjects: anticancer agents -- DNA alkylation -- nitrogen mustards -- pancreatic cancer -- spheroids; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.202000814
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: 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. Abstract : Balancing act : Following our development of bis‐3‐chloropiperidines (B‐CePs), a new class of sustainable mustard‐based alkylating agents, we demonstrate that B‐CePs bearing appended aromatic groups in linkers show tropism toward pancreatic tumour models. In addition, we describe how the critical balance between DNA reactivity and water stability can affect the properties of this class of compounds.