Aromatic Linkers Unleash the Antiproliferative Potential of 3‐Chloropiperidines Against Pancreatic Cancer Cells. (15th September 2020)

• Record Type: Journal Article
• Authors: Helbing, Tim; Carraro, Caterina; Francke, Alexander; Sosic, Alice; De Franco, Michele; Gandin, Valentina; Göttlich, Richard; Gatto, Barbara
• Is Part Of: ChemMedChem. Volume 15:Number 21(2020)
• Page Start: 2040
• Page End: 2051
• Publication Date: 2020-09-15
• Subjects: alkylating agents -- aromatic chloropiperidines -- DNA damage -- pancreatic cancer spheroids -- structure-activity relationships; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.202000457
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: In this study, we describe the synthesis and biological evaluation of a set of bis ‐3‐chloropiperidines (B−CePs) containing rigid aromatic linker structures. A modification of the synthetic strategy also enabled the synthesis of a pilot tris ‐3‐chloropiperidine (Tri‐CeP) bearing three reactive meta ‐chloropiperidine moieties on the aromatic scaffold. A structure–reactivity relationship analysis of B−CePs suggests that the arrangement of the reactive units affects the DNA alkylating activity, while also revealing correlations between the electron density of the aromatic system and the reactivity with biologically relevant nucleophiles, both on isolated DNA and in cancer cells. Interestingly, all aromatic 3‐chloropiperidines exhibited a marked cytotoxicity and tropism for 2D and 3D cultures of pancreatic cancer cells. Therefore, the new aromatic 3‐chloropiperidines appear to be promising contenders for further development of mustard‐based anticancer agents aimed at pancreatic cancers. Abstract : As keen as mustard : Aromatic 3‐chloropiperidines designed to improve the therapeutic potential of mustard‐based DNA alkylating agents have been synthesized and evaluated. These small molecules exhibited a marked anti‐proliferative effect preferentially against BxPC‐3 pancreatic adenocarcinoma cells in 2D and 3D cultures, thus demonstrating themselves to be promising candidates for the further development of sustainable chemotherapeutics active against pancreatic tumors.