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Aromatic Linkers Unleash the Antiproliferative Potential of 3-Chloropiperidines Against Pancreatic Cancer Cells |
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| Authors: | Tim Helbing Caterina Carraro Alexander Francke Dr Alice Sosic Michele De Franco Prof?Dr Valentina Gandin Prof?Dr Richard Göttlich Prof?Dr Barbara Gatto |
| Affiliation: | 1. Institute of Organic Chemistry, Justus Liebig University Giessen, Heinrich-Buff-Ring 17, 35392 Giessen, Germany
These authors contributed equally.;2. Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Francesco Marzolo 5, 35131 Padova, Italy These authors contributed equally.;3. Institute of Organic Chemistry, Justus Liebig University Giessen, Heinrich-Buff-Ring 17, 35392 Giessen, Germany;4. Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Francesco Marzolo 5, 35131 Padova, Italy |
| 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. |
| Keywords: | alkylating agents aromatic chloropiperidines DNA damage pancreatic cancer spheroids structure-activity relationships |
