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Aromatic Linkers Unleash the Antiproliferative Potential of 3‐Chloropiperidines Against Pancreatic Cancer Cells
Author(s) -
Helbing Tim,
Carraro Caterina,
Francke Alexander,
Sosic Alice,
De Franco Michele,
Gandin Valentina,
Göttlich Richard,
Gatto Barbara
Publication year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000457
Subject(s) - pancreatic cancer , reactivity (psychology) , cytotoxicity , chemistry , linker , combinatorial chemistry , cancer cell , dna , nucleophile , aromaticity , biochemistry , cancer , stereochemistry , cancer research , in vitro , biology , organic chemistry , molecule , medicine , genetics , alternative medicine , pathology , computer science , catalysis , operating system
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.