Behind the Mirror: Chirality Tunes the Reactivity and Cytotoxicity of Chloropiperidines as Potential Anticancer Agents

ACS Med Chem Lett. 2019 Feb 13;10(4):552-557. doi: 10.1021/acsmedchemlett.8b00580.

Caterina Carraro ¹, Alexander Francke ², Alice Sosic ¹, Franziska Kohl ¹, Tim Helbing ², Michele De Franco ¹, Daniele Fabris ³, Richard Göttlich ², Barbara Gatto ¹

Affiliations

1 Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Francesco Marzolo 5, 35131 Padova, Italy.
2 Institute of Organic Chemistry, Justus Liebig University Giessen, Heinrich-Buff-Ring 17, 35392 Giessen, Germany.
3 Departments of Chemistry and Biological Sciences, University at Albany, State University of New York, 1400 Washington Avenue, Albany, New York 12222, United States.

PMID: 30996795 DOI: 10.1021/acsmedchemlett.8b00580

Abstract

The pressing demand for sustainable antitumor drugs prompted us to investigate 3-chloropiperidines as potential mustard-based Anticancer agents. In this study, an explorative set of variously decorated monofunctional 3-chloropiperidines (M-CePs) was efficiently synthesized through a fast and affordable route providing high yields of pure racemates and enantiomers. Consistently with their reactivity, M-CePs were demonstrated to alkylate DNA in vitro. On a panel of carcinoma cell lines, M-CePs exhibited low nanomolar cytotoxicity indexes, which showed their remarkable activity against pancreatic Cancer cells and in all cases performed strikingly better than the chlorambucil control. Very interestingly, stereochemistry modulated the activity of M-CePs in unexpected ways, pointing to additional molecular mechanisms of action beyond the direct damage of genomic DNA. This encouraging combination of efficacy and sustainability suggests they are valid candidates for Anticancer agent development.

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