Direct and Topoisomerase II Mediated DNA Damage by Bis-3-chloropiperidines: The Importance of Being an Earnest G

Overview

Journal ChemMedChem

Specialties Chemistry
Pharmacology

Date 2017 Jul 21

PMID 28724198

Citations 8

Authors

Alice Sosic

Ivonne Zuravka

Nina-Katharina Schmitt

Angelica Miola

Richard Gottlich

Dan Fabris

Barbara Gatto

Affiliations

Soon will be listed here.

Abstract

Bis-3-chloropiperidines are a new class of DNA-active compounds capable of alkylating nucleobases and inducing strand cleavage. In this study, we investigated the reactivity of these mustard-based agents with both single- and double-stranded DNA constructs. Polyacrylamide gel electrophoresis (PAGE) and electrospray ionization mass spectrometry (ESI-MS) were used to obtain valuable insight into their mechanism at the molecular level and to investigate their time- and concentration-dependent activity. The results revealed the preferential formation of mono- and bifunctional adducts at nucleophilic guanine sites. In a stepwise fashion, alkylation was followed by depurination and subsequent strand scission at the ensuing apurinic site. We demonstrated that the covalent modifications introduced by this new class of compounds can inhibit the activity of essential DNA-processing proteins, such as topoisomerase IIα, thereby suggesting that bis-3-chloropiperidines may have excellent anticancer potential.

Citing Articles

Secondary 3-Chloropiperidines: Powerful Alkylating Agents.

Georg M, Laping L, Billo V, Gatto B, Friedhoff P, Gottlich R ChemistryOpen. 2023; 13(6):e202300181.

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Decoding mechanism of action and sensitivity to drug candidates from integrated transcriptome and chromatin state.

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In Vitro Evaluation of Bis-3-Chloropiperidines as RNA Modulators Targeting TAR and TAR-Protein Interaction.

Sosic A, Olivato G, Carraro C, Gottlich R, Fabris D, Gatto B Int J Mol Sci. 2022; 23(2).

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B-CePs as cross-linking probes for the investigation of RNA higher-order structure.

Sosic A, Gottlich R, Fabris D, Gatto B Nucleic Acids Res. 2021; 49(12):6660-6672.

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