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Direct and Topoisomerase II Mediated DNA Damage by Bis‐3‐chloropiperidines: The Importance of Being an Earnest G
Author(s) -
Sosic Alice,
Zuravka Ivonne,
Schmitt NinaKatharina,
Miola Angelica,
Göttlich Richard,
Fabris Dan,
Gatto Barbara
Publication year - 2017
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.201700368
Subject(s) - depurination , chemistry , topoisomerase , dna , guanine , ap site , nucleobase , electrospray ionization , gel electrophoresis , bifunctional , dna damage , stereochemistry , cleavage (geology) , helicase , covalent bond , adduct , biochemistry , combinatorial chemistry , mass spectrometry , nucleotide , biology , chromatography , organic chemistry , paleontology , rna , fracture (geology) , gene , catalysis
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.