Direct and Topoisomerase II Mediated DNA Damage by Bis‐3‐chloropiperidines: The Importance of Being an Earnest G. (10th August 2017)

• Record Type: Journal Article
• Authors: Sosic, Alice; Zuravka, Ivonne; Schmitt, Nina‐Katharina; Miola, Angelica; Göttlich, Richard; Fabris, Dan; Gatto, Barbara
• Is Part Of: ChemMedChem. Volume 12:Number 17(2017)
• Page Start: 1471
• Page End: 1479
• Publication Date: 2017-08-10
• Subjects: anticancer agents -- bis-3-chloropiperidines -- DNA alkylation -- DNA depurination -- topoisomerase IIα inhibition; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201700368
• Languages: English
• ISSNs: 1860-7179

Abstract

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. Abstract : The assault on guanines ! In exploring the molecular details of the reactivity of bis‐3‐chloropiperidines with DNA, our results demonstrate that the initial attack is directed toward the N7 position of guanine, generating both mono‐ and bi‐functional adducts. The DNA damage inflicted by bis‐3‐chloropiperidines has meaningful properties on the activity of human topoisomerases IIα to develop this class of DNA‐active compounds as anticancer agents.