Synthesis and evaluation of a bis-3-chloropiperidine derivative incorporating an anthraquinone pharmacophore.
With the aim to attain an alkylating agent with enhanced DNA-affinity, we have successfully synthesised lysine-linked bis-3-chloropiperidine 1 bearing an anthraquinone moiety known to bind double-stranded DNA. Consistent with our expectations, compound 1 appears to intercalate into the DNA double helix, which can be observed by conformational changes of plasmid DNA suggesting alkylation and intercalation-induced DNA unwinding. The results of this work can provide a meaningful starting point for investigating the molecular mechanism of action of this novel DNA alkylating conjugate 1 with improved affinity for DNA.
Institute of Organic Chemistry, Justus Liebig University Giessen, Heinrich-Buff-Ring 58, 35392 Giessen, Germany; Dipartimento di Scienze del Farmaco, Università di Padova, via Marzolo 5, 35131 Padova, Italy.
Ivonne
I
Zuravka
Dipartimento di Scienze del Farmaco, Università di Padova, via Marzolo 5, 35131 Padova, Italy.
Alice
A
Sosic
Dipartimento di Scienze del Farmaco, Università di Padova, via Marzolo 5, 35131 Padova, Italy. Electronic address: barbara.gatto@unipd.it.
Barbara
B
Gatto
Institute of Organic Chemistry, Justus Liebig University Giessen, Heinrich-Buff-Ring 58, 35392 Giessen, Germany. Electronic address: richard.goettlich@uni-giessen.de.
Richard
R
Göttlich
D000880:Anthraquinones / Q000737:chemistry / Q000494:pharmacology*; D004247:DNA / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D015394:Molecular Structure; D009690:Nucleic Acid Conformation / Q000187:drug effects*; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010957:Plasmids; D013329:Structure-Activity Relationship
D000880:Anthraquinones; D010880:Piperidines; C000608299:bis-3-chloropiperidine; D004247:DNA
Alkylating agents; Anthraquinone; DNA cleavage; Intercalation; Nitrogen mustard