title: Synthesis and DNA cleavage activity of Bis-3-chloropiperidines as alkylating agents.
abstract: Nitrogen mustards are an important class of bifunctional alkylating agents routinely used in chemotherapy. They react with DNA as electrophiles through the formation of highly reactive aziridinium ion intermediates. The antibiotic 593A, with potential antitumor activity, can be considered a naturally occurring piperidine mustard containing a unique 3-chloropiperidine ring. However, the total synthesis of this antibiotic proved to be rather challenging. With the aim of designing simplified analogues of this natural product, we developed an efficient bidirectional synthetic route to bis-3-chloropiperidines joined by flexible, conformationally restricted, or rigid diamine linkers. The key step involves an iodide-catalyzed double cyclization of unsaturated bis-N-chloroamines to simultaneously generate both piperidine rings. Herein we describe the synthesis and subsequent evaluation of a series of novel nitrogen-bridged bis-3-chloropiperidines, enabling the study of the impact of the linker structure on DNA alkylation properties. Our studies reveal that the synthesized compounds possess DNA alkylating abilities and induce strand cleavage, with a strong preference for guanine residues.
authors.affiliation: Institute of Organic Chemistry, Justus Liebig University Giessen, Heinrich-Buff-Ring 58, 35392 Giessen (Germany); Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Francesco Marzolo 5, 35131 Padova (Italy).
authors.forename: Ivonne
authors.initials: I
authors.lastname: Zuravka
authors.forename: Rolf
authors.initials: R
authors.lastname: Roesmann
authors.forename: Alice
authors.initials: A
authors.lastname: Sosic
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wende
authors.forename: Alfred
authors.initials: A
authors.lastname: Pingoud
authors.forename: Barbara
authors.initials: B
authors.lastname: Gatto
authors.forename: Richard
authors.initials: R
authors.lastname: Göttlich
mesh_terms: D000477:Alkylating Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D000478:Alkylation; D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis* / Q000494:pharmacology*; D003500:Cyclization; D053837:DNA Cleavage / Q000187:drug effects*; D008968:Molecular Conformation; D009588:Nitrogen Mustard Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D010879:Piperazines / Q000138:chemical synthesis / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D010957:Plasmids / Q000187:drug effects
chemical_list: D000477:Alkylating Agents; D018906:Antineoplastic Agents, Alkylating; D009588:Nitrogen Mustard Compounds; D010879:Piperazines; D010880:Piperidines; C003905:3,6-bis(5-chloro-2-piperidyl)-2,5-piperazinedione
keywords: DNA cleavage; antitumor agents; cyclization; nitrogen heterocycles; structure-activity relationships