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.
The
pressing demand for sustainable antitumor drugs prompted us
to investigate 3-chloropiperidines as potential mustard-based anticancer
agents. In this study, an explorative set of variously decorated monofunctional
3-chloropiperidines (M-CePs) was efficiently synthesized through a
fast and affordable route providing high yields of pure racemates
and enantiomers. Consistently with their reactivity, M-CePs were demonstrated
to alkylate DNA
in vitro
. On a panel of carcinoma
cell lines, M-CePs exhibited low nanomolar cytotoxicity indexes, which
showed their remarkable activity against pancreatic cancer cells and
in all cases performed strikingly better than the chlorambucil control.
Very interestingly, stereochemistry modulated the activity of M-CePs
in unexpected ways, pointing to additional molecular mechanisms of
action beyond the direct damage of genomic DNA. This encouraging combination
of efficacy and sustainability suggests they are valid candidates
for anticancer agent development.
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