Many biologically active natural products contain electrophilic Michael acceptor fragments.
For example, curcumin and 4-hydroxyderricin contain an acyclic α,β-unsaturated ketone
that alkylates cysteines. Other antitumor or anti-inflammatory herbal compounds such
as Withaferin A or zerumbone contain cyclic α,β-unsaturated ketones and react with
nucleophilic residues of proteins. These observations contributed to a paradigm shift
in drug design and development in the last two decades: various drugs with covalent
warhead have been developed and approved. Despite the apparent importance and success
of covalent warheads in current drug design and developments, the applied warheads
display a rather limited structural variance and complexity which automatically limits
the attainable chemical space. Furthermore, to minimize possible side-reactions during
the synthesis of drugs, the applied warheads are added appendages in the late-stage
of the synthetic route, thus a warhead scaffold that can be synthetically easily varied
using orthogonal chemistry and used as a tunable covalent warhead is still missing.
Such a structurally more complex scaffold would be much more like the warheads of
the natural products and is expected to be more selective in targeting nucleophiles
found on the proteins. Moreover, owing to a larger contact surface, it might be more
suitable for targeting shallow protein surfaces involved in protein-protein interactions.
