1 research outputs found
Activity Enhancement of the Synthetic Syrbactin Proteasome Inhibitor Hybrid and Biological Evaluation in Tumor Cells
Syrbactins belong to a recently emergent class of bacterial
natural
product inhibitors that irreversibly inhibit the proteasome of eukaryotes
by a novel mechanism. The total syntheses of the syrbactin molecules
syringolin A, syringolin B, and glidobactin A have been achieved,
which allowed the preparation of syrbactin-inspired derivatives, such
as the syringolin A–glidobactin A hybrid molecule (SylA–GlbA).
To determine the potency of SylA–GlbA, we employed both in
vitro and cell culture-based proteasome assays that measure the subcatalytic
chymotrypsin-like (CT-L), trypsin-like (T-L), and caspase-like (C-L)
activities. We further studied the inhibitory effects of SylA–GlbA
on tumor cell growth using a panel of multiple myeloma, neuroblastoma,
and ovarian cancer cell lines and showed that SylA–GlbA strongly
blocks the activity of NF-κB. To gain more insights into the
structure–activity relationship, we cocrystallized SylA–GlbA
in complex with the proteasome and determined the X-ray structure.
The electron density map displays covalent binding of the Thr1O<sup>γ</sup> atoms of all active sites to the macrolactam ring of
the ligand via ether bond formation, thus providing insights into
the structure–activity relationship for the improved affinity
of SylA–GlbA for the CT-L activity compared to those of the
natural compounds SylA and GlbA. Our study revealed that the novel
synthetic syrbactin compound represents one of the most potent proteasome
inhibitors analyzed to date and therefore exhibits promising properties
for improved drug development as an anticancer therapeutic