TY - JOUR
T1 - Synthetic and structural studies on syringolin A and B reveal critical determinants of selectivity and potency of proteasome inhibition
AU - Clerc, Jérôme
AU - Groll, Michael
AU - Illich, Damir J.
AU - Bachmann, André S.
AU - Huber, Robert
AU - Schellenberg, Barbara
AU - Dudler, Robert
AU - Kaiser, Markus
PY - 2009/4/21
Y1 - 2009/4/21
N2 - Syrbactins, a family of natural products belonging either to the syringolin or glidobactin class, are highly potent proteasome inhibitors. Although sharing similar structural features, they differ in their macrocyclic lactam core structure and exocyclic side chain. These structural variations critically influence inhibitory potency and proteasome subsite selectivity. Here, we describe the total synthesis of syringolin A and B, which together with enzyme kinetic and structural studies, allowed us to elucidate the structural determinants underlying the proteasomal subsite selectivity and binding affinity of syrbactins. These findings were used successfully in the rational design and synthesis of a syringolin A-based lipophilic derivative, which proved to be the most potent syrbactin-based proteasome inhibitor described so far. With a K ! 1 of 8.65 ± 1.13 nM for the chymotryptic activity, this syringolin A derivative displays a 100-fold higher potency than the parent compound syringolin A. In light of the medicinal relevance of proteasome inhibitors as anticancer compounds, the present findings may assist in the rational design and development of syrbactin-based chemotherapeutics.
AB - Syrbactins, a family of natural products belonging either to the syringolin or glidobactin class, are highly potent proteasome inhibitors. Although sharing similar structural features, they differ in their macrocyclic lactam core structure and exocyclic side chain. These structural variations critically influence inhibitory potency and proteasome subsite selectivity. Here, we describe the total synthesis of syringolin A and B, which together with enzyme kinetic and structural studies, allowed us to elucidate the structural determinants underlying the proteasomal subsite selectivity and binding affinity of syrbactins. These findings were used successfully in the rational design and synthesis of a syringolin A-based lipophilic derivative, which proved to be the most potent syrbactin-based proteasome inhibitor described so far. With a K ! 1 of 8.65 ± 1.13 nM for the chymotryptic activity, this syringolin A derivative displays a 100-fold higher potency than the parent compound syringolin A. In light of the medicinal relevance of proteasome inhibitors as anticancer compounds, the present findings may assist in the rational design and development of syrbactin-based chemotherapeutics.
KW - Enzyme inhibitor
KW - Natural product
KW - Syrbactins
KW - X-ray analysis
UR - http://www.scopus.com/inward/record.url?scp=66149090781&partnerID=8YFLogxK
U2 - 10.1073/pnas.0901982106
DO - 10.1073/pnas.0901982106
M3 - Article
C2 - 19359491
AN - SCOPUS:66149090781
SN - 0027-8424
VL - 106
SP - 6507
EP - 6512
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 16
ER -