4j70

Publication Abstract from PubMed

The natural product belactosin A (1) with a trans-cyclopropane structure is a useful prototype compound for developing potent proteasome (core particle, CP) inhibitors. To date, 1 and its analogs are the only CP ligands bind to both the non-primed S1 pocket as well as the primed substrate binding channel, however, these molecules harbor a high IC50 value of more than 1 microM. We have performed structure activity relationship studies, hereby elucidating unnatural cis-cyclopropane derivatives of 1 that exhibit high potency to primarily block the chymotrypsin-like active site of the human constitutive (cCP) and immunoproteasome (iCP). The most active compound 3e reversibly inhibits cCP and iCP similarly with an IC50 of 5.7 nM. X-ray crystallographic analysis of the yeast proteasome in complex with 3e revealed that the ligand accommodates predominantly to the primed substrate binding channel and covalently binds to the active site threonine residue via its beta-lactone ring-opening.

Potent Proteasome Inhibitors Derived from the Unnatural Cis-Cyclopropane Isomer of Belactosin A: Synthesis, Biological Activity, and Mode of Action.,Shuto S, Kawamura S, Unnno Y, List A, Sasaki T, Tanaka M, Arisawa M, Asai A, Groll M J Med Chem. 2013 Apr 2. PMID:23547757^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.