ABSTRACT
Development of selective or dual proteasome subunit inhibitors based on syringolin B as a scaffold is described. We focused our efforts on a structure-activity relationship study of inhibitors with various substituents at the 3-position of the macrolactam moiety of syringolin B analogue to evaluate whether this would be sufficient to confer subunit selectivity by using sets of analogues with hydrophobic, basic and acidic substituents, which were designed to target Met45, Glu53 and Arg45 embedded in the S1 subsite, respectively. The structure-activity relationship study using systematic analogues provided insight into the origin of the subunit-selective inhibitory activity. This strategy would be sufficient to confer subunit selectivity regarding ß5 and ß2 subunits.
Subject(s)
Proteasome Endopeptidase Complex , Proteasome Inhibitors , Structure-Activity Relationship , Proteasome Endopeptidase Complex/metabolism , Proteasome Endopeptidase Complex/chemistry , Proteasome Inhibitors/pharmacology , Proteasome Inhibitors/chemistry , Proteasome Inhibitors/chemical synthesis , Humans , Peptides, Cyclic/chemistry , Peptides, Cyclic/pharmacology , Protein Subunits/antagonists & inhibitors , Protein Subunits/metabolism , Protein Subunits/chemistry , Molecular StructureABSTRACT
A synthesis strategy for the production of a key synthetic intermediate of gulmirecin A was described. The key reaction in the preparation of the 12-membered macrolactone is the Ni(0)-mediated reductive cyclization reaction of ynal using an N-heterocyclic carbene ligand and silane reductant. In addition, the α-selective glycosylation reaction of the macrolactone was performed to demonstrate the synthesis of gulmirecin and disciformycin precursors.
ABSTRACT
Proteasome inhibitors (PI), mainly targeting the ß5 subunit of the 20S proteasome, are widely used in the treatment of multiple myeloma (MM). However, PI resistance remains an unresolved problem in the therapy of relapsed and refractory MM. To develop a new PI that targets other proteasome subunits, we examined the anti-MM activity of a novel syringolin analog, syringolog-1, which inhibits the activity of both the ß5 and ß2 subunits. Syringolog-1 exhibited marked cytotoxicity against various MM cell lines and anti-tumor activity towards bortezomib (Btz)-resistant MM cells through the dual inhibition of chymotrypsin-like (ß5 subunit) and trypsin-like (ß2 subunit) activities. MM cells, including Btz-resistant cells, showed elevated CHOP and NOXA expression after syringolog-1 treatment, indicating the induction of excessive endoplasmic reticulum stress during syringolog-1 treatment. Similar activities of syringolog-1 were also observed in freshly prepared MM cells derived from patients. To clarify the anti-tumor mechanism of dual inhibition of both the ß5 and ß2 subunits of the proteasome, PSMB5 and PSMB7 were co-inhibited in MM cells. This resulted in increased apoptosis of MM cells accompanied by accumulation of ubiquitinated proteins compared to inhibition of either PSMB7 or PSMB5 alone, indicating an enhanced effect by double inhibition of ß2 and ß5 activities. In conclusion, this syringolin analog, a dual inhibitor of proteasome ß2 and ß5 activities, exhibited potent anti-tumor effects on MM cells and may be useful for overcoming Btz-resistance in the treatment of MM.
ABSTRACT
In this study, we designed and synthesized a structurally simplified syringolin A analogue 4, which could have a switched hydrogen bonding interaction with the ß5 subunit of 20S proteasome. This analogue exhibits potent ß5 proteasome inhibitory activity with an IC50 value of 107 nM. It also shows cytotoxicity against a range of human cancer cells at submicromolar level (109-254 nM). This analogue is expected to be a lead compound as a next generation proteasome inhibitor because of its simple structure.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Drug Design , Peptides, Cyclic/chemistry , Peptides, Cyclic/pharmacology , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Conformation , Peptides, Cyclic/chemical synthesis , Structure-Activity RelationshipABSTRACT
Isosyringolin A, which is an isomer of the proteasome-inhibiting natural product syringolin A, was designed and synthesized to develop analogues that are step economical and synthetically accessible in a practical manner. It was revealed that isosyringolin A exhibited proteasome-inhibitory activity comparable to that of syringolin A and that its derivatization leads to great enhancement in its proteasome inhibitory activity as well as its cytotoxicity against human myeloma cells.
