Journal of Medicinal Chemistry p. 7177 - 7187 (2016)
Update date:2022-07-29
Topics:
Xin, Bo-Tao
De Bruin, Gerjan
Huber, Eva M.
Besse, Andrej
Florea, Bogdan I.
Filippov, Dmitri V.
Van Der Marel, Gijsbert A.
Kisselev, Alexei F.
Van Der Stelt, Mario
Driessen, Christoph
Groll, Michael
Overkleeft, Herman S.
This work reports the development of highly potent and selective inhibitors of the β5c catalytic activity of human constitutive proteasomes. The work describes the design principles, large hydrophobic P3 residue and small hydrophobic P1 residue, that led to the synthesis of a panel of peptide epoxyketones; their evaluation and the selection of the most promising compounds for further analyses. Structure-activity relationships detail how in a logical order the β1c/i, β2c/i, and β5i activities became resistant to inhibition as compounds were diversified stepwise. The most effective compounds were obtained as a mixture of cis- and trans-biscyclohexyl isomers, and enantioselective synthesis resolved this issue. Studies on yeast proteasome structures complexed with some of the compounds provide a rationale for the potency and specificity. Substitution of the N-terminus in the most potent compound for a more soluble equivalent led to a cell-permeable molecule that selectively and efficiently blocks β5c in cells expressing both constitutive proteasomes and immunoproteasomes.
View MoreBeijing Wisdom Chemicals Co., Ltd.
Contact:+86-10-52350335
Address:F2, BLDG 19, Liando Valley U, Majuqiao, Tongzhou District, Beijing, China
Suzhou Lixin Pharmaceutical Co., Ltd.
Contact:86-512-88169812
Address:21 Tangxi Road, Suzhou New District, Suzhou 215151
Taizhou Crene Biotechnology co.ltd
Contact:86-576-88813233 88205808
Address:Economic Developed Zone of Taizhou Zhejiang China
Contact:021-36356756
Address:Room601,Building No.14,280 Yangcheng Road,Shanghai
KA-SHING Business Trade Macau Co., Ltd.
Contact:00853-28430045
Address:23rd Floor, Block 3 La Cite, Areia Preta, Macao
Doi:10.1016/j.ica.2019.119374
(2020)Doi:10.1021/jo8020049
(2008)Doi:10.1021/jo00389a062
(1987)Doi:10.1021/jo01044a067
(1963)Doi:10.1039/P29860001667
(1986)Doi:10.1016/S0040-4039(00)85021-2
(1986)