Green asymmetric synthesis of epoxypeptidomimetics and evaluation as human cathepsin K inhibitors

被引：6

作者：

Silva, Taynara L. ^{[1
,2
,3
]}

dos Santos, Deborah A. ^{[4
]}

de Jesus, Hugo C. R. ^{[1
]}

Bromme, Dieter ^{[2
,3
]}

Fernandes, Joao B. ^{[1
]}

Paixao, Marcio W. ^{[4
]}

Correa, Arlene G. ^{[4
]}

Vieira, Paulo C. ^{[4
,5
]}

机构：

[1] Univ Fed Sao Carlos, Dept Chem, BR-13565905 Sao Carlos, SP, Brazil

[2] Fac Dent, 2350 Hlth Sci Mall, Vancouver, BC V6T 1Z3, Canada

[3] UBC Ctr Blood Res, 2350 Hlth Sci Mall, Vancouver, BC V6T 1Z3, Canada

[4] Univ Fed Sao Carlos, Ctr Excellence Res Sustainable Chem, Dept Chem, BR-13565905 Sao Carlos, SP, Brazil

[5] Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, BR-14040903 Ribeirao Preto, SP, Brazil

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2020年 / 28卷 / 15期

基金：

加拿大健康研究院; 巴西圣保罗研究基金会;

关键词：

Cathepsin K; Cysteine proteases; Inhibitors; Peptidomimetics; POTENT; DERIVATIVES; CHALCONES; E-64;

D O I：

10.1016/j.bmc.2020.115597

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Cathepsin K (CatK) is a cysteine protease known for its potent collagenolytic activity, being recognized as an important target to the development of therapies for the treatment of bone disorders. Epoxypeptidomimetics have been reported as potent inhibitors of cathepsins, thus in this work we present a green synthesis of new peptidomimetics by using a one-pot asymmetric epoxidation/Ugi multicomponent reaction. The compounds were evaluated against CatK showing selectivity when compared with cathepsin L, with an inhibition profile in the low micromolar IC50 range. Investigation of the mechanism of action carried out for compounds LSPN428 and LSPN694 suggested a mixed inhibition mode and docking studies allowed a better understanding about interactions of inhibitors with the enzyme.

引用

页数：8

共 33 条

[1]

Abdel-Magid Ahmed F, 2015, ACS Med Chem Lett, V6, P628, DOI 10.1021/acsmedchemlett.5b00189

[2] The Rosetta All-Atom Energy Function for Macromolecular Modeling and Design [J].

Alford, Rebecca F. ;

Leaver-Fay, Andrew ;

Jeliazkov, Jeliazko R. ;

O'Meara, Matthew J. ;

DiMaio, Frank P. ;

Park, Hahnbeom ;

Shapovalov, Maxim V. ;

Renfrew, P. Douglas ;

Mulligan, Vikram K. ;

Kappel, Kalli ;

Labonte, Jason W. ;

Pacella, Michael S. ;

Bonneau, Richard ;

Bradley, Philip ;

Dunbrack, Roland L., Jr. ;

Das, Rhiju ;

Baker, David ;

Kuhlman, Brian ;

Kortemme, Tanja ;

Gray, Jeffrey J. .

JOURNAL OF CHEMICAL THEORY AND COMPUTATION, 2017, 13 (06) :3031-3048

[3] Solution Phase Synthesis of a Combinatorial Library of Chalcones and Flavones as Potent Cathepsin V Inhibitors [J].

Alvim, Joel, Jr. ;

Severino, Richele P. ;

Marques, Emerson F. ;

Martinelli, Ariane M. ;

Vieira, Paulo C. ;

Fernandes, Joao B. ;

da Silva, M. Fatima das G. F. ;

Correa, Arlene G. .

JOURNAL OF COMBINATORIAL CHEMISTRY, 2010, 12 (05) :687-695

[4] Cathepsin K-dependent Toll-like receptor 9 signaling revealed in experimental arthritis [J].

Asagiri, Masataka ;

Hirai, Toshitake ;

Kunigami, Toshihiro ;

Kamano, Shunya ;

Gober, Hans-Juergen ;

Okamoto, Kazuo ;

Nishikawa, Keizo ;

Latz, Eicke ;

Golenbock, Douglas T. ;

Aoki, Kazuhiro ;

Ohya, Keiichi ;

Imai, Yuuki ;

Morishita, Yasuyuki ;

Miyazono, Kohei ;

Kato, Shigeaki ;

Saftig, Paul ;

Takayanagi, Hiroshi .

SCIENCE, 2008, 319 (5863) :624-627

[5] L-TRANS-EPOXYSUCCINYL-LEUCYLAMIDO(4-GUANIDINO)BUTANE (E-64) AND ITS ANALOGS AS INHIBITORS OF CYSTEINE PROTEINASES INCLUDING CATHEPSINS B, H AND L [J].

BARRETT, AJ ;

KEMBHAVI, AA ;

BROWN, MA ;

KIRSCHKE, H ;

KNIGHT, CG ;

TAMAI, M ;

HANADA, K .

BIOCHEMICAL JOURNAL, 1982, 201 (01) :189-198

[6] The societal burden of osteoporosis [J].

Becker D.J. ;

Kilgore M.L. ;

Morrisey M.A. .

Current Rheumatology Reports, 2010, 12 (3) :186-191

[7] Inhibition of Cathepsin K for Treatment of Osteoporosis [J].

Boonen, Steven ;

Rosenberg, Elizabeth ;

Claessens, Frank ;

Vanderschueren, Dirk ;

Papapoulos, Socrates .

CURRENT OSTEOPOROSIS REPORTS, 2012, 10 (01) :73-79

[8] HUMAN CATHEPSIN O2, A NOVEL CYSTEINE PROTEASE HIGHLY EXPRESSED IN OSTEOCLASTOMAS AND OVARY MOLECULAR-CLONING, SEQUENCING AND TISSUE DISTRIBUTION [J].

BROMME, D ;

OKAMOTO, K .

BIOLOGICAL CHEMISTRY HOPPE-SEYLER, 1995, 376 (06) :379-384

[9]

Bromme D., 2001, Curr Protoc Protein Sci

[10]

Brömme D, 2009, EXPERT OPIN INV DRUG, V18, P585, DOI [10.1517/13543780902832661 , 10.1517/13543780902832661]

← 1 2 3 4 →