3-氰基-3-氮杂-β-氨基酸衍生物作为人半胱氨酸组织蛋白酶抑制剂
3-Cyano-3-aza-β-amino Acid Derivatives as Inhibitors of Human Cysteine Cathepsins.
作者信息
Schmitz Janina, Beckmann Anna-Madeleine, Dudic Adela, Li Tianwei, Sellier Robert, Bartz Ulrike, Gütschow Michael
机构信息
Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn , An der Immenburg 4, D-53121 Bonn, Germany ; Department of Natural Sciences, University of Applied Sciences Bonn-Rhein-Sieg , von-Liebig-Strasse 20, D-53359 Rheinbach, Germany.
Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn , An der Immenburg 4, D-53121 Bonn, Germany.
出版信息
ACS Med Chem Lett. 2014 Aug 11;5(10):1076-81. doi: 10.1021/ml500238q. eCollection 2014 Oct 9.
Abstract
Nitrile-type inhibitors are known to interact with cysteine proteases in a covalent-reversible manner. The chemotype of 3-cyano-3-aza-β-amino acid derivatives was designed in which the N-cyano group is centrally arranged in the molecule to allow for interactions with the nonprimed and primed binding regions of the target enzymes. These compounds were evaluated as inhibitors of the human cysteine cathepsins K, S, B, and L. They exhibited slow-binding behavior and were found to be exceptionally potent, in particular toward cathepsin K, with second-order rate constants up to 52 900 × 10(3) M(-1) s(-1).
摘要
已知腈类抑制剂以共价可逆的方式与半胱氨酸蛋白酶相互作用。设计了3-氰基-3-氮杂-β-氨基酸衍生物的化学类型，其中N-氰基位于分子中心，以便与靶酶的非引发和引发结合区域相互作用。评估了这些化合物作为人半胱氨酸组织蛋白酶K、S、B和L的抑制剂。它们表现出慢结合行为，并且发现具有异常高的活性，特别是对组织蛋白酶K，二级速率常数高达52 900 × 10(3) M(-1) s(-1)。
相似文献
1
3-Cyano-3-aza-β-amino Acid Derivatives as Inhibitors of Human Cysteine Cathepsins.3-氰基-3-氮杂-β-氨基酸衍生物作为人半胱氨酸组织蛋白酶抑制剂
ACS Med Chem Lett. 2014 Aug 11;5(10):1076-81. doi: 10.1021/ml500238q. eCollection 2014 Oct 9.
2
Novel, nonpeptidic cyanamides as potent and reversible inhibitors of human cathepsins K and L.新型非肽类氰胺作为人组织蛋白酶K和L的强效可逆抑制剂
J Med Chem. 2001 Jan 4;44(1):94-104. doi: 10.1021/jm0003440.
3
New peptidic cysteine protease inhibitors derived from the electrophilic alpha-amino acid aziridine-2,3-dicarboxylic acid.源自亲电α-氨基酸氮丙啶-2,3-二羧酸的新型肽类半胱氨酸蛋白酶抑制剂。
J Med Chem. 1999 Feb 25;42(4):560-72. doi: 10.1021/jm981061z.
4
N-Sulfonyl dipeptide nitriles as inhibitors of human cathepsin S: In silico design, synthesis and biochemical characterization.N-磺酰基二肽腈作为人组织蛋白酶 S 的抑制剂：基于计算机的设计、合成和生化特性分析。
Bioorg Med Chem Lett. 2020 Sep 15;30(18):127420. doi: 10.1016/j.bmcl.2020.127420. Epub 2020 Jul 17.
5
Active Site Mapping of Human Cathepsin F with Dipeptide Nitrile Inhibitors.人组织蛋白酶F与二肽腈抑制剂的活性位点图谱
ChemMedChem. 2015 Aug;10(8):1365-77. doi: 10.1002/cmdc.201500151. Epub 2015 Jun 26.
6
A novel class of nonpeptidic biaryl inhibitors of human cathepsin K.一类新型的人组织蛋白酶K非肽类联芳基抑制剂。
J Med Chem. 2003 Aug 14;46(17):3709-27. doi: 10.1021/jm0301078.
7
Irreversible inhibition of human cathepsins B, L, S and K by hypervalent tellurium compounds.高价碲化合物对人组织蛋白酶B、L、S和K的不可逆抑制作用。
Biol Chem. 2009 Nov;390(11):1205-12. doi: 10.1515/BC.2009.125.
8
Cross-class inhibition of the cysteine proteinases cathepsins K, L, and S by the serpin squamous cell carcinoma antigen 1: a kinetic analysis.丝氨酸蛋白酶抑制剂鳞状细胞癌抗原1对半胱氨酸蛋白酶组织蛋白酶K、L和S的交叉抑制作用：动力学分析
Biochemistry. 1998 Apr 14;37(15):5258-66. doi: 10.1021/bi972521d.
9
3-Acylamino-azetidin-2-one as a novel class of cysteine proteases inhibitors.3-酰基氨基氮杂环丁烷-2-酮作为一类新型半胱氨酸蛋白酶抑制剂。
Bioorg Med Chem Lett. 2003 Jan 6;13(1):139-41. doi: 10.1016/s0960-894x(02)00831-4.
10
Development of calpain-specific inactivators by screening of positional scanning epoxide libraries.通过筛选位置扫描环氧化合物文库开发钙蛋白酶特异性失活剂。
J Biol Chem. 2007 Mar 30;282(13):9600-9611. doi: 10.1074/jbc.M610372200. Epub 2007 Jan 11.
引用本文的文献
1
Design, Synthesis, and Evaluation of Aza-Peptide Michael Acceptors as Human 20S Proteasome Inhibitors: Extension to the Prime Site.氮杂肽迈克尔受体作为人20S蛋白酶体抑制剂的设计、合成与评价：向活性中心的拓展
ACS Omega. 2025 Jul 16;10(29):31549-31567. doi: 10.1021/acsomega.5c02128. eCollection 2025 Jul 29.
2
Highly potent inhibitors of cathepsin K with a differently positioned cyanohydrazide warhead: structural analysis of binding mode to mature and zymogen-like enzymes.具有不同定位氰基酰肼弹头的强效组织蛋白酶 K 抑制剂：成熟酶和酶原样酶结合模式的结构分析。
J Enzyme Inhib Med Chem. 2022 Dec;37(1):515-526. doi: 10.1080/14756366.2021.2024527.
3
Design, synthesis, and evaluation of aza-peptide aldehydes and ketones as novel and selective protease inhibitors.设计、合成和评价氮杂肽醛酮类作为新型和选择性蛋白酶抑制剂。
J Enzyme Inhib Med Chem. 2020 Dec;35(1):1387-1402. doi: 10.1080/14756366.2020.1781107.
4
Mapping the S1 and S1' subsites of cysteine proteases with new dipeptidyl nitrile inhibitors as trypanocidal agents.利用新型二肽基腈抑制剂对半胱氨酸蛋白酶的 S1 和 S1'亚位点进行作图，作为杀变形虫剂。
PLoS Negl Trop Dis. 2020 Mar 12;14(3):e0007755. doi: 10.1371/journal.pntd.0007755. eCollection 2020 Mar.
5
Addition of 2-(ethylamino)acetonitrile group to nitroxoline results in significantly improved anti-tumor activity and .将2-(乙氨基)乙腈基团添加到硝氧喹啉上可显著提高其抗肿瘤活性，并且……（原文此处不完整）
Oncotarget. 2017 Jul 17;8(35):59136-59147. doi: 10.18632/oncotarget.19296. eCollection 2017 Aug 29.
6
Azanitrile Cathepsin K Inhibitors: Effects on Cell Toxicity, Osteoblast-Induced Mineralization and Osteoclast-Mediated Bone Resorption.氮腈组织蛋白酶K抑制剂：对细胞毒性、成骨细胞诱导矿化和破骨细胞介导的骨吸收的影响
PLoS One. 2015 Jul 13;10(7):e0132513. doi: 10.1371/journal.pone.0132513. eCollection 2015.
本文引用的文献
1
Synthesis and biochemical evaluation of thiochromanone thiosemicarbazone analogues as inhibitors of cathepsin L.硫代色满酮缩氨基硫脲类似物作为组织蛋白酶L抑制剂的合成及生化评价
ACS Med Chem Lett. 2012 Apr 18;3(6):450-3. doi: 10.1021/ml200299g. eCollection 2012 Jun 14.
2
Antiresorptive drugs beyond bisphosphonates and selective oestrogen receptor modulators for the management of postmenopausal osteoporosis.除双膦酸盐和选择性雌激素受体调节剂之外的抗吸收药物用于绝经后骨质疏松症的管理
Drugs Aging. 2014 Jun;31(6):413-24. doi: 10.1007/s40266-014-0179-z.
3
New therapeutics for osteoporosis.骨质疏松症的新型疗法
Curr Opin Pharmacol. 2014 Jun;16:58-63. doi: 10.1016/j.coph.2014.03.004. Epub 2014 Mar 31.
4
A coumarin-labeled vinyl sulfone as tripeptidomimetic activity-based probe for cysteine cathepsins.一种香豆素标记的乙烯砜作为基于三肽模拟活性的半胱氨酸组织蛋白酶探针。
Chembiochem. 2014 May 5;15(7):955-9. doi: 10.1002/cbic.201300806. Epub 2014 Mar 19.
5
Highly selective aza-nitrile inhibitors for cathepsin K, structural optimization and molecular modeling.高选择性的天冬氨酸蛋白酶 K 的氮杂腈抑制剂，结构优化和分子模拟。
Org Biomol Chem. 2013 Sep 21;11(35):5847-52. doi: 10.1039/c3ob41165f.
6
Synthesis and radiopharmacological characterisation of a fluorine-18-labelled azadipeptide nitrile as a potential PET tracer for in vivo imaging of cysteine cathepsins.合成及氟-18 标记的氮杂二肽腈作为半胱氨酸蛋白酶体内成像的潜在正电子发射断层扫描示踪剂的放射药理学特征。
ChemMedChem. 2013 Aug;8(8):1330-44. doi: 10.1002/cmdc.201300135. Epub 2013 Jun 19.
7
Cathepsin K: a unique collagenolytic cysteine peptidase.组织蛋白酶 K：一种独特的胶原降解胱氨酸肽酶。
Biol Chem. 2013 Sep;394(9):1163-79. doi: 10.1515/hsz-2013-0134.
8
Small-molecule inhibitors of cathepsin L incorporating functionalized ring-fused molecular frameworks.包含功能化环合分子框架的组织蛋白酶 L 的小分子抑制剂。
Bioorg Med Chem Lett. 2013 May 1;23(9):2801-7. doi: 10.1016/j.bmcl.2012.12.025. Epub 2012 Dec 20.
9
An access to aza-Freidinger lactams and E-locked analogs.氮杂-Freidinger 内酰胺及其 E-锁类似物的获得途径。
Org Lett. 2013 Feb 1;15(3):448-51. doi: 10.1021/ol3030583. Epub 2013 Jan 15.
10
Highly selective azadipeptide nitrile inhibitors for cathepsin K: design, synthesis and activity assays.高度选择性的角蛋白酶抑制剂：设计、合成与活性测定。
Org Biomol Chem. 2013 Feb 21;11(7):1143-8. doi: 10.1039/c2ob26624e.
Zotero 插件