Cbz-Asp(O-tBu)-Glu(O-tBu)-Val-NH-NH2 | 646532-71-0

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: Cbz-Asp(O-tBu)-Glu(O-tBu)-Val-NH-NH2
• 英文别名: tert-butyl (S)-4-((S)-2-(((benzyloxy)carbonyl)amino)-4-(tert-butoxy)-4-oxobutanamido)-5-(((S)-1-hydrazinyl-3-methyl-1-oxobutan-2-yl)amino)-5-oxopentanoate；Cbz-Asp(OtBu)-Glu(OtBu)-Val-NHNH2；tert-butyl (4S)-5-[[(2S)-1-hydrazinyl-3-methyl-1-oxobutan-2-yl]amino]-4-[[(2S)-4-[(2-methylpropan-2-yl)oxy]-4-oxo-2-(phenylmethoxycarbonylamino)butanoyl]amino]-5-oxopentanoate
• CAS: 646532-71-0
• 化学式: C₃₀H₄₇N₅O₉
• 分子量: 621.731
• InChiKey: ORLVWSLZNYWABH-HFMPRLQTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  44
• 可旋转键数：
  19
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  204
• 氢给体数：
  5
• 氢受体数：
  10

上下游信息

• 下游产品

  中文名称	英文名称	CAS号	化学式	分子量
  ——	Cbz-Asp(O-t-Bu)-Glu(O-t-Bu)-Val-NHNHCH2COO-t-Bu	646532-79-8	C36H57N5O11	735.875
  ——	(2R,3R)-3-(N'-{(S)-2-[(S)-2-((S)-2-Benzyloxycarbonylamino-3-tert-butoxycarbonyl-propionylamino)-4-tert-butoxycarbonyl-butyrylamino]-3-methyl-butyryl}-N-tert-butoxycarbonylmethyl-hydrazinocarbonyl)-oxirane-2-carboxylic acid ethyl ester	646531-07-9	C42H63N5O15	877.987
  ——	(2S,3S)-3-(N'-{(S)-2-[(S)-2-((S)-2-Benzyloxycarbonylamino-3-tert-butoxycarbonyl-propionylamino)-4-tert-butoxycarbonyl-butyrylamino]-3-methyl-butyryl}-N-tert-butoxycarbonylmethyl-hydrazinocarbonyl)-oxirane-2-carboxylic acid ethyl ester	646531-05-7	C42H63N5O15	877.987

反应信息

• 作为反应物：
  描述：

  Cbz-Asp(O-tBu)-Glu(O-tBu)-Val-NH-NH2 在 N-甲基吗啉 、 氯甲酸异丁酯 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 21.0h， 生成 4-(2-benzyloxycarbonylamino-3-tert-butoxycarbonyl-propionylamino)-4-(1-{N'-tert-butoxycarbonylmethyl-N'-[3-(1-carbamoyl-2-phenyl-ethylcarbamoyl)-oxiranecarbonyl]-hydrazinocarbonyl}-2-methyl-propylcarbamoyl)-butyric acid tert-butyl ester
  参考文献：
  名称：

  Design, Synthesis, and Evaluation of Aza-Peptide Epoxides as Selective and Potent Inhibitors of Caspases-1, -3, -6, and -8

  摘要：

  Aza-peptide epoxides, a novel class of irreversible protease inhibitors, are specific for the clan CD cysteine proteases. Aza-peptide epoxides with an aza-Asp residue at PI are excellent irreversible inhibitors of caspases-1, -3, -6, and -8 with second-order inhibition rates up to 1910 000 M-1 s(-1). In general, the order of reactivity of aza-peptide epoxides is S'S > R,R > trans > cis. Interestingly, some of the R,R epoxides while being less potent are actually more selective than the S,S epoxides. Our aza-peptide epoxides designed For caspases are stable, potent, and specific inhibitors, as they show little to no inhibition of other proteases such as the aspartyl proteases porcine pepsin, human cathepsin D, plasmepsin 2 from P. falciparum, HIV-1 protease, and the secreted aspartic proteinase 2 (SAP-2) from Candida albicans; the serine proteases granzyme B and alpha-chymotrypsin; and the cysteine proteases cathepsin B and papain (clan CA), and legumain (clan CD).

  DOI：

  10.1021/jm0305016
• 作为产物：
  描述：

  methyl (5S,8S,11S)-5-(2-(tert-butoxy)-2-oxoethyl)-8-(3-(tert-butoxy)-3-oxopropyl)-11-isopropyl-3,6,9-trioxo-1-phenyl-2-oxa-4,7,10-triazadodecan-12-oate 在 肼 作用下， 以 甲醇 为溶剂， 反应 18.0h， 以100%的产率得到Cbz-Asp(O-tBu)-Glu(O-tBu)-Val-NH-NH2
  参考文献：
  名称：

  设计，合成和体外评估作为新型和选择性蛋白酶抑制剂的氮杂-肽醛和酮。

  摘要：

  摘要 氮杂-肽醛和酮是一类新的可逆蛋白酶抑制剂，对蛋白酶体和氏族CD半胱氨酸蛋白酶具有特异性。我们设计并合成了对蛋白酶体的胰凝乳蛋白酶样活性位点特异的aza-Leu衍生物，可有效抑制caspases-3和-6的aza-Asp衍生物，以及可抑制曼氏梭菌和I的aza-Asn衍生物。蓖麻毒素豆。caspase-3的晶体结构与我们的caspase特异的aza-肽甲基酮抑制剂在P1处具有aza-Asp残基相结合，揭示了抑制剂羰基碳和活性位半胱氨酸硫之间的共价键。氮杂肽醛和酮对组织蛋白酶B或胰凝乳蛋白酶没有交叉反应性。最初的这些抑制剂的体外选择性使其成为进一步发展成治疗剂的潜在候选药物，以潜在地治疗多发性骨髓瘤，神经退行性疾病和寄生虫感染。

  DOI：

  10.1080/14756366.2020.1781107

文献信息

• Aza-Peptide Epoxides:  A New Class of Inhibitors Selective for Clan CD Cysteine Proteases
  作者：Juliana L. Asgian、Karen Ellis James、Zhao Zhao Li、Wendy Carter、Alan J. Barrett、Jowita Mikolajczyk、Guy S. Salvesen、James C. Powers

  DOI：10.1021/jm025581c

  日期：2002.11.1

  Aza-peptide epoxides, a new class of irreversible protease inhibitors, are specific for the clan CD cysteine proteases. The inhibitors have second-order rate constants up to 10(5) M(-1) s(-1), with the most potent epoxides having the S,S stereochemistry. The aza-Asn derivatives are effective legumain inhibitors, while the aza-Asp epoxides were specific for caspases. The inhibitors have little or no inhibition

  氮杂肽环氧化物是一类新的不可逆的蛋白酶抑制剂，对氏族CD半胱氨酸蛋白酶具有特异性。抑制剂具有高达10（5）M（-1）s（-1）的二阶速率常数，最有效的环氧化物具有S，S立体化学。氮杂-Asn衍生物是有效的豆蔻蛋白酶抑制剂，而氮杂-Asp环氧化物对胱天蛋白酶具有特异性。抑制剂对其他蛋白酶（如胰凝乳蛋白酶，木瓜蛋白酶或组织蛋白酶B）几乎没有抑制作用。
• [EN] AZA-PEPTIDE ALDEHYDES AND KETONES<br/>[FR] ALDÉHYDES ET CÉTONES AZA-PEPTIDIQUES
  申请人：OHIO STATE INNOVATION FOUNDATION

  公开号：WO2017151587A1

  公开（公告）日：2017-09-08

  The present disclosure relates to compositions for inhibiting proteases, methods for synthesizing the compositions, and methods of using the disclosed protease inhibitors. Aspects of the invention include aza-peptide aldehyde and ketone compositions that inhibit proteases. The disclosed compounds, pharmaceutically acceptable salts, pharmaceutically acceptable derivatives, prodrugs, or combinations thereof can be used to treat disease or pathological conditions related to the activity of proteases associated with a specific disease or condition.

  本公开涉及用于抑制蛋白酶的组合物，合成这些组合物的方法，以及使用所披露的蛋白酶抑制剂的方法。发明的方面包括抑制蛋白酶的氮杂肽醛和酮组合物。所披露的化合物、药学上可接受的盐、药学上可接受的衍生物、前药或其组合物可用于治疗与特定疾病或病况相关的蛋白酶活性相关的疾病或病理条件。
• Design, Synthesis, and Evaluation of Aza-Peptide Michael Acceptors as Selective and Potent Inhibitors of Caspases-2, -3, -6, -7, -8, -9, and -10
  作者：Özlem Doǧan Ekici、Zhao Zhao Li、Amy J. Campbell、Karen Ellis James、Juliana L. Asgian、Jowita Mikolajczyk、Guy S. Salvesen、Rajkumar Ganesan、Stjepan Jelakovic、Markus G. Grütter、James C. Powers

  DOI：10.1021/jm0601405

  日期：2006.9.1

  novel class of inhibitors that are potent and specific for caspases-2, -3, -6, -7, -8, -9, and -10. The second-order rate constants are in the order of 10(6) M(-1) s(-1). The aza-peptide Michael acceptor inhibitor 18t (Cbz-Asp-Glu-Val-AAsp-trans-CH=CH-CON(CH(2)-1-Naphth)(2) is the most potent compound and it inhibits caspase-3 with a k(2) value of 5620000 M(-1) s(-1). The inhibitor 18t is 13700, 190

  氮杂肽迈克尔受体是一类新颖的抑制剂，对caspases-2，-3，-6，-7，-8，-9和-10具有特异性。二阶速率常数约为10（6）M（-1）s（-1）。氮杂肽迈克尔受体抑制剂18t（Cbz-Asp-Glu-Val-AAsp-trans-CH = CH-CON（CH（2）-1-Naphth）（2）是最有效的化合物，它抑制caspase-3 ak（2）值为5620000 M（-1）s（-1）。抑制剂18t对caspase-3的选择性比caspases-2，-6高13700、190、6.4、594、37500和173倍（分别为-7，-8，-9和-10），以caspase特异性序列设计的氮杂肽Michael受体具有选择性，并且与氏族CA半胱氨酸蛋白酶（如木瓜蛋白酶，组织蛋白酶B和钙蛋白酶）没有任何交叉反应性。
• Aza-Peptide Michael Acceptors:  A New Class of Inhibitors Specific for Caspases and Other Clan CD Cysteine Proteases
  作者：Özlem Doǧan Ekici、Marion G. Götz、Karen Ellis James、Zhao Zhao Li、Brian J. Rukamp、Juliana L. Asgian、Conor R. Caffrey、Elizabeth Hansell、Jan Dvořák、James H. McKerrow、Jan Potempa、James Travis、Jowita Mikolajczyk、Guy S. Salvesen、James C. Powers

  DOI：10.1021/jm049938j

  日期：2004.4.1

  Aza-peptide Michael acceptors are a new class of irreversible inhibitors that are highly potent and specific for clan CD cysteine proteases. The aza-Asp derivatives were specific for caspases, while aza-Asn derivatives were effective legumain inhibitors. Aza-Lys and aza-Orn derivatives were potent inhibitors of gingipain K and clostripain. Aza-peptide Michael acceptors showed no cross reactivity toward papain, cathepsin B, and calpain.
• AZA-PEPTIDE ALDEHYDES AND KETONES
  申请人：OHIO STATE INNOVATION FOUNDATION

  公开号：US20190055283A1

  公开（公告）日：2019-02-21

  The present disclosure relates to compositions for inhibiting proteases, methods for synthesizing the compositions, and methods of using the disclosed protease inhibitors. Aspects of the invention include aza-peptide aldehyde and ketone compositions that inhibit proteases. The disclosed compounds, pharmaceutically acceptable salts, pharmaceutically acceptable derivatives, prodrugs, or combinations thereof can be used to treat disease or pathological conditions related to the activity of proteases associated with a specific disease or condition.