diphenyl 1-benzyloxycarbonylamino-2-{4-[N,N'-bis(tert-butyloxycarbonyl)guanidino]phenyl}ethanephosphonate | 695172-02-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: diphenyl 1-benzyloxycarbonylamino-2-{4-[N,N'-bis(tert-butyloxycarbonyl)guanidino]phenyl}ethanephosphonate
• 英文别名: benzyl N-[2-[4-[bis[(2-methylpropan-2-yl)oxycarbonylamino]methylideneamino]phenyl]-1-diphenoxyphosphorylethyl]carbamate
• CAS: 695172-02-2
• 化学式: C₃₉H₄₅N₄O₉P
• 分子量: 744.781
• InChiKey: CRAFOPFOFZLBMP-UHFFFAOYSA-N

物化性质

• 密度：
  1.21±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  9.2
• 重原子数：
  53
• 可旋转键数：
  18
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  163
• 氢给体数：
  3
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  diphenyl 1-benzyloxycarbonylamino-2-{4-[N,N'-bis(tert-butyloxycarbonyl)guanidino]phenyl}ethanephosphonate 在 palladium on activated charcoal PS-carbodiimide 、 氢气 、 1-羟基苯并三唑 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 8.17h， 生成 diphenyl 1-[(N-m-methylbenzoyl-O-tert-butyl-D-seryl)-L-alanyl]amino-2-[4-(N,N'-bis(tert-butyloxycarbonyl)guanidino)phenyl]ethanephosphonate
  参考文献：
  名称：

  Diphenyl Phosphonate Inhibitors for the Urokinase-Type Plasminogen Activator:  Optimization of the P4 Position

  摘要：

  This paper describes the structure-activity relationship in a series of tripeptidyl diphenyl phosphonate irreversible urokinase plasminogen activator (uPA) inhibitors, originally derived from an arginyltripeptide. uPA is considered an interesting target in anticancer drug design. The selectivity of these inhibitors for uPA is enhanced by the optimization of the P4 position. The most interesting compound shows an IC50 of 5 nM, with a selectivity index of more than 3000 toward other Arg/Lys-specific proteases such as tissue-type plasminogen activator, plasmin, factor Xa, and thrombin. A synthetic strategy for the preparation of small libraries of diphenyl phosphonate analogues of capped tripeptides is described. It is shown that uPA is irreversibly inhibited, and interactions with the active site were modeled. Finally, a diparacetamol phosphonate analogue was developed to circumvent the release of cytotoxic phenol.

  DOI：

  10.1021/jm060622g
• 作为产物：
  描述：

  对氨基苯甲醇 在 sodium hydroxide 、 TEA 、 copper(II) bis(trifluoromethanesulfonate) 、 戴斯-马丁氧化剂 、 三氟乙酸 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 乙腈 为溶剂， 反应 10.0h， 生成 diphenyl 1-benzyloxycarbonylamino-2-{4-[N,N'-bis(tert-butyloxycarbonyl)guanidino]phenyl}ethanephosphonate
  参考文献：
  名称：

  Development of Irreversible Diphenyl Phosphonate Inhibitors for Urokinase Plasminogen Activator

  摘要：

  In this letter we report the synthesis and biochemical evaluation of selective, irreversible diphenyl phosphonate inhibitors for urokinase plasminogen activator (uPA). A diphenyl phosphonate group was introduced on the substratelike peptide Z-D-Ser-Ala-Arg, and modification of the guanidine side chain was investigated. A guanylated benzyl group appeared the most promising side chain modification. A k(app) value in the 10(3) M-1 s(-1) range for uPA was obtained, together with a selectivity index higher than 240 toward other trypsin-like proteases such as tPA, thrombin, plasmin, and FXa.

  DOI：

  10.1021/jm0499209

文献信息

• A <i>p</i>-[¹⁸F]Fluoroethoxyphenyl Bicyclic Nucleoside Analogue as a Potential Positron Emission Tomography Imaging Agent for Varicella-Zoster Virus Thymidine Kinase Gene Expression
  作者：Satish K. Chitneni、Christophe M. Deroose、Jan Balzarini、Rik Gijsbers、Sofie Celen、Zeger Debyser、Luc Mortelmans、Alfons M. Verbruggen、Guy M. Bormans

  DOI：10.1021/jm700971p

  日期：2007.12.27

  We recently reported a new positron emission tomography (PET) reporter gene, namely, varicella-zoster virus thymidine kinase (VZV-tk) in combination, with carbon-11 or fluorine-18 labeled m-alkoxyphenyl bicyclic nucleoside analogues (BCNAs) as PET reporter probes. We now report the synthesis and evaluation of p-alkoxyphenyl-BCNA tracers ([11C]-4 and [18F]-5), which are found to be superior to the m-alkoxyphenyl-BCNA

  我们最近报道了一个新的正电子发射断层扫描（PET）报告基因，即水痘-带状疱疹病毒胸苷激酶（VZV-tk）与碳11或氟18标记的间烷氧基苯基双环核苷类似物（BCNA）组合使用记者调查。现在，我们报告了对-烷氧基苯基-BCNA示踪剂的合成和评估（[11C] -4和[18F] -5），发现它们优于间烷氧基苯基-BCNA示踪剂。特别是，氟18标记的示踪剂（[18F] -5，IC50为4.2 microM）在VZV-tk表达细胞中比以前报道的间甲氧基苯基BCNA显示更高的积累。通过将苯酚前体3分别与作为烷基化剂的11CH 3I和18FCH 2CH 2Br加热来合成[11C] -4和[18F] -5。在293T细胞中对[11C] -4和[18F] -5进行的体外评估显示，其摄取量增加了约14倍和54倍，与对照细胞相比，它们分别进入了VZV-tk基因转导的细胞。LC-MS分析证实，VZV TK催化形成5
• The first potent diphenyl phosphonate KLK4 inhibitors with unexpected binding kinetics
  作者：Jeroen van Soom、Giuliana Cuzzucoli Crucitti、Rafaela Gladysz、Pieter van der Veken、Roberto Di Santo、Ingmar Stuyver、Victoria Buck、Anne-Marie Lambeir、Viktor Magdolen、Jurgen Joossens、Koen Augustyns

  DOI：10.1039/c5md00288e

  日期：——

  We report the first highly potent and selective small-molecule KLK4 inhibitors, showing surprising reversible binding kinetics.

  我们报告了第一批高效、选择性的小分子KLK4抑制剂，显示出令人惊讶的可逆结合动力学。
• Novel Urokinase Inhibitors
  申请人：Augustyns Koen

  公开号：US20080312191A1

  公开（公告）日：2008-12-18

  The present invention relates to novel compounds with inhibitory activity towards urokinase plasminogen activator (uPA); to methods for preparation of said uPA inhibitor compounds; to pharmaceutical compositions comprising said uPA inhibitor compounds; to the use of said uPA inhibitor compounds as a medicament and the use of said uPA inhibitor compounds for the preparation of a medicament for the treatment of conditions chosen from the group comprising cancer, tumour growth, tumour invasion, tumour metastasis, diabetic retinopathy, hemorrhagic atherosclerosis and inflammatory conditions, such as rheumatoid arthritis and psoriasis.

  本发明涉及具有抑制尿激酶纤溶酶原活化物（uPA）活性的新化合物；制备所述uPA抑制剂化合物的方法；包括所述uPA抑制剂化合物的药物组合物；将所述uPA抑制剂化合物用作药物的用途以及将所述uPA抑制剂化合物用于制备用于治疗癌症、肿瘤生长、肿瘤侵袭、肿瘤转移、糖尿病视网膜病变、出血性动脉粥样硬化和类风湿性关节炎和银屑病等条件的药物的用途。
• Small, Potent, and Selective Diaryl Phosphonate Inhibitors for Urokinase-Type Plasminogen Activator with In Vivo Antimetastatic Properties
  作者：Jurgen Joossens、Omar M. Ali、Ibrahim El-Sayed、Georgiana Surpateanu、Pieter Van der Veken、Anne-Marie Lambeir、Buddy Setyono-Han、John A. Foekens、Anneliese Schneider、Wolfgang Schmalix、Achiel Haemers、Koen Augustyns

  DOI：10.1021/jm700962j

  日期：2007.12.27

  A set of small nonpeptidic diaryl phosphonate inhibitors was prepared. Some of these inhibitors show potent and highly selective irreversible uPA inhibition. The biochemical and modeling data prove that the combination of a benzylguanidine moiety with a diaryl phosphonate ester results in optimized molecules for derivatizing the serine alcohol in the uPA active site. Selected compounds show significant antimetastatic effects in the BN-472 rat mammary carcinoma model. We report in this paper a preclinical proof of concept that selective, irreversible uPA inhibitors could be valuable in antimetastatic therapy.
• Phosphonate inhibitors of West Nile virus NS2B/NS3 protease
  作者：Marcin Skoreński、Aleksandra Milewska、Krzysztof Pyrć、Marcin Sieńczyk、Józef Oleksyszyn

  DOI：10.1080/14756366.2018.1506772

  日期：2019.1.1

  West Nile virus (WNV) is a member of the flavivirus genus belonging to the Flaviviridae family. The viral serine protease NS2B/NS3 has been considered an attractive target for the development of anti-WNV agents. Although several NS2B/NS3 protease inhibitors have been described so far, most of them are reversible inhibitors. Herein, we present a series of alpha-aminoalkylphosphonate diphenyl esters and their peptidyl derivatives as potent inhibitors of the NS2B/NS3 protease. The most potent inhibitor identified was Cbz-Lys-Arg-(4-GuPhe)(P)(OPh)(2) displaying K-i and k(2)/K-i values of 0.4 mu M and 28 265 M(-1)s(-1), respectively, with no significant inhibition of trypsin, cathepsin G, and HAT protease.