Fmoc-3,3-diphenyl-D-alanine

• 分子结构分类: 有机化合物 - 苯类化合物 - 芴
• 英文名称: Fmoc-3,3-diphenyl-D-alanine
• 英文别名: Fmoc-D-Dip-OH；Fmoc-3,3-diphenyl-D-Ala-OH；Fmoc-3,3-diphenyl-D-Ala；Fmoc-D-3,3-Diphenylalanine；(2R)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3,3-diphenylpropanoic acid
• 化学式: C₃₀H₂₅NO₄
• mdl: MFCD00672338
• 分子量: 463.533
• InChiKey: PENQOTJCVODUQU-MUUNZHRXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.1
• 重原子数：
  35
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.133
• 拓扑面积：
  75.6
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  Fmoc-3,3-diphenyl-D-alanine 在 1-羟基苯并三唑 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 苯甲醚 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 三氟乙酸 、 4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐 、 N,N'-二异丙基碳二亚胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.93h， 生成
  参考文献：
  名称：

  Chemically Accessible Hsp90 Inhibitor That Does Not Induce a Heat Shock Response

  摘要：

  Recent cancer therapies have focused on targeting biology networks through a single regulatory protein. Heat shock protein 90 (hsp90) is an ideal oncogenic target as it regulates over 400 client proteins and cochaperones. However, clinical inhibitors of hsp90 have had limited success; the primary reason being that they induce a heat shock response. We describe the synthesis and biological evaluation of a new hsp90 inhibitor, SM253. The previous generation on which SM253 is based (SM145) has poor overall synthetic yields, low solubility, and micromolar cytotoxicity. By comparison SM253 has relatively high overall yields, good aqueous solubility, and is more cytotoxic than its parent compound. Verification that hsp90 is SM253's target was accomplished using pull-down and protein folding assays. SM253 is superior to both SM145 and the clinical candidate 17-AAG as it decreases proteins related to the heat shock response by 2-fold, versus a 2-4-fold increase observed when cells are treated with 17-AAG.

  DOI：

  10.1021/ml500114p

文献信息

• Reinventing Hsp90 Inhibitors: Blocking C-Terminal Binding Events to Hsp90 by Using Dimerized Inhibitors
  作者：Yen Chin Koay、Hendra Wahyudi、Shelli R. McAlpine

  DOI：10.1002/chem.201603464

  日期：2016.12.19

  promising anticancer target. Classical inhibitors that block the binding of adenine triphosphate (ATP) to the N‐terminus of Hsp90 are highly toxic to cells and trigger a resistance mechanism within cells. This resistance mechanism comprises a large increase in prosurvival proteins, namely, heat shock protein 70 (Hsp70), heat shock protein 27 (Hsp27), and heat shock factor 1 (HSF‐1). Molecules that modulate

  热激蛋白90（Hsp90）是一种分子伴侣（90 kDa），起二聚体的作用。这种蛋白质有助于负责癌症发展和进程的400多种蛋白质的折叠，组装和稳定化。抑制Hsp90的功能将同时关闭多种癌症驱动的途径，因为致癌客户严重依赖Hsp90，这使得该分子伴侣成为有希望的抗癌靶标。阻止三磷酸腺嘌呤（ATP）与Hsp90 N末端结合的经典抑制剂对细胞具有高毒性，并会触发细胞内的抗药性机制。这种抗性机制包括大量的生存蛋白，即热休克蛋白70（Hsp70），热休克蛋白27（Hsp27）和热休克因子1（HSF-1）。调节Hsp90 C末端的分子可有效诱导癌细胞死亡，而无需激活耐药机制。在本文中，我们描述了一系列二聚化的C末端Hsp90调节剂的设计，合成和生物结合亲和力。我们表明，这些C末端调节剂的二聚体可协同抑制Hsp90相对于单体。
• Hitting a Moving Target: How Does an<i>N</i>-Methyl Group Impact Biological Activity?
  作者：Yen Chin Koay、Nicole L. Richardson、Samantha S. Zaiter、Jessica Kho、Sheena Y. Nguyen、Daniel H. Tran、Ka Wai Lee、Laura K. Buckton、Shelli R. McAlpine

  DOI：10.1002/cmdc.201500572

  日期：2016.4.19

  interactions as therapeutic targets. Herein we report the synthesis of seven new cyclic peptide molecules and their biological activity. These macrocycles were designed to understand how moving an N‐methyl moiety around the peptide backbone impacts biological activity. Because the lead non‐methylated structure inhibits the oncogenic regulator heat‐shock protein 90 (Hsp90), two of the most potent analogues

  在解决特定的蛋白质间相互作用作为治疗目标时，大环化合物相对于小分子药物具有多个优势。在这里，我们报告了七个新的环肽分子的合成及其生物学活性。设计这些大环化合物是为了了解围绕肽主链移动N-甲基部分如何影响生物活性。由于铅的非甲基化结构抑制了致癌调节物热休克蛋白90（Hsp90），因此对两个最有效的类似物的Hsp90抑制活性进行了评估。我们证明结合了N甲基部分控制着大环的构象，这极大地影响了对Hsp90的细胞毒性和结合亲和力。因此，在大环内放置一个N-甲基化氨基酸会对该化合物的构象产生不可预测的变化，从而导致其生物活性发生不可预测的变化。
• Structure−Activity Relationships of the Melanocortin Tetrapeptide Ac-His-<scp>d</scp>-Phe-Arg-Trp-NH₂ at the Mouse Melanocortin Receptors. 4. Modifications at the Trp Position
  作者：Jerry Ryan Holder、Zhimin Xiang、Rayna M. Bauzo、Carrie Haskell-Luevano

  DOI：10.1021/jm020296e

  日期：2002.12.1

  possessed nanomolar MC1R and MC5R potency but micromolar MC3R and MC4R agonist potency. Additionally, these studies identified that substitution of the Trp amino acid with either Nal(2') or D-Nal(2') resulted in equipotent melanocortin receptor potency, suggesting that the chemically reactive Trp indole side chain may be replaced with the nonreactive Nal(2') moiety for the design of nonpeptide melanocortin

  黑皮质素途径参与几种生理功能的调节，包括皮肤色素沉着，类固醇生成，肥胖，能量稳态和外分泌腺功能。该黑皮质素途径由五个已知的G蛋白偶联受体，源自proopiomelanocortin（POMC）基因转录物的内源激动剂，内源性拮抗剂Agouti和Agouti相关蛋白（AGRP）组成，并通过细胞内cAMP信号转导途径发出信号。内源性黑皮质素激动剂包含推定的信息序列“ His-Phe-Arg-Trp”，假定其对黑皮质素受体分子的识别和刺激很重要。在此，我们报告了基于模板Ac-His-D-Phe-Arg-Trp-NH（2）的四肽文库，由20个成员组成，这些成员在Trp（9）位置（alpha-MSH编号）已被修饰，并在药理上表征了小鼠黑皮质素受体MC1R，MC3R，MC4R和MC5R的激动剂活性。这项研究的结果产生了化合物，其药理学性质从等效性到最高100 microM浓度的黑皮质素受体活性丧失。有趣
• MACROCYCLIC COMPOUNDS FOR INHIBITION OF TUMOR NECROSIS FACTOR ALPHA
  申请人：Lee Jinbo

  公开号：US20100152099A1

  公开（公告）日：2010-06-17

  The invention provides macrocyclic compounds and methods for their synthesis and use. In particular, the invention provides macrocyclic compounds that modulate the activity of tumor necrosis factor alpha and/or are useful in the treatment of medical conditions, such as, rheumatoid arthritis, psoriasis, and asthma.

  该发明提供了大环化合物及其合成和使用方法。具体而言，该发明提供了调节肿瘤坏死因子α活性和/或用于治疗医学状况（如类风湿性关节炎、银屑病和哮喘）的大环化合物。
• Three Rounds of Stability-Guided Optimization and Systematical Evaluation of Oncolytic Peptide LTX-315
  作者：Xing-Yan Fu、Hao Yin、Xi-Tong Chen、Jing-Fang Yao、Yan-Nan Ma、Min Song、Huan Xu、Qian-Yao Yu、Shan-Shan Du、Yun-Kun Qi、Ke-Wei Wang

  DOI：10.1021/acs.jmedchem.3c02232

  日期：2024.3.14

  Oncolytic peptides represent promising novel candidates for anticancer treatments. In our efforts to develop oncolytic peptides possessing both high protease stability and durable anticancer efficiency, three rounds of optimization were conducted on the first-in-class oncolytic peptide LTX-315. The robust synthetic method, in vitro and in vivo anticancer activity, and anticancer mechanism were investigated

  溶瘤肽代表了有希望的新型抗癌治疗候选物。为了开发兼具高蛋白酶稳定性和持久抗癌功效的溶瘤肽，我们对一流的溶瘤肽LTX-315进行了三轮优化。研究了稳健的合成方法、体外和体内抗癌活性以及抗癌机制。以FXY-12为代表的D型肽具有显着提高的蛋白水解稳定性和持续的抗癌效率。引人注目的是，含有一个 FXY-12 和两个喜树碱部分的新型杂合肽 FXY-30 表现出最有效的体外和体内抗癌活性。机制探索表明，FXY-30表现出快速的溶膜作用，并诱导严重的DNA双链断裂，从而引发细胞凋亡。总的来说，这项研究不仅建立了提高溶瘤肽稳定性和抗癌潜力的强有力策略，而且为未来开发基于D型肽的混合抗癌化疗药物提供了有价值的参考。