NAc-Sar-Gly-Val-(D-allo-Ile)-Thr-Nva-Ile-Arg-ProNEt | 251579-55-2

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: NAc-Sar-Gly-Val-(D-allo-Ile)-Thr-Nva-Ile-Arg-ProNEt
• 英文别名: NAc-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-Pro-NHEt；ABT-510；acetyl-sarcosine-glycine-valine-D-alloisoleucine-threonine-norvaline-isoleucine-arginine-proline-ethylamide；(2S)-1-[(2S)-2-[[(2S,3S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2R,3S)-2-[[(2S)-2-[[2-[[2-[acetyl(methyl)amino]acetyl]amino]acetyl]amino]-3-methylbutanoyl]amino]-3-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]pentanoyl]amino]-3-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]-N-ethylpyrrolidine-2-carboxamide
• CAS: 251579-55-2
• 化学式: C₄₆H₈₃N₁₃O₁₁
• 分子量: 994.246
• InChiKey: RIWLPSIAFBLILR-WVNGMBSFSA-N

物化性质

• 密度：
  1.30±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0
• 重原子数：
  70
• 可旋转键数：
  30
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.76
• 拓扑面积：
  358
• 氢给体数：
  11
• 氢受体数：
  12

制备方法与用途

ABT-510是一种抗血管生成的TSP肽，类似于血栓调节蛋白，它在上皮性卵巢癌的原位同基因模型中能够诱导细胞凋亡并抑制肿瘤生长。此外，ABT-510还能减少炎症性肠病小鼠模型中的血管生成和炎症反应。因此，ABT-510适用于癌症（尤其是上皮性卵巢癌）和炎症性肠病（IBD）的研究。

反应信息

• 作为产物：
  描述：

  以89的产率得到NAc-Sar-Gly-Val-(D-allo-Ile)-Thr-Nva-Ile-Arg-ProNEt
  参考文献：
  名称：

  J. Pept. Sci. 2015, 21, 691-695

  摘要：

  DOI：

文献信息

• Hydrophobic benzyl amines as supports for liquid-phase C-terminal amidated peptide synthesis: application to the preparation of ABT-510
  作者：Emiko Matsumoto、Yuko Fujita、Yohei Okada、Esko I. Kauppinen、Hidehiro Kamiya、Kazuhiro Chiba

  DOI：10.1002/psc.2791

  日期：2015.9

  tag‐assisted liquid‐phase peptide synthesis as supports, leading to the total synthesis of ABT‐510 (2). Although an ethyl amide‐forming type was used in the present work, different types of hydrophobic benzyl amines could also be simply designed and prepared through versatile reductive aminations in one step. The standard acidic treatment used in the final deprotection step for peptide synthesis gave the desired

  C端酰胺化是最常见的肽修饰之一，并经常在生物活性肽中发现。但是，C末端修饰必须具有创造性，因为当前的肽化学合成技术主要由C末端保护载体的使用决定。因此，必须在除去此类载体后进行，这会使反应处理和产物分离变得复杂。在这种情况下，疏水性苄基胺已成功地添加到了不断增长的可溶性标签辅助液相肽合成工具箱中，作为支持物，从而实现了ABT-510的全合成（2）。尽管在目前的工作中使用的是形成乙基酰胺的类型，但也可以通过通用的还原胺化一步来简单设计和制备不同类型的疏水性苄基胺。在最终脱保护步骤中用于肽合成的标准酸性处理过程可得到所需的C-末端仲酰胺化肽，且没有差向异构化。版权所有©2015欧洲肽协会和John Wiley＆Sons，Ltd.
• Facile Preparation of Peptides with C-Terminal <i>N</i>-Alkylamide <i>via</i> Radical-Initiated Dethiocarboxylation
  作者：Tatsuhiko Shimizu、Rin Miyajima、Naoto Naruse、Kosuke Yamaoka、Keisuke Aihara、Akira Shigenaga、Akira Otaka

  DOI：10.1248/cpb.c15-01025

  日期：——

  A new synthetic method has been developed to prepare peptides bearing a C-terminal N-alkylamide from peptide thioacids via a radical-initiated dethiocarboxylation process. This method enables the introduction of various alkyl groups to C-terminal amides simply by replacing the amino acid building block. Its application to the preparation of anti-cancer drug ABT-510 is also reported.

  已经开发了一种新的合成方法，该方法通过自由基引发的脱硫羧化工艺从肽硫酸制备带有C端N-烷基酰胺的肽。该方法能够简单地通过取代氨基酸结构单元而将各种烷基引入C-末端酰胺。还报道了其在制备抗癌药ABT-510中的应用。
• Thrombospondin-1 Mimetic Peptide Inhibitors of Angiogenesis and Tumor Growth:  Design, Synthesis, and Optimization of Pharmacokinetics and Biological Activities
  作者：Fortuna Haviv、Michael F. Bradley、Douglas M. Kalvin、Andrew J. Schneider、Donald J. Davidson、Sandra M. Majest、Laura M. McKay、Catherine J. Haskell、Randy L. Bell、Bach Nguyen、Kennan C. Marsh、Bruce W. Surber、John T. Uchic、James Ferrero、Yi-Chun Wang、Juan Leal、Rae D. Record、Jason Hodde、Stephen F. Badylak、Richard R. Lesniewski、Jack Henkin

  DOI：10.1021/jm0401560

  日期：2005.4.1

  The heptapeptide 1, NAc-Gly-Val-DIle-Thr-Arg-Ile-ArgNHEt, a structurally modified fragment derived from the second type-1 repeat of thrombospondin-1 (TSP-1), is known to possess antiangiogenic activity. However, therapeutic utility could not be demonstrated because this peptide has a very short half-life in rodents. To optimize the PD/PK profile of 1, we initiated a systematic SAR study. The initial structural modifications were performed at positions 5 and 7 of peptide 1 and at the N- and C-termini. Out of several hundred peptides synthesized, the nonapeptide 5 (ABT-526) emerged as a promising lead. ABT-526 inhibited VEGF-induced HMVEC cell migration and tube formation in the nanomolar range and increased apoptosis of HUAEC cells. ABT-526 showed acceptable PK in rodents, dog, and monkey. ABT-526, when incorporated in an angiogenic pellet implanted in the rat cornea at 10 mu M, reduced neovascularization by 92%. Substitution of DalloIle in place of DIle in ABT-526 provided nonapeptide 6 (ABT-510), which was 30-fold less active than ABT-526 in the EC migration but 20-fold more active in the tube formation assay. In comparison to ABT-526, ABT-510 has increased water solubility and slower clearance in dog and monkey. Radiolabeled ABT-510 demonstrated saturable binding to HMVEC cells at 0.02-20 nM concentrations and was displaceable by TSP-1. ABT-510 and ABT-526 were shown to significantly increase apoptosis of HUAEC cells. ABT-510 was effective in blocking neovascularization in the mouse Matrigel plug model and inhibited tumor growth in the mouse Lewis lung carcinoma model. Previous studies had shown that ABT-510 was effective in inhibiting the outgrowth of murine melanoma metastases in syngeneic mice and in blocking the growth of human bladder carcinoma implanted in nude mice. It had been also shown that ABT-510 could regress tumor lesions in pet dogs or cause unexpected stabilization of the disease in advanced canine cancer. ABT-526 and ABT-510 are the first compounds in the class of potent inhibitors of angiogenesis that mimic the antiangiogenic function of TSP-1. ABT-510 is currently in phase II clinical studies.