N-Boc-D-Leu-L-Leu-OMe | 88621-07-2

• 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: N-Boc-D-Leu-L-Leu-OMe
• 英文别名: Boc-D-Leu-Leu-OMe；methyl (2S)-4-methyl-2-[[(2R)-4-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]pentanoyl]amino]pentanoate
• CAS: 88621-07-2
• 化学式: C₁₈H₃₄N₂O₅
• 分子量: 358.478
• InChiKey: LFRFWMCLWQNBFR-KGLIPLIRSA-N

物化性质

• 沸点：
  479.2±25.0 °C(Predicted)
• 密度：
  1.027±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  25
• 可旋转键数：
  11
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.83
• 拓扑面积：
  93.7
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N-Boc-D-Leu-L-Leu-OMe 在 lithium hydroxide 作用下， 以 甲醇 为溶剂， 以95%的产率得到Boc-D-Leu-L-Leu-OH
  参考文献：
  名称：

  Sansalvamide A衍生物的合成及其在MSS结肠癌细胞系HT-29中的细胞毒性。

  摘要：

  我们报告了36种Sansalvamide A衍生物的合成及其对结肠癌HT-29细胞系（一种微卫星稳定（MSS）结肠癌细胞系）的生物活性。这三十六种化合物可分为三个子集，其中化合物的第一子集包含L-氨基酸，第二个子集包含D-氨基酸，而第三子集包含D-和L-氨基酸。五种化合物表现出出色的抑制活性（抑制率> 75％）。化合物的结构活性关系（SAR）确定了位置2或3上的单个D-氨基酸比Sansalvamide A肽的细胞毒性提高了10倍。这项工作强调了残基2和3的重要性以及D-氨基酸在该类化合物的非常规SAR中的作用。

  DOI：

  10.1016/j.bmc.2006.04.031
• 作为产物：
  描述：

  (2S)-2-氨基-4-甲基戊酸甲酯 、 BOC-D-亮氨酸 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 以88%的产率得到N-Boc-D-Leu-L-Leu-OMe
  参考文献：
  名称：

  Isolation, Structure Elucidation and Total Synthesis of Lajollamide A from the Marine Fungus Asteromyces cruciatus

  摘要：

  从美国圣地亚哥拉荷亚海岸获得的海洋来源丝状真菌Asteromyces cruciatus 763，产出了新的五肽lajollamide A (1)，以及已知化合物regiolone (2)、hyalodendrin (3)、gliovictin (4)、1N-norgliovicitin (5)和bis-N-norgliovictin (6)。lajollamide A (1)的平面结构通过核磁共振(NMR)光谱和质谱结合确定。lajollamide A (1)的绝对构型通过全合成得到明确解决，合成过程中获得了三个额外的非对映异构体，并揭示了在化学降解过程中l-亮氨酸和l-N-甲基亮氨酸残基发生了意外的酸介导部分消旋化(2:1)。对分离的代谢物的生物活性，特别是抗菌性质进行了系列检测。

  DOI：

  10.3390/md10122912

文献信息

• Synthesis of Sansalvamide A derivatives and their cytotoxicity in the MSS colon cancer cell line HT-29
  作者：Thomas J. Styers、Ahmet Kekec、Rodrigo Rodriguez、Joseph D. Brown、Julia Cajica、Po-Shen Pan、Emily Parry、Chris L. Carroll、Irene Medina、Ricardo Corral、Stephanie Lapera、Katerina Otrubova、Chung-Mao Pan、Kathleen L. McGuire、Shelli R. McAlpine

  DOI：10.1016/j.bmc.2006.04.031

  日期：2006.8

  thirty-six Sansalvamide A derivatives, and their biological activity against colon cancer HT-29 cell line, a microsatellite stable (MSS) colon cancer cell-line. The thirty-six compounds can be divided into three subsets, where the first subset of compounds contains L-amino acids, the second subset contains D-amino acids, and the third subset contains both D- and L-amino acids. Five compounds exhibited

  我们报告了36种Sansalvamide A衍生物的合成及其对结肠癌HT-29细胞系（一种微卫星稳定（MSS）结肠癌细胞系）的生物活性。这三十六种化合物可分为三个子集，其中化合物的第一子集包含L-氨基酸，第二个子集包含D-氨基酸，而第三子集包含D-和L-氨基酸。五种化合物表现出出色的抑制活性（抑制率> 75％）。化合物的结构活性关系（SAR）确定了位置2或3上的单个D-氨基酸比Sansalvamide A肽的细胞毒性提高了10倍。这项工作强调了残基2和3的重要性以及D-氨基酸在该类化合物的非常规SAR中的作用。
• Stereoselective reduction of N-hydroxy-α-iminocarbonyl-oligopeptide methyl esters with Zn–MsOH
  作者：Naoki Kise、Shuji Takaoka、Masahiro Yamauchi、Nasuo Ueda

  DOI：10.1016/s0040-4039(02)01752-5

  日期：2002.10

  The reduction of N-hydroxy-α-imino esters with Zn–MsOH in THF afforded α-amino esters in high yields. The reduction of N-hydroxy-α-iminocarbonyl-oligopeptide methyl esters prepared from l-phenylalanine and l-leucine di-, tri-, tetrapeptides gave the corresponding S-formed oligopeptide methyl esters in moderate diastereoselectivities.

  在THF中用Zn-MsOH还原N-羟基-α-亚氨基酯可高产率获得α-氨基酯。由1-苯丙氨酸和1-亮氨酸二-，三-，四肽制备的N-羟基-α-亚氨基羰基-寡肽甲酯的还原得到中等中等非对映选择性的相应的S-形成的寡肽甲酯。
• Synthesis of Second-Generation Sansalvamide A Derivatives: Novel Templates as Potential Antitumor Agents
  作者：Rodrigo A. Rodriguez、Po-Shen Pan、Chung-Mao Pan、Suchitra Ravula、Stephanie Lapera、Erinprit K. Singh、Thomas J. Styers、Joseph D. Brown、Julia Cajica、Emily Parry、Katerina Otrubova、Shelli R. McAlpine

  DOI：10.1021/jo061830j

  日期：2007.3.1

  We report the synthesis of 34 second-generation Sansalvamide A derivatives. San A derivatives have unique anticancer properties and target multiple cancers, including colon, pancreatic, breast, prostate, and melanoma. As novel templates, the derivatives described herein explore the role of stereochemistry, amide bond geometry, transannular hydrogen bonding, and polarity on antitumor potency. Testing the chemotherapeutic activity of these derivatives against multiple cancer cell lines will provide clear structural motifs and identify conformational space that is important for cytotoxicity. The 34 compounds presented are divided into six series, where five series involve the insertion of D-amino acids in conjunction with four structural features at each of the five positions of the macrocycle. The sixth series involves comparison between all L- and all D-amino acid derivatives with N-methyls placed at each position around the macrocyclic core. The four structural features explored in conjunction with D-amino acids include N-methyl amino acids, aromatic amino acids, polar amino acids, and hydrophobic alkyl amino acids.
• Comprehensive Study of Sansalvamide A Derivatives and their Structure–Activity Relationships against Drug-Resistant Colon Cancer Cell Lines
  作者：Katerina Otrubova、Gerald Lushington、David Vander Velde、Kathleen L. McGuire、Shelli R. McAlpine

  DOI：10.1021/jm070731a

  日期：2008.2.1

  We report an extensive structure-activity relationship (SAR) of 62 compounds active against two drug-resistant colon cancer cell lines. Our comprehensive evaluation of two generations of compounds utilizes SAR, NMR, and molecular modeling to evaluate the key 3D features of potent compounds. Of the seven most potent compounds reported here, five are second-generation, emphasizing our ability to incorporate potent features found in the first generation and utilize their structures to design potency into the second generation. These analogs share no structural homology to current colon cancer drugs, are cytotoxic at levels on par with existing drugs treating other cancers, and demonstrate selectivity for drug-resistant colon cancer cell lines over noncancerous cell lines. Thus, we have established sansalvamide A as an excellent lead for treating, multiple drug-resistant colon cancers.
• Design and synthesis of Hsp90 inhibitors: Exploring the SAR of Sansalvamide A derivatives
  作者：Robert P. Sellers、Leslie D. Alexander、Victoria A. Johnson、Chun-Chieh Lin、Jeremiah Savage、Ricardo Corral、Jason Moss、Tim S. Slugocki、Erinprit K. Singh、Melinda R. Davis、Suchitra Ravula、Jamie E. Spicer、Jenna L. Oelrich、Andrea Thornquist、Chung-Mao Pan、Shelli R. McAlpine

  DOI：10.1016/j.bmc.2010.07.042

  日期：2010.9

  Utilizing the structure-activity relationship we have developed during the synthesis of the first two generations and mechanism of action studies that point to the interaction of these molecules with the key oncogenic protein Hsp90, we report here the design of 32 new Sansalvamide A derivatives and their synthesis. Our new structures, designed from previously reported potent compounds, were tested for cytotoxicity on the HCT116 colon cancer cell line, and their binding to the biological target was analyzed using computational studies involving blind docking of derivatives using Autodock. Further, we show new evidence that our molecules bind directly to Hsp90 and modulate Hsp90's binding with client proteins. Finally, we demonstrate that we have integrated good ADME properties into a new derivative. Published by Elsevier Ltd.