N-Boc-(S)-Val-(R)-boroPro (1S,2S,3R,5S)-pinanediol ester | 149716-75-6

• 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-(S)-Val-(R)-boroPro (1S,2S,3R,5S)-pinanediol ester
• 英文别名: tert-butyl N-[(2S)-3-methyl-1-oxo-1-[(2R)-2-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]pyrrolidin-1-yl]butan-2-yl]carbamate
• CAS: 149716-75-6
• 化学式: C₂₄H₄₁BN₂O₅
• 分子量: 448.411
• InChiKey: GEBWAJNTTBAAGK-GVJYWCCQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.79
• 重原子数：
  32
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.92
• 拓扑面积：
  77.1
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N-Boc-(S)-Val-(R)-boroPro (1S,2S,3R,5S)-pinanediol ester 在 三氯化硼 、 水 作用下， 以 二氯甲烷 为溶剂， 反应 1.0h， 生成 [(2R)-1-[(2S)-2-氨基-3-甲基丁酰基]吡咯烷-2-基]硼酸
  参考文献：
  名称：

  Identification of Selective and Potent Inhibitors of Fibroblast Activation Protein and Prolyl Oligopeptidase

  摘要：

  Fibroblast activation protein (FAP) is a serine protease selectively expressed on reactive stromal fibroblasts of epithelial carcinomas. It is widely believed to play a role in tumor invasion and metastasis and therefore to represent a potential new drug target for cancer. Investigation into its biological function, however, has been hampered by the current unavailability of selective inhibitors. The challenge has been in identifying inhibitors that are selective for PAP over both the dipeptidyl peptidases (DPPs), with which it shares exopeptidase specificity, and prolyl oligopeptidase (PREP), with which it shares endopeptidase specificity. Here, we report the first potent FAP inhibitor with selectivity over both the DPPs and PREP, N-(pyridine-4-carbonyl)-D-Ala-boroPro (ARI-3099, 6). We also report a similarly potent and selective PREP inhibitor, N-(pyridine-3-carbonyl)-Val-boroPro (ARI-3531, 22). Both are boronic acid based inhibitors, demonstrating that high selectivity can be achieved using this electrophile. The inhibitors are stable, easy to synthesize, and should prove to be useful in helping to elucidate the biological functions of these two unique and interesting enzymes, as well as their potential as drug targets.

  DOI：

  10.1021/jm400351a
• 作为产物：
  描述：

  (R)-2-吡咯烷硼酸蒎烷二醇酯盐酸盐 、 N-Boc-L-缬氨酸 在 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 以92%的产率得到N-Boc-(S)-Val-(R)-boroPro (1S,2S,3R,5S)-pinanediol ester
  参考文献：
  名称：

  Inhibition of Dpp8/9 Activates the Nlrp1b Inflammasome

  摘要：

  Val-boroPro (PT-100, Talabostat) induces powerful anti-tumor immune responses in syngeneic cancer models, but its mechanism of action has not yet been established. Val-boroPro is a non-selective inhibitor of post-proline-cleaving serine proteases, and the inhibition of the highly related cytosolic serine proteases Dpp8 and Dpp9 (Dpp8/9) by Val-boroPro was recently demonstrated to trigger an immunostimulatory form of programmed cell death known as pyroptosis selectively in monocytes and macrophages. Here we show that Dpp8/9 inhibition activates the inflammasome sensor protein Nlrp1b, which in turn activates pro-caspase-1 to mediate pyroptosis. This work reveals a previously unrecognized mechanism for activating an innate immune pattern recognition receptor and suggests that Dpp8/9 serve as an intracellular checkpoint to restrain Nlrp1b and the innate immune system.

  DOI：

  10.1016/j.chembiol.2017.12.013

文献信息

• Pro-Soft Val-boroPro: A Strategy for Enhancing in Vivo Performance of Boronic Acid Inhibitors of Serine Proteases
  作者：Sarah E. Poplawski、Jack H. Lai、David G. Sanford、James L. Sudmeier, Wengen Wu、William W. Bachovchin

  DOI：10.1021/jm100972f

  日期：2011.4.14

  Val-boroPro, 1, is a potent, but relatively nonspecific inhibitor of the prolyl peptidases. It has antihyperglycemic activity from inhibition of DPPIV but also striking anticancer activity and a toxicity for which the mechanisms are unknown. 1 cyclizes at physiological pH, which attenuates its inhibitory potency > 100-fold, which is a "soft drug" effect. Here we show that this phenomenon can be exploited to create prodrugs with unique properties and potential for selective in vivo targeting. Enzyme-mediated release delivers 1 to the target in the active form at physiological pH; cyclization attenuates systemic pharmacological effects from subsequent diffusion. This "pro-soft" design is demonstrated with a construct activated by and targeted to DPPIV, including in vivo results showing improved antihyperglycemic activity and reduced toxicity relative to I. Pro-soft derivatives of 1 can help to illuminate the mechanisms underlying the three biological activities, or to help localize 1 at a tumor and thereby lead to improved anticancer agents with reduced toxicity. The design concept can also be applied to a variety of other boronic acid inhibitors.