4-deoxy-4α-phorbol

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 异戊烯醇脂质
• 英文名称: 4-deoxy-4α-phorbol
• 英文别名: 4-deoxy-4alpha-phorbol；Deoxyphorbol；(1R,2R,6R,10S,11R,13S,14R,15R)-1,13,14-trihydroxy-8-(hydroxymethyl)-4,12,12,15-tetramethyltetracyclo[8.5.0.02,6.011,13]pentadeca-3,8-dien-5-one
• 化学式: C₂₀H₂₈O₅
• 分子量: 348.439
• InChiKey: RTJAYUGZUOLFMY-YLKPGCRESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.1
• 重原子数：
  25
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  98
• 氢给体数：
  4
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-deoxy-4α-phorbol 在 吡啶 作用下， 反应 25.0h， 生成 12-O-decanoyl(4-deoxy-4α-phorbol) 13,20-diacetate
  参考文献：
  名称：

  Inhibition of Cytopathic Effect of Human Immunodeficiency Virus Type-1 by Various Phorbol Derivatives.

  摘要：

  四十八种分子的phorbol（9）和isophorbol（14）被评估其对人类免疫缺陷病毒（HIV）-1诱导的细胞病变效应（CPE）在MT-4细胞上的抑制作用，以及其激活蛋白激酶C（PKC）的能力，分别作为抗HIV-1和肿瘤促进活性的指标。在这些化合物中，12-O-十四酸酯phorbol 13-醋酸酯（8）和12-O-乙酰phorbol 13-癸酸酯（6）显示出对CPE的最强抑制作用。前者也表现出最强的PKC激活活性，而后者在10 ng/ml时未显示活性。这两种活性通常是在具有A/B反式构型的phorbol衍生物中观察到的，而不是在具有A/B顺式构型的isophorbol衍生物中。对phorbol衍生物中的20-OH进行乙酰化显著降低了对CPE的抑制，正如在12-O-、20-O-二乙酰phorbol 13-癸酸酯（6a）（IC100=15.6 μg/ml）与化合物6（IC100=0.0076 μg/ml）之间的对比，以及在12-O-十四酸酯phorbol 13,20-二乙酸酯（8a）（IC100=15.6 μg/ml）与12-O-十四酸酯phorbol 13-醋酸酯（8）（IC100=0.00048 μg/ml）之间的对比，除了在12-O-癸酸酯phorbol 13-(2-甲基丁酸酯)（4）和phorbol 12,13-二乙酸酯（9c）情况下。C-3碳基团的去除突然降低了对CPE的抑制，正如在3β-羟基phorbol 12,13,20-三乙酸酯（9f）（IC100=500 μg/ml）与phorbol 12,13,20-三乙酸酯（9d）（IC100=62.5 μg/ml）之间的对比所观察到的。尽管8在抑制CPE和激活PKC方面具有同等效力，但20-OH的乙酰化和4-OH的甲基化（如在8a和4-O-甲基-12-O-十四酸酯phorbol 13,20-二乙酸酯（8b）中）都急剧降低了这两种活性。另一方面，其位置异构体（12-O-乙酰phorbol 13-十四酸酯（8c）则表现出两种活性均无）。在8中去除长的酰基团导致这两种活性的显著丧失，如在phorbol 13-醋酸酯（9b）中所示。在12-O-乙酰-13-O-酰基phorbol衍生物中，6显示出对CPE的最高抑制，C-13处具有十二酸酯残基。脂肪酸碳链数量的增加和减少均导致对CPE抑制作用的显著降低。

  DOI：

  10.1248/cpb.50.523
• 作为产物：
  描述：

  12-O-,13-O-,20-O-triacetyl(4-deoxy-4α-phorbol) 在 水 、 sodium methylate 作用下， 反应 1.0h， 以80 mg的产率得到4-deoxy-4α-phorbol
  参考文献：
  名称：

  Synthesis and Biological Evaluation of 12-Aminoacylphorboids

  摘要：

  Spurred by the paradoxical anti-inflammatory activity of some aminoacylphorbol derivatives, the naturally occuring and epimeric N,N-dimethylvalinoyl-4 alpha-4-deoxyphorbol derivatives 3b and 3d have been prepared from 4 alpha-4-deoxyphorbol (3e), a byproduct of the isolation of phorbol from Croton oil and a phorboid polyol so far largely overlooked in terms of biological activity. The configuration of the side chain stereocenter was confirmed for both natural products and to investigate the side chain structure-activity relationships within this class of compounds, their corresponding, N,N-dimethylglycinate (3g) and nor (3h) and di-nor derivatives (3i, 3j) were also prepared. By using a PKC-sensitive model of, HIV-1 latency (activation of HIV- gene expression in Jurkat-LAT-GFP cells), it was found that both 3b and 3d can activate PKC-dependent responses, while a series of experiments with isoform-spcefic PKC inhibitors showed that these compounds target PKC alpha and -delta. Both N,N-dimethylation and the presence of side chain alpha-substitution were critical for activity. Selective PKC binding, rather than COX inhibition, might explain the paradoxical anti-inflammatory activity of extracts containing aminoacylphorboids in the mouse ear edema assay.

  DOI：

  10.1021/np9006553

文献信息

• Modulation of the Transient Receptor Potential Vanilloid Channel TRPV4 by 4α-Phorbol Esters: A Structure−Activity Study
  作者：Thomas Kjær Klausen、Alberto Pagani、Alberto Minassi、Abdellah Ech-Chahad、Jean Prenen、Grzegorz Owsianik、Else Kay Hoffmann、Stine Falsig Pedersen、Giovanni Appendino、Bernd Nilius

  DOI：10.1021/jm9001007

  日期：2009.5.14

  The mechanism of activation of the transient receptor potential vanilloid 4 (TRPV4) channel by 4 alpha-phorbol esters was investigated by combining information from chemical modification of 4 alpha-phorbol-didecanoate (4 alpha-PDD, 2a), site-directed mutagenesis, Ca2+ imaging, and electrophysiology. Binding of 4 alpha-phorbol esters occurs in a loop in the TM3-TM4 domain of TRPV4 that is analogous to the capsaicin binding site of TRPV1, and the ester decoration of ring C and the A,B ring junction are critical for activity. The lipophilic ester groups on ring C serve mainly as a steering element, affecting the orientation of the diterpenoid core into the ligand binding pocket, while the nature of the A,B ring junction plays an essential role in the Ca2+-dependence of the TRPV4 response. Taken together, our results show that 4 alpha-phorbol is a useful template to investigate the molecular details of TRPV4 activation by small molecules and obtain information for the rational design of structurally simpler ligands for this ion channel.