2(R)-<5(R)-<1(S)-<(tert-butyloxycarbonyl)amino>-2-cyclohexylethyl>-2,2-dimethyl-4(R)-dioxolanyl>-3-methylbutanoic acid | 112190-45-1

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: 2(R)-<5(R)-<1(S)-<(tert-butyloxycarbonyl)amino>-2-cyclohexylethyl>-2,2-dimethyl-4(R)-dioxolanyl>-3-methylbutanoic acid
• 英文别名: (2R)-2-[(4R,5R)-5-[(1S)-2-cyclohexyl-1-[(2-methylpropan-2-yl)oxycarbonylamino]ethyl]-2,2-dimethyl-1,3-dioxolan-4-yl]-3-methylbutanoic acid
• CAS: 112190-45-1
• 化学式: C₂₃H₄₁NO₆
• 分子量: 427.582
• InChiKey: OAELQKGMGHSJQA-WJFTUGDTSA-N

物化性质

• 沸点：
  546.2±25.0 °C(Predicted)
• 密度：
  1.062±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.73
• 重原子数：
  30.0
• 可旋转键数：
  7.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.91
• 拓扑面积：
  94.09
• 氢给体数：
  2.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  2(R)-<5(R)-<1(S)-<(tert-butyloxycarbonyl)amino>-2-cyclohexylethyl>-2,2-dimethyl-4(R)-dioxolanyl>-3-methylbutanoic acid 在 盐酸 、 ethandithiol 、 氰基磷酸二乙酯 、 N,N-二异丙基乙胺 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 8.0h， 生成 3-{2-[2-(2-Methoxy-ethoxy)-ethoxy]-ethoxy}-pyridine-2-carboxylic acid [(1S,2R,3R,4R)-1-cyclohexylmethyl-2,3-dihydroxy-4-((1S,2R)-2-hydroxy-indan-1-ylcarbamoyl)-5-methyl-hexyl]-amide
  参考文献：
  名称：

  来自人类免疫缺陷病毒的蛋白酶的抑制剂：一系列含有二羟基乙烯过渡态等排体的化合物的合成，酶抑制和抗病毒活性。

  摘要：

  制备了许多含有二羟基乙烯等排物的潜在HIV蛋白酶抑制肽，并评估了它们在细胞培养物中的酶结合亲和力和抗病毒活性。从先前报道的活性肽A的模板中，评估在N-和C-末端基团上的修饰以潜在维持所得肽的良好抑制活性。在发现的活性肽中，肽X显示出有效的酶抑制活性。有趣的是，先前报道的用于制备非常活性的HIV蛋白酶抑制肽的有效的1（S）-氨基-2（R）-羟基茚满C-末端基团不能应用于肽XVIII的模板。以肽A的X射线晶体结构为起点，研究了肽XVIII的分子模型，以便研究活性部位裂口中肽XVIII的可能构象。获得了肽A和XVIII的相对结合构象，尽管在本报告中对许多同类肽的结合亲和力差的原因尚不十分清楚。然而，更重要的是，发现肽XVIII在HIV-1 / PBMC分析中显示出比参考肽A更有效的抗病毒活性，参考肽A先前据报道在该分析中的功效与逆转录酶抑制剂AZT大致相等。尽管在本报告中对许多同类肽的结合亲和力

  DOI：

  10.1021/jm00060a001
• 作为产物：
  描述：

  4(R)-methyl-3-(1-oxo-3-methylbutyl)-5(S)-phenyl-2-oxazolidinone 在 ruthenium trichloride 、 过碘酸 作用下， 以 四氯化碳 、 水 、 乙腈 为溶剂， 反应 2.0h， 生成 2(R)-<5(R)-<1(S)-<(tert-butyloxycarbonyl)amino>-2-cyclohexylethyl>-2,2-dimethyl-4(R)-dioxolanyl>-3-methylbutanoic acid
  参考文献：
  名称：

  Inhibitors of the protease from human immunodeficiency virus: design and modeling of a compound containing a dihydroxyethylene isostere insert with high binding affinity and effective antiviral activity

  摘要：

  The peptidomimetic template and the dihydroxyethylene isostere insert that were applied successfully to the design of renin inhibitors have been extended to the related protease from human immunodeficiency virus (HIV). The present report describes the structure-activity study leading to the identification of an inhibitor with a K(i) of < 1 nM for the HIV type-1 protease (compound II). This compound, containing a diol insert, is highly effective in blocking polyprotein processing in in vitro cell culture assays. Results obtained from kinetic analysis, studies of the stereochemistry of the insert, and modeling have led to insights as to the requisites involved in the active site-inhibitor interaction.

  DOI：

  10.1021/jm00112a005

文献信息

• Evaluation of a vitamin-cloaking strategy for oligopeptide therapeutics: biotinylated HIV-1 protease inhibitors
  作者：I. Islam、K. Y. Ng、K. T. Chong、T. J. McQuade、J. O. Hui、K. F. Wilkinson、B. D. Rush、M. J. Ruwart、R. T. Borchardt、J. F. Fisher

  DOI：10.1021/jm00028a013

  日期：1994.1

  The outstanding limitations to the oligopeptide as a therapeutic agent are poor oral availability and rapid biliary clearance. To address these concerns a series of eight peptidic HIV-1 protease inhibitors containing the structural segment of the vitamin biotin have been prepared. These have been evaluated with regard to the hypothesis that this vitamin would cloak the peptidic character of these oligopeptides, and thus impart to these inhibitors the potential for absorption and distribution via biotin transporters and receptors. By iterative optimization about a -Chal psi[CH- (OH)CH(OH)]Val- core inhibitory insert, three particularly potent inhibitors (K-i less than or equal to 10 nM) of the HIV-1 protease were obtained. Although excellent cell culture antiviral activity is observed for other peptidic protease inhibitors of comparable affinity, none in this series exhibited satisfactory antiviral activity. This failure is-attributed to the incompatibility of the hydrophilic and hydrogen-bonding biotin segment, with the facile membrane permeability and intracellular access presumably required for antiviral activity. The ability of the biotin to cloak the peptide, and thus render the overall appearance of the conjugate as that of a vitamin, was evaluated. Four of this series were evaluated for recognition by the Caco-2 cell intestinal biotin transporter, None inhibited competitively biotin uptake, indicating a lack of recognition. A vitamin may bind to a specific protein carrier, and thus attain an improved serum profile (by resistance to biliary clearance) and advantageous delivery to cells. Therefore, the serum concentrations of three were evaluated following an iv bolus in a rat model for serum clearance. One of the three protease inhibitors (L-idonamide, 6-cyclohexyl-2,5,6-trideoxy-2-(1-methylethyl)-5-[[3-methyl-1-oxo-2-[[5-(hexahydro-2-oxo-1H-thieno[3,4-d]imidazol-4-yl)-1-oxopentyl]amino]butyl]amino]-N-[2-methyl-1-[[(2-pyridinylmethyl)amino] carbonyl]butyl]-, [3aS-[3a alpha,4 beta(1R*,2R*;3R*),6a alpha]]-) sustained a more than 5-fold increase in serum concentration at all time points relative to the benchmark structure. The remaining two had serum concentrations at least equal to the benchmark, suggestive of improved resistance to clearance. One(L-idonamide, 6-cyclohexyl-2,5,6-trideoxy-5-[[2-[[5-(hexahydro-2-oxo-1H-thieno-[3,4-d]imidazol-4-yl)pentyl]thio]benzoyl]amino]-2-(1-methylethyl)-N-[2-methyl-1-[[(2-pyridinyl- methyl)amino]carbonyl]butyl]-, [3aS-[3a alpha,4 beta(1R*,2R*),6a alpha]]-) was prepared as a complex with the biotin-binding protein avidin. Avidin may resemble an endogenous serum biotin carrier protein. The antiviral activity (evaluated in an H9-HTLV(IIIB) acute HIV-1 infection assay) of the inhibitor and the avidin complex was identical. This suggests that the avidin-inhibitor complex is capable of cell internalization. Although the weak antiviral activity of these biotinylated inhibitors precludes consideration as practical HIV therapeutics, the overall data remain suggestive of vitamin cloaking of oligopeptides as a strategy of potential value.