A43-D | 161795-96-6

• 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: A43-D
• 英文别名: [(1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-(7-aminoheptylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-prop-1-en-2-yl-1,2,3,4,5,6,7,7a,9,10,11,11b,12,13,13a,13b-hexadecahydrocyclopenta[a]chrysen-9-yl] acetate
• CAS: 161795-96-6
• 化学式: C₃₉H₆₆N₂O₃
• 分子量: 610.965
• InChiKey: ITTASPNNRJBJEH-WKZPCIAFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  9.6
• 重原子数：
  44
• 可旋转键数：
  11
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.9
• 拓扑面积：
  81.4
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  A43-D 在 甲醇 、 sodium hydroxide 作用下， 以 四氢呋喃 为溶剂， 生成
  参考文献：
  名称：

  用于设计和合成作为HIV-1 gp41融合核心形成抑制剂的桦木酸-多酚偶联物的两亲偶联方法。

  摘要：

  探索HIV-1 gp41融合核心形成的有效抑制剂是发现用于治疗HIV-1感染的小分子HIV-1进入抑制剂的有前途的策略。在本文中，设计了一系列新型的桦木酸-多酚共轭物，并通过分子模型指导了在gp41 N端七肽重复序列（NHR）三聚体上凹槽中的桦木酸（BA）和酚式没食子酰基/咖啡酰基团的结合盘绕线圈。这些缀合物是通过将没食子酰基和咖啡酰基团与BA在C‐28位置缀合而合成的。使用尺寸排阻HPLC评估了它们对NHR肽N36和C末端七肽重复序列（CHR）肽C34之间的HIV gp41六螺旋束（6-HB）形成的抑制活性。发现带有没食子酰基的缀合物比母体化合物BA具有高出四到六倍的抑制活性，这表明它们可以用作靶向gp41的HIV-1融合/进入抑制剂。对BA及其衍生物的对接研究表明，疏水性和氢键结合口袋存在于gp41 NHR三聚体卷曲螺旋的凹槽中，有效的抑制剂应具有两亲结构，以与两个口袋协同相互作用。通

  DOI：

  10.1002/cmdc.201100149
• 作为产物：
  描述：

  白桦脂酸 在 吡啶 、 草酰氯 作用下， 以 二氯甲烷 为溶剂， 反应 0.5h， 生成 A43-D
  参考文献：
  名称：

  用于设计和合成作为HIV-1 gp41融合核心形成抑制剂的桦木酸-多酚偶联物的两亲偶联方法。

  摘要：

  探索HIV-1 gp41融合核心形成的有效抑制剂是发现用于治疗HIV-1感染的小分子HIV-1进入抑制剂的有前途的策略。在本文中，设计了一系列新型的桦木酸-多酚共轭物，并通过分子模型指导了在gp41 N端七肽重复序列（NHR）三聚体上凹槽中的桦木酸（BA）和酚式没食子酰基/咖啡酰基团的结合盘绕线圈。这些缀合物是通过将没食子酰基和咖啡酰基团与BA在C‐28位置缀合而合成的。使用尺寸排阻HPLC评估了它们对NHR肽N36和C末端七肽重复序列（CHR）肽C34之间的HIV gp41六螺旋束（6-HB）形成的抑制活性。发现带有没食子酰基的缀合物比母体化合物BA具有高出四到六倍的抑制活性，这表明它们可以用作靶向gp41的HIV-1融合/进入抑制剂。对BA及其衍生物的对接研究表明，疏水性和氢键结合口袋存在于gp41 NHR三聚体卷曲螺旋的凹槽中，有效的抑制剂应具有两亲结构，以与两个口袋协同相互作用。通

  DOI：

  10.1002/cmdc.201100149

文献信息

• Synthesis and anti-HIV activity of bi-functional betulinic acid derivatives
  作者：Li Huang、Phong Ho、Kuo-Hsiung Lee、Chin-Ho Chen

  DOI：10.1016/j.bmc.2005.11.016

  日期：2006.4

  Betulinic acid (BA) derivatives with a side chain at C-3 can inhibit HIV-1 maturation. On the other hand, BA derivatives with a side chain at C-28 can block HIV-1 entry. In order to combine the anti-maturation and anti-entry activities in a single molecule, new bi-functional BA derivatives containing side chains at C-3 and C-28 have been synthesized. The most potent compound ([[N-[3beta-O-(3',3'-d

  在C-3处带有侧链的桦木酸（BA）衍生物可以抑制HIV-1的成熟。另一方面，在C-28带有侧链的BA衍生物可以阻止HIV-1进入。为了在单个分子中结合抗成熟和抗进入活性，已经合成了在C-3和C-28处含有侧链的新的双功能BA衍生物。最有效的化合物（[[[N- [3beta-O-（3'，3'-二甲基琥珀酰基）-lup-20（29）-en-28-oyl] -7-氨基庚基] -carBA moyl]甲烷抑制HIV -1在EC26为0.0026 microM时，效力至少是抗成熟铅化合物DSB或抗进入铅化合物IC9564的20倍。这种双功能BA衍生物对HIV的进入和成熟均具有活性。
• Betulinic Acid Derivatives:  A New Class of Specific Inhibitors of Human Immunodeficiency Virus Type 1 Entry
  作者：Françoise Soler、Christèle Poujade、Michel Evers、Jean-Christophe Carry、Yvette Hénin、Anne Bousseau、Thierry Huet、Rudi Pauwels、Erik De Clercq、Jean-François Mayaux、Jean-Bernard Le Pecq、Norbert Dereu

  DOI：10.1021/jm950669u

  日期：1996.1.1

  A novel series of omega-aminoalkanoic acid derivatives of betulinic acid were synthesized and evaluated for their activity against human immunodeficiency virus (HIV). The anti-HIV-1 activity of several members of this new series was found to be in the nanomolar range in CEM 4 and MT-4 cell cultures. The optimization of the omega-aminoalkanoic acid side chain is described. The presence of an amide function within the side chain was found important for optimal activity. RPR 103611 (14g), a statine derivative, was found to be inactive against HIV-1 protease, reverse transcriptase, and integrase as well as on gp120/CD4 binding. ''Time of addition'' experiments suggested interaction with an early step of HIV-1 replication. As syncytium formation, but not virus-cell binding, seems to be affected, betulinic acid derivatives are assumed to interact with the postbinding virus-cell fusion process.
• Synthesis of betulinic acid derivatives as entry inhibitors against HIV-1 and bevirimat-resistant HIV-1 variants
  作者：Zhao Dang、Keduo Qian、Phong Ho、Lei Zhu、Kuo-Hsiung Lee、Li Huang、Chin-Ho Chen

  DOI：10.1016/j.bmcl.2012.06.080

  日期：2012.8

  Betulinic acid derivatives modified at the C28 position are HIV-1entry inhibitors such as compound A43D; however, modified at the C3 position instead of C28 give HIV-1 maturation inhibitor such as bevirimat. Bevirimat exhibited promising pharmacokinetic profiles in clinical trials, but its effectiveness was compromised by the high baseline drug resistance of HIV-1 variants with polymorphism in the putative drug binding site. In an effort to determine whether the viruses with bevirimat resistant polymorphism also altered their sensitivities to the betulinic acid derivatives that inhibit HIV-1 entry, a series of new betulinic acid entry inhibitors were synthesized and tested for their activities against HIV-1 NL4-3 and NL4-3 variants resistant to bevirimat. The results show that the bevirimat resistant viruses were approximately 5- to10-fold more sensitive to three new glutamine ester derivatives (13, 15 and 38) and A43D in an HIV-1 multi-cycle replication assay. In contrast, the wild type NL4-3 and the bevirimat resistant variants were equally sensitive to the HIV-1 RT inhibitor AZT. In addition, these three new compounds markedly improved microsomal stability compared to A43D. (c) 2012 Elsevier Ltd. All rights reserved.
• New Betulinic Acid Derivatives for Bevirimat-Resistant Human Immunodeficiency Virus Type-1
  作者：Zhao Dang、Phong Ho、Lei Zhu、Keduo Qian、Kuo-Hsiung Lee、Li Huang、Chin-Ho Chen

  DOI：10.1021/jm3016969

  日期：2013.3.14

  Bevirimat (1, BVM) is an anti-HIV agent that blocks HIV-1 replication by interfering with HIV-1 Gag-SP1 processing at a late stage of viral maturation. However, clinical trials of 1 have revealed a high baseline drug resistance that is attributed to naturally occurring polymorphisms in HIV-1 Gag. To overcome the drug resistance, 28 new derivatives of 1 were synthesized and tested against compound 1-resistant (BVM-R) HIV-1 variants. Among them, compound 6 exhibited much improved activity against several HIV-1 strains carrying BVM-R polymorphisms. Compound 6 was at least 20-fold more potent than 1 against the replication of NL4-3/V370A, which carries the most prevalent clinical BVM-R polymorphism in HIV-1 Gag-SP1. Thus, compound 6 merits further development as a potential anti-AIDS clinical trial candidate.
• Betulinic Acid Derivatives as Human Immunodeficiency Virus Type 2 (HIV-2) Inhibitors
  作者：Zhao Dang、Weihong Lai、Keduo Qian、Phong Ho、Kuo-Hsiung Lee、Chin-Ho Chen、Li Huang

  DOI：10.1021/jm9004253

  日期：2009.12.10

  We previously reported that [[N-[3 beta-hydroxyllup-20(29)-en-28-oyl]-7-aminoheptyl]carbamoyl]methane (A43D, 4) was a potent HIV-1 entry inhibitor. However, 4 was inactive against HIV-2 virus, suggesting the structural requirements for targeting these two retroviruses are different. In this study, a series of new betulinic acid derivatives were synthesized, and some of them displayed selective anti-HIV-2 activity at nanomolar concentrations. In comparison to compounds with anti-HIV-1 activity, a shorter C-28 side chain is required for optimal anti-HIV-2 activity.