JAV-146 | 139727-68-7

• 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: JAV-146
• 英文别名: (+)-octahydro-3,6α-dimethyl-3,12-epoxy-9β-(2'-phenylpropyl)-12H-pyrano[4,3-j]-1,2-benzodioxepin-10(3H)-one；(1R,4S,5R,8S,9R,12S,13R)-1,5-dimethyl-9-(3-phenylpropyl)-11,14,15,16-tetraoxatetracyclo[10.3.1.04,13.08,13]hexadecan-10-one
• CAS: 139727-68-7
• 化学式: C₂₃H₃₀O₅
• 分子量: 386.488
• InChiKey: SBCGDCBRWXAAIF-WWYMACMNSA-N

物化性质

• 沸点：
  510.8±50.0 °C(Predicted)
• 密度：
  1.21±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  28
• 可旋转键数：
  4
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.7
• 拓扑面积：
  54
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  JAV-146 在 sodium tetrahydroborate 、 三氟化硼乙醚 作用下， 以 四氢呋喃 为溶剂， 以50%的产率得到(+)-octahydro-3,6α-dimethyl-3,12-epoxy-9β-(3'-phenylpropyl)-12H-pyrano[4,3j]-1,2-benzodioxepin
  参考文献：
  名称：

  抗疟药青蒿素的构效关系。5. 在 C-3 和 C-9 处取代的 10-脱氧青蒿素类似物。

  摘要：

  10-脱氧青蒿素 3 的新型 3-和 9-取代类似物 (4-19) 是从相应的已知内酯通过硼氢化钠和三氟化硼乙醚合一锅还原制备的。在小规模反应中遇到了与这种非均相反应相关的重现性问题，因此寻求替代方法来减少这种反应。使用两步序列，包括用二异丁基氢化铝低温还原，然后在三乙基硅烷的存在下用三氟化硼醚合物脱氧，通过相应的中间体内酯将内酯转化为四氢吡喃的重现性更高。以这种方式，10-脱氧青蒿素（3）可以从青蒿素（1）中获得，总产率超过 95%。所有类似物都针对恶性疟原虫的 W-2 和 D-6 菌株进行了体外测试。一些类似物比天然产物 (+)-青蒿素 (1) 或 10-脱氧青蒿素 (3) 更具活性。讨论了与生物测定数据相关的常规构效关系。

  DOI：

  10.1021/jm9603577
• 作为产物：
  描述：

  青蒿素 在 偶氮二异丁腈 、 三正丁基氢锡 、 碳酸氢钠 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 间氯过氧苯甲酸 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 二氯甲烷 、 苯 为溶剂， 反应 21.0h， 生成 JAV-146
  参考文献：
  名称：

  Structure−Activity Relationships of the Antimalarial Agent Artemisinin. 8. Design, Synthesis, and CoMFA Studies toward the Development of Artemisinin-Based Drugs against Leishmaniasis and Malaria

  摘要：

  Artemisinin (1) and its analogues have been well studied for their antimalarial activity. Here we present the antimalarial activity of some novel C-9-modified artemisinin analogues synthesized using artemisitene as the key intermediate. Further, antileishmanial activity of more than 70 artemisinin derivatives against Leishmania donovani promastigotes is described for the first time. A comprehensive structure-activity relationship study using CoMFA is discussed. These analogues exhibited leishmanicidal activity in micromolar concentrations, and the overall activity profile appears to be similar to that against malaria. Substitution at the C-9beta position was shown to improve the activity in both cases. The 10-deoxo derivatives showed better activity compared to the corresponding lactones. In general, compounds with C-9alpha substitution exhibited lower antimalarial as well as antileishmanial activities compared to the corresponding C-9beta analogues. The importance of the peroxide group for the observed activity of these analogues against leishmania was evident from the fact that 1-deoxyartemisinin analogues did not exhibit antileishmanial activity. The study suggests the possibility of developing artemisinin analogues as potential drug candidates against both malaria and leishmaniasis.

  DOI：

  10.1021/jm030181q

文献信息

• Structure-activity relationships of the antimalarial agent artemisinin. 1. Synthesis and comparative molecular field analysis of C-9 analogs of artemisinin and 10-deoxoartemisinin
  作者：Mitchell A. Avery、Fenglan Gao、Wesley K. M. Chong、Sanjiv Mehrotra、Wilbur K. Milhous

  DOI：10.1021/jm00078a017

  日期：1993.12

  series of C-9 beta-substituted artemisinin analogs (2-21) were synthesized via dianion alkylation of the total synthetic intermediate 57 followed by subsequent ozonolysis/acidification, or by alkylation of the enolate derived from (+)-9-desmethylartemisinin, 2. Inactive acyclic analogs 22 and 23 were synthesized by nucleophilic epoxide opening and the ring contracted analog 24 was prepared by an alternate

  一系列 C-9 β 取代的青蒿素类似物 (2-21) 是通过总合成中间体 57 的二价阴离子烷基化合成的，随后进行臭氧分解/酸化，或通过从 (+)-9-去甲基青蒿素衍生的烯醇化物的烷基化， 2.通过亲核环氧化物开环合成无活性无环类似物22和23，通过替代路线制备环收缩类似物24。10-Deoxo-9-烷基衍生物68和70是从制备9-烷基衍生物的中间体集中合成的。在抗药性恶性疟原虫的 W-2 和 D-6 克隆中进行体外生物测定。9-烷基内酯衍生物的比较分子场分析 (CoMFA) 提供了一个具有交叉验证 r2 = 0.793 的模型。包含无活性的 1-脱氧青蒿素类似物 26-42 提供了一个值为 0.857 的模型。使用 CoMFA 模型以良好的准确性预测了许多其他不同结构的类似物 (43-56) 的活性。
• [EN] ARTEMISININ-BASED PEROXIDE COMPOUNDS AS BROAD SPECTRUM ANTI-INFECTIVE AGENTS<br/>[FR] COMPOSES DE PEROXYDE A BASE D'ARTEMISININE TENANT LIEU D'AGENTS ANTI-INFECTIEUX A LARGE SPECTRE
  申请人：UNIV MISSISSIPI

  公开号：WO2003095444A1

  公开（公告）日：2003-11-20

  Described herein is the synthesis, bioassay results and utility of new C-9 and C-10 substituted artemisinin derivatives with easily functionalizable groups attached to the artemisinin skeleton through carbon chain or heteroatoms. Described also is the demonstration of this class of compounds for their broad-spectrum anti-parasitic activity. Certain of these analogs possess noticeable cytotoxicity deliberately focused on treatment of cancerous diseases.

  本文描述了合成、生物测定结果以及新的C-9和C-10取代青蒿素衍生物的用途，这些衍生物具有易于功能化的基团，通过碳链或杂原子连接到青蒿素骨架上。同时还展示了这类化合物在广谱抗寄生虫活性方面的表现。其中一些类似物具有明显的细胞毒性，专门用于治疗癌症性疾病。
• Copper(I) Catalyzed Conjugate Addition of Grignard Reagents to Acrylic Acids: Homologation of Artemisinic Acid and Subsequent Conversion to 9-Substituted Artemisinin Analogs
  作者：Jeffrey A Vroman、Ikhlas A Khan、Mitchell A Avery

  DOI：10.1016/s0040-4039(97)01428-7

  日期：1997.9

  A new route to novel 9-substituted-10-deoxoartemisinin analogs (13, 14) was developed employing photoxygenation of homologated derivatives of artemisinic acid (9, 10). Conjugate addition to the acrylate moiety of artemisinic acid 2 was made possible by in situ protection as a silyl ester, Cu(I)-catalyzed 1,4-addition of RMgX, and deprotection. © 1997 Elsevier Science Ltd.

  利用青蒿酸的同系衍生物（9、10）的光合作用，开发了一种新的9-取代-10-脱氧青蒿素类似物的新途径（13、14）。通过原位保护甲硅烷基酯，Cu（I）催化的RMgX的1,4-加成反应和脱保护作用，可以使青蒿酸2的丙烯酸酯部分进行共轭加成。©1997爱思唯尔科学有限公司。
• Structure−Activity Relationships of the Antimalarial Agent Artemisinin. 7. Direct Modification of (+)-Artemisinin and In Vivo Antimalarial Screening of New, Potential Preclinical Antimalarial Candidates
  作者：Mitchell A. Avery、Maria Alvim-Gaston、Jeffrey A. Vroman、Baogen Wu、Arba Ager、Wallace Peters、Brian L. Robinson、William Charman

  DOI：10.1021/jm020142z

  日期：2002.9.1

  On the basis of earlier reported quantitative structure-activity relationship studies, a series of 9beta-16-(arylalkyl)-10-deoxoartemisinins were proposed for synthesis. Several of the new compounds 7 and 10-14 were synthesized, employing the key synthetic intermediate 23. In a second approach, the natural product (+)-artemisinic acid was utilized as an acceptor for conjugate addition, and the resultant homologated acids were subjected to singlet oxygenation and acid treatment to provide artemisinin analogues. Under a new approach, we developed A one step reaction for the interconversion of artemisinin 1 into artemisitene 22 that did not employ selenium-based reagents and found that 2-arylethyliodides would undergo facile radical-induced conjugate addition to the exomethylene lactone of 22 in good yield. The lactone carbonyls, were removed sequentially by diisobutylaluminum hydride reduction followed directly by a second reduction (BF3-etherate/Et3SiH) to afford the desired corresponding pyrans. Six additional halogen-substituted aromatic side chains were installed via 22 furnishing the bioassay candidates 15-20. The analogues were examined for in vitro antimalarial activity in the W-2 and D-6 clones of Plasmodium falciparum and were additionally tested. in vivo in Plasmodium berghei- and/or Plasmodium yoelii-infected mice. Several of the compounds emerged as highly potent orally active candidates without obvious toxicity, Of these, two were chosen for pharmacokinetic evaluation, 14 and 17.