8-Hydroxymanzamine A | 154466-37-2

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 哈马拉生物碱
• 英文名称: 8-Hydroxymanzamine A
• 英文别名: (1R,2R,4R,5Z,12R,13S,16Z)-25-(8-hydroxy-9H-pyrido[3,4-b]indol-1-yl)-11,22-diazapentacyclo[11.11.2.12,22.02,12.04,11]heptacosa-5,16,25-trien-13-ol
• CAS: 154466-37-2
• 化学式: C₃₆H₄₄N₄O₂
• 分子量: 564.771
• InChiKey: AMSNINGPDSUBHZ-WAUQNXBMSA-N

物化性质

• 沸点：
  793.6±60.0 °C(Predicted)
• 密度：
  1.31±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  42
• 可旋转键数：
  1
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  75.6
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  8-Hydroxymanzamine A 在 palladium on activated charcoal 氢气 作用下， 以 乙醇 为溶剂， 反应 4.0h， 以51.7%的产率得到15,16,32,33-tetrahydro-8-hydroxymanzamine A
  参考文献：
  名称：

  Glycogen Synthase Kinase-3 (GSK-3) Inhibitory Activity and Structure–Activity Relationship (SAR) Studies of the Manzamine Alkaloids. Potential for Alzheimer’s Disease

  摘要：

  Manzamine A and related derivatives isolated from a common Indonesian sponge, Acanthostrongylophora, have been identified as a new class of GSK-3 beta inhibitors. The semisynthesis of new analogues and the first structure-activity relationship studies with GSK-3 beta are also reported. Moreover, manzamine A proved to be effective in decreasing tau hyperphosphorylation in human neuroblastoma cell lines, a demonstration of its ability to enter cells and interfere with tau pathology. Inhibition studies of manzamine A against a selected panel of five different kinases related to GSK-3 beta, specifically CDK-1, PKA, CDK-5, MAPK, and GSK-3 alpha, show the specific inhibition of manzamine A on GSK-3 beta and CDK-5, the two kinases involved in tau pathological hyperphosphorylation. These results suggest that manzamine A constitutes a promising scaffold from which more potent and selective GSK-3 inhibitors could be designed as potential therapeutic agents for Alzheimer's disease.

  DOI：

  10.1021/np060092r

文献信息

• Structure−Activity Relationship and Mechanism of Action Studies of Manzamine Analogues for the Control of Neuroinflammation and Cerebral Infections
  作者：Jiangnan Peng、Sucheta Kudrimoti、Sivaprakasam Prasanna、Srinivas Odde、Robert J. Doerksen、Hari K Pennaka、Yeun-Mun Choo、Karumanchi V. Rao、Babu L. Tekwani、Vamsi Madgula、Shabana I. Khan、Bin Wang、Alejandro M. S. Mayer、Melissa R. Jacob、Lan Chun Tu、Jürg Gertsch、Mark T. Hamann

  DOI：10.1021/jm900672t

  日期：2010.1.14

  Structure−activity relationship studies were carried out by chemical modification of manzamine A (1), 8-hydroxymanzamine A (2), manzamine F (14), and ircinal isolated from the sponge Acanthostrongylophora. The derived analogues were evaluated for antimalarial, antimicrobial, and antineuroinflammatory activities. Several modified products exhibited potent and improved in vitro antineuroinflammatory, antimicrobial

  构效关系研究是通过对曼扎明 A ( 1 )、8-羟基曼扎明A ( 2 )、曼扎明 F ( 14 ) 和从海绵棘圆线虫中分离的 ircinal 进行化学修饰来进行的。对衍生类似物的抗疟、抗微生物和抗神经炎症活性进行了评估。几种改良产品在体外表现出有效和改进的抗神经炎症、抗菌和抗疟活性。在多剂量和单剂量体内实验中，与氯喹相比，图1对疟疾的活性有所提高。小鼠疟疾的 100% 治愈率揭示了显着的抗疟潜力，一次给药 100 mg/kg 的1. Manzamines 的强效抗神经炎症活性将为预防和治疗脑部感染（例如，隐球菌和疟原虫）提供巨大的益处。此外，在使用 MDR-MDCK 单层的体外模型中，1显示可渗透穿过血脑屏障 (BBB)。对接研究支持2与糖原合成激酶-3β (GSK-3β) 的 ATP 非竞争性口袋结合，这是 manzamines 的推定目标。基于此处介绍的结果，将有可能围绕这种天然产物支
• Semisynthetic Studies on the Manzamine Alkaloids
  作者：Khalid A. El Sayed、Ashraf A. Khalil、Muhammad Yousaf、Guillermo Labadie、Gundluru M. Kumar、Scott G. Franzblau、Alejandro M. S. Mayer、Mitchell A. Avery、Mark T. Hamann

  DOI：10.1021/np0703702

  日期：2008.3.1

  Chemical transformation studies were conducted on (-)-8-hydroxymanzamine A ( 1), (-)-manzamine F ( 2), manzamine A ( 3), and (+)-8-hydroxymanzamine A ( 4), isolated from Indo-Pacific Acanthostrongylophora sponges. Thirteen new semisynthetic manzamine derivatives, including four Delta (34,35) manzamines ( 5, 6, 8, and 9) and the unprecedented manzamine derivative 17, are reported. The potent in vitro

  对从印度分离得到的 (-)-8-羟基曼扎明 A (1)、(-)-羟基曼扎明 F (2)、曼扎明 A (3) 和 (+)-8-羟基曼扎明 A (4) 进行了化学转化研究-太平洋棘圆线虫海绵。报道了 13 种新的半合成曼扎胺衍生物，包括四种 Delta (34,35) 曼扎胺（5、6、8 和 9）和前所未有的曼扎胺衍生物 17。展示了所获得的半合成曼扎胺针对激活的脑小胶质细胞和艾滋病机会性感染病原体结核分枝杆菌的有效体外活性。
• Kinetic Studies and Bioactivity of Potential Manzamine Prodrugs
  作者：Abbas Gholipour Shilabin、Noer Kasanah、Babu L. Tekwani、Mark T. Hamann

  DOI：10.1021/np800163u

  日期：2008.7.1

  effort to generate manzamine prodrugs with improved antimalarial activity and reduced GI toxicity, we prepared acetylated 8-hydroxymanzamine A analogues including 8-acetoxymanzamine A (3) and 8,12-diacetoxymanzamine A (4), and 8-methoxymanzamine A (5) beginning with 8-hydroxymanzamine A (2). The semisynthetic analogues were assayed for antimalarial and antimicrobial activities, cytotoxicity, and biological

  Manzamines 代表一类海洋天然产物，在控制疟疾方面显示出相当大的前景，但在高剂量口服时会导致啮齿动物胃肠道不适。为了产生具有改善的抗疟活性和降低 GI 毒性的 manzamine 前药，我们制备了乙酰化 8-羟基 manzamine A 类似物，包括 8-acetoxymanzamine A (3) 和 8,12-diacetoxymanzamine A (4) 和 8-methoxymanzamine A (5) ) 以 8-羟基曼扎明 A (2) 开头。测定了半合成类似物的抗疟和抗微生物活性、细胞毒性以及生物和化学稳定性。由于酯基的逐渐水解，研究了单乙酸酯 3 作为抗疟前药的应用。体外和体内生物测定表明，乙酰化类似物表现出显着的抗疟活性（IC50(3) 9.6-30 ng/mL），与母体分子相当；然而，当口服给药时，单乙酸酯 3 在 30 mg/kg 时实际上会产生更高的毒性。