7α,12α-diacetoxy-5β-cholan-24-oic acid-3-spiro-6'-(1',2',4',5'-tetraoxacyclohexane)-3'-spirocyclohexane | 452302-71-5

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 英文名称: 7α,12α-diacetoxy-5β-cholan-24-oic acid-3-spiro-6'-(1',2',4',5'-tetraoxacyclohexane)-3'-spirocyclohexane
• CAS: 452302-71-5
• 化学式: C₃₄H₅₂O₁₀
• 分子量: 620.781
• InChiKey: YRZOFWYSUVSYSR-VKARVTOHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.6
• 重原子数：
  44
• 可旋转键数：
  8
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.91
• 拓扑面积：
  127
• 氢给体数：
  1
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  7α,12α-diacetoxy-5β-cholan-24-oic acid-3-spiro-6'-(1',2',4',5'-tetraoxacyclohexane)-3'-spirocyclohexane 在 氯化铵 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 3.0h， 生成 7α,12α-diacetoxy-5β-cholan-24-amide-3-spiro-6'-(1',2',4',5'-tetraoxacyclohexane)-3'-spirocyclohexane
  参考文献：
  名称：

  Mixed Steroidal 1,2,4,5-Tetraoxanes:  Antimalarial and Antimycobacterial Activity

  摘要：

  Mixed 1,2,4,5-tetraoxanes possessing simple spirocycloalkane and spirocholic acid-derived substituents were prepared and shown to have significantly higher in vitro antimalarial activity than bis-substituted tetraoxanes. Out of 41 synthesized tetraoxanes, 12 were in vitro more potent against Plasmodium falciparum chloroquine-resistant W2 clone than artemisinin, and the most potent one was 2.4 times as active as arteether. In addition, 9 compounds exhibit higher activity than chloroquine against P. falciparum chloroquine-susceptible D6 clone. Cytotoxicity was assessed for most active compounds against the Vero cell line, showing a cytotoxicity/antimalarial potency ratio of 1/(1400-9500). For the first time, tetraoxanes were screened against Mycobacterium tuberculosis with MICs as low as 4.73 muM against H37Rv strain. Mixed tetraoxanes were synthesized in a simple procedure from cholic acid methyl esters by direct coupling of steroidal gem-dihydroperoxide to simple ketones and further transformed into corresponding acids and amides.

  DOI：

  10.1021/jm020891g
• 作为产物：
  描述：

  methyl 7α,12α-diacetoxy-5β-cholan-24-oate-3-spiro-6'-(1',2',4',5'-tetraoxacyclohexane)-3'-spirocyclohexane 在 sodium hydroxide 作用下， 以 水 、 异丙醇 为溶剂， 反应 0.5h， 以89%的产率得到7α,12α-diacetoxy-5β-cholan-24-oic acid-3-spiro-6'-(1',2',4',5'-tetraoxacyclohexane)-3'-spirocyclohexane
  参考文献：
  名称：

  Mixed Steroidal 1,2,4,5-Tetraoxanes:  Antimalarial and Antimycobacterial Activity

  摘要：

  Mixed 1,2,4,5-tetraoxanes possessing simple spirocycloalkane and spirocholic acid-derived substituents were prepared and shown to have significantly higher in vitro antimalarial activity than bis-substituted tetraoxanes. Out of 41 synthesized tetraoxanes, 12 were in vitro more potent against Plasmodium falciparum chloroquine-resistant W2 clone than artemisinin, and the most potent one was 2.4 times as active as arteether. In addition, 9 compounds exhibit higher activity than chloroquine against P. falciparum chloroquine-susceptible D6 clone. Cytotoxicity was assessed for most active compounds against the Vero cell line, showing a cytotoxicity/antimalarial potency ratio of 1/(1400-9500). For the first time, tetraoxanes were screened against Mycobacterium tuberculosis with MICs as low as 4.73 muM against H37Rv strain. Mixed tetraoxanes were synthesized in a simple procedure from cholic acid methyl esters by direct coupling of steroidal gem-dihydroperoxide to simple ketones and further transformed into corresponding acids and amides.

  DOI：

  10.1021/jm020891g

文献信息

• New Chimeric Antimalarials with 4-Aminoquinoline Moiety Linked to a Tetraoxane Skeleton
  作者：Igor Opsenica、Dejan Opsenica、Charlotte Anne Lanteri、Lalaine Anova、Wilbur K. Milhous、Kirsten S. Smith、Bogdan A. Šolaja

  DOI：10.1021/jm8006905

  日期：2008.10.9

  The synthesis of the chimeric molecules consisting of two pharmacophores, tetraoxane and 7-chloro-4-aminoquinoline, is reported. The tetraoxanes 2, 4, and 8 show relatively potent in vitro antimalarial activities, with IC90 values for the Plasmodium falciparum strain W2 of 2.26, 12.44, and 10.74 nM, respectively. In addition, two compounds, 2 and 4, cured mice in a modified Thompson test for antimalarial blood stage activity, with a minimum curative dose of 80 mg/kg, a minimum active dose of 20 mg/kg/day, and a maximum tolerated dose of > 960 mg/kg.
• Chemical Stability of the Peroxide Bond Enables Diversified Synthesis of Potent Tetraoxane Antimalarials
  作者：Igor Opsenica、Dejan Opsenica、Kirsten S. Smith、Wilbur K. Milhous、Bogdan A. Šolaja

  DOI：10.1021/jm701417a

  日期：2008.4.1

  The development of widespread drug resistance to chloroquine (CQ(a)) has resulted in severe health issues for countries in malaria endemic regions. The antimalarial properties of artemisinin 2 and of other peroxides, such as 1,2,4,5-tetraoxacy-cloalkanes (tetraoxanes), have recently begun to be exploited in the development of new approaches to fighting CQ-resistant strains of malaria. New tetraoxanes employing a steroidal backbone have now been prepared that are highly active, are inexpensive, and demonstrate low toXieity.(5,6) A part of our research in this field is focused on the development of a new type of tetraoxane with nonidentical substituents(6) that utilize a steroid and small cyclohexylidene carriers possessing secondary amide bonds. Also, during our work in this field we discovered that tetraoxanes are unusually stable, even. at pH 1.6,(6c) a characteristic that subsequently allowed the synthesis of many interesting derivatives. This communication encompasses the synthesis of various amino-functionalized antimalarials based on the appreciable stability of the tetraoxane moiety to reaction conditions such as reductive amination and LiAlH4 reduction. Their respective antimalarial activities and the pronounced antiproliferative activity of certain products are reported along with in vitro metabolism studies.
• Deoxycholic Acid-Derived Tetraoxane Antimalarials and Antiproliferatives
  作者：Nataša Terzić、Dejan Opsenica、Dragana Milić、Bernard Tinant、Kirsten S. Smith、Wilbur K. Milhous、Bogdan A. Šolaja

  DOI：10.1021/jm070684m

  日期：2007.10.1

  The synthesis of deoxycholic acid (DCA)- and cholic acid (CA)-derived mixed tetraoxanes revealed that N-(2-dimethylamino)ethyl derivatives are potent antimalarials in vitro and in vivo. The tetraoxanes presented in this paper are dual inhibitors: besides curing mice in vivo without observed toxic effects, they kill cancer cell lines at very low concentrations. For example, DCA and CA derivatives 16 and 25 cured 3/5 (160 mg/kg/day) and 2/5 (40 mg/kg/day, MTD >960 mg/kg), respectively, and they were extremely active against melanoma LOX IMVI cancer, LC50 = 22 nM and 69 nM, respectively.
• Mixed Steroidal 1,2,4,5-Tetraoxanes:  Antimalarial and Antimycobacterial Activity
  作者：Bogdan A. Šolaja、Nataša Terzić、Gabriella Pocsfalvi、Lucia Gerena、Bernard Tinant、Dejan Opsenica、Wilbur K. Milhous

  DOI：10.1021/jm020891g

  日期：2002.8.1

  Mixed 1,2,4,5-tetraoxanes possessing simple spirocycloalkane and spirocholic acid-derived substituents were prepared and shown to have significantly higher in vitro antimalarial activity than bis-substituted tetraoxanes. Out of 41 synthesized tetraoxanes, 12 were in vitro more potent against Plasmodium falciparum chloroquine-resistant W2 clone than artemisinin, and the most potent one was 2.4 times as active as arteether. In addition, 9 compounds exhibit higher activity than chloroquine against P. falciparum chloroquine-susceptible D6 clone. Cytotoxicity was assessed for most active compounds against the Vero cell line, showing a cytotoxicity/antimalarial potency ratio of 1/(1400-9500). For the first time, tetraoxanes were screened against Mycobacterium tuberculosis with MICs as low as 4.73 muM against H37Rv strain. Mixed tetraoxanes were synthesized in a simple procedure from cholic acid methyl esters by direct coupling of steroidal gem-dihydroperoxide to simple ketones and further transformed into corresponding acids and amides.