<1S-<1α-(4R*,5S*),3α,4β,5α,6α(2E,4R*,6R*),7β>>-1-<4-(acetyloxy)-5-methyl-3-methylene-6-phenylhexyl>-4,6,7-trihydroxy-2,8-dioxabicyclo<3.2.1>octane-3,4,5-tricarboxylic acid, 6-(4,6-dimethyl-6-octenoate), 4,5-dimethyl ester | 144548-73-2

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: <1S-<1α-(4R*,5S*),3α,4β,5α,6α(2E,4R*,6R*),7β>>-1-<4-(acetyloxy)-5-methyl-3-methylene-6-phenylhexyl>-4,6,7-trihydroxy-2,8-dioxabicyclo<3.2.1>octane-3,4,5-tricarboxylic acid, 6-(4,6-dimethyl-6-octenoate), 4,5-dimethyl ester
• 英文别名: (1S,3S,4S,5R,6R,7R)-1-((4S,5R)-4-Acetoxy-5-methyl-3-methylene-6-phenyl-hexyl)-6-((E)-(4S,6S)-4,6-dimethyl-oct-2-enoyloxy)-4,7-dihydroxy-2,8-dioxa-bicyclo[3.2.1]octane-3,4,5-tricarboxylic acid 4,5-dimethyl ester；(1S,3S,4S,5R,6R,7R)-1-[(4S,5R)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-6-[(E,4S,6S)-4,6-dimethyloct-2-enoyl]oxy-4,7-dihydroxy-4,5-bis(methoxycarbonyl)-2,8-dioxabicyclo[3.2.1]octane-3-carboxylic acid
• CAS: 144548-73-2
• 化学式: C₃₇H₅₀O₁₄
• 分子量: 718.796
• InChiKey: ZELOLEVIELMWJY-SLHPNUJXSA-N

物化性质

• 沸点：
  787.9±60.0 °C(predicted)
• 密度：
  1.28±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.5
• 重原子数：
  51
• 可旋转键数：
  21
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  201
• 氢给体数：
  3
• 氢受体数：
  14

反应信息

• 作为反应物：
  描述：

  <1S-<1α-(4R*,5S*),3α,4β,5α,6α(2E,4R*,6R*),7β>>-1-<4-(acetyloxy)-5-methyl-3-methylene-6-phenylhexyl>-4,6,7-trihydroxy-2,8-dioxabicyclo<3.2.1>octane-3,4,5-tricarboxylic acid, 6-(4,6-dimethyl-6-octenoate), 4,5-dimethyl ester 在 吡啶 、 N-羟基丁二酰亚胺 、 1-环已基-2-吗啉乙基碳二亚胺对甲苯磺酸盐 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 生成 (1S,3R,4S,5R,6R,7R)-1-((4S,5R)-4-Acetoxy-5-methyl-3-methylene-6-phenyl-hexyl)-6-((E)-(4S,6S)-4,6-dimethyl-oct-2-enoyloxy)-4,7-dihydroxy-3-(toluene-4-sulfonyloxymethyl)-2,8-dioxa-bicyclo[3.2.1]octane-4,5-dicarboxylic acid dimethyl ester
  参考文献：
  名称：

  squalestatins：三环3,4-β-内​​酯和3,4-氧杂环丁烷系统

  摘要：

  在温和的还原条件下（硼氢化钠）将角鲨抑制素3,4-β-内​​酯-4,5-二甲基酯（8）还原性开环以产生角鲨抑制素3-羟甲基-4,5-二甲基酯（6）。类似地，squalestatin 3,4-氧杂环丁烷-4,5-二甲基酯（10）被发现环打开到3-碘甲基squalestatin（15用来切割的甲基酯官能团的条件下）（碘化锂/ 2,4- 6-三甲基吡啶）。

  DOI：

  10.1016/s0040-4039(00)01286-7
• 作为产物：
  描述：

  zaragozic acid A trimethyl ester 在 sodium hydroxide 作用下， 以 四氢呋喃 为溶剂， 反应 21.0h， 生成 <1S-<1α-(4R*,5S*),3α,4β,5α,6α(2E,4R*,6R*),7β>>-1-<4-(acetyloxy)-5-methyl-3-methylene-6-phenylhexyl>-4,6,7-trihydroxy-2,8-dioxabicyclo<3.2.1>octane-3,4,5-tricarboxylic acid, 6-(4,6-dimethyl-6-octenoate), 4,5-dimethyl ester
  参考文献：
  名称：

  squalestatins：一些经C3修饰的类似物的合成和生物活性；用等电子杂环官能团取代羧酸或甲酯。

  摘要：

  制备了一系列在C3位修饰有杂环功能的角鲨烯抑制素，并作为角鲨烯合酶（SQS）的抑制剂进行了体外评估。具有C6（S1类似物）的4,6-二甲基辛烯酸的化合物的结构活性关系与缺少C6酯的类似物（H1类似物）的结构-活性关系不同，这更多地取决于H1系列的C3取代基的性质。相当于H1的强效SQS抑制活性被C3-（四唑-5-基）类似物（即羧酸模拟物）保留。C3-甲基酯衍生物的活性比H1低10倍，与SQS相似的SQS抑制活性仅保留在那些C3杂环取代的H1类似物中，这些C3取代基的静电势图非常接近类似于甲酯。

  DOI：

  10.1021/jm00018a010

文献信息

• The Squalestatins: Synthesis and Biological Activity of Some C3-Modified Analogs; Replacement of a Carboxylic Acid or Methyl Ester with an Isoelectronic Heterocyclic Functionality
  作者：Mark J. Bamford、Chuen Chan、Andrew P. Craven、Brian W. Dymock、Darren Green、Richard A. Henson、Barrie E. Kirk、Michael G. Lester、Panayiotis A. Procopiou

  DOI：10.1021/jm00018a010

  日期：1995.9

  dependence on the nature of the C3-substituent for the H1 series. Potent SQS inhibitory activity equivalent to that of H1 is retained by a C3-(tetrazol-5-yl) analogue, i.e., a carboxylic acid mimetic. The C3-methyl ester derivative is 10-fold less active than H1, and SQS inhibitory activity similar to that of the methyl ester was retained only in those C3-heterocycle-substituted H1 analogues for which electrostatic

  制备了一系列在C3位修饰有杂环功能的角鲨烯抑制素，并作为角鲨烯合酶（SQS）的抑制剂进行了体外评估。具有C6（S1类似物）的4,6-二甲基辛烯酸的化合物的结构活性关系与缺少C6酯的类似物（H1类似物）的结构-活性关系不同，这更多地取决于H1系列的C3取代基的性质。相当于H1的强效SQS抑制活性被C3-（四唑-5-基）类似物（即羧酸模拟物）保留。C3-甲基酯衍生物的活性比H1低10倍，与SQS相似的SQS抑制活性仅保留在那些C3杂环取代的H1类似物中，这些C3取代基的静电势图非常接近类似于甲酯。
• The squalestatins: C-3 Decarboxylation studies and rearrangement to the 6,8-dioxabicyclo[3.2.1]octane ring system
  作者：Chuen Chan、Graham Ga Inglis、Panayiotis A. Procopiou、Barry C. Ross、Anton Rp Srikantha、Nigel S. Watson

  DOI：10.1016/s0040-4039(00)61752-5

  日期：1993.9

  3-Decarboxy squalestatins 3 and 4 were synthesised via photolysis of t-butyl peroxyester 7. Lactol 10 was isolated unexpectedly from both HCl-dioxan cleavage of 8, a by-product of the photolysis, and attempted Barton decarboxylation of 6. In TFA under anhydrous conditions, 8 was converted to the tricyclic ether 11.

  3脱羧squalestatins 3和4合成了通过光解吨丁基过氧酯7。意外地从光解反应的副产物8的HCl-二恶烷裂解中分离出了Lactol 10，并尝试进行6的Barton脱羧。在无水条件下的TFA中，将8转化为三环醚11。
• The Squalestatins:  Inhibitors of Squalene Synthase. Enzyme Inhibitory Activities and <i>in</i> <i>Vivo</i> Evaluation of C3-Modified Analogues
  作者：Panayiotis A. Procopiou、Brian Cox、Barrie E. Kirk、Michael G. Lester、Alun D. McCarthy、Meenu Sareen、Peter J. Sharratt、Michael A. Snowden、Stephen J. Spooner、Nigel S. Watson、Julia Widdowson

  DOI：10.1021/jm950893j

  日期：1996.1.1

  Squalestatin analogues modified at C3 were prepared and evaluated for their ability to inhibit rat liver microsomal squalene synthase in vitro. While the 4,6-dimethyloctenoate ester group at C6 was maintained, a number of modifications to the C3 carboxylic acid were well tolerated. However, in the absence of the C6 ester group, similar modifications to the C3 carboxyl group caused loss of activity. Selected compounds were evaluated for their ability to inhibit cholesterol biosynthesis in vivo in rats 1 and 6 h postadministration. Analogues of squalestatin 1 (S1) modified at C3 were found to possess a shorter duration of effect in vivo which is reflected in their substantially reduced ability to lower serum cholesterol levels in marmosets. Significant cholesterol lowering (up to 62%) for the C3 hydroxymethyl analogue Ib was observed only; when this compound was dosed three times a day for 3 days.
• The squalestatins: tricyclic 3,4-β-lactone and 3,4-oxetane systems
  作者：Brian Cox、Nicolas Morley、Panayiotis A Procopiou、Peter J Sharratt、Nigel S Watson、Deborah Wild

  DOI：10.1016/s0040-4039(00)01286-7

  日期：2000.9

  Squalestatin 3,4-β-lactone-4,5-dimethyl ester (8) was reductively ring-opened to yield squalestatin 3-hydroxymethyl-4,5-dimethyl ester (6) using mild reducing conditions (sodium borohydride). Similarly, squalestatin 3,4-oxetane-4,5-dimethyl ester (10) was found to ring-open to 3-iodomethyl squalestatin (15) under the conditions used to cleave the methyl ester functions (lithium iodide/2,4,6-trimethylpyridine)

  在温和的还原条件下（硼氢化钠）将角鲨抑制素3,4-β-内​​酯-4,5-二甲基酯（8）还原性开环以产生角鲨抑制素3-羟甲基-4,5-二甲基酯（6）。类似地，squalestatin 3,4-氧杂环丁烷-4,5-二甲基酯（10）被发现环打开到3-碘甲基squalestatin（15用来切割的甲基酯官能团的条件下）（碘化锂/ 2,4- 6-三甲基吡啶）。