6-甲氧基当归素 | 483-66-9

• 物质功能分类: 天然产物 - 香豆素
• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 香豆素及其衍生物
• 中文名称: 6-甲氧基当归素
• 中文别名: 牛防风素
• 英文名称: sphondin
• 英文别名: 6-methoxy-2H-furo[2,3-h]chromen-2-one；6-methoxyfuro[2,3-H]chromen-2-one；sfondin；6-methoxy-furo[2,3-h]chromen-2-one；6-Methoxy-furo[2,3-h]chromen-2-on
• CAS: 483-66-9
• 化学式: C₁₂H₈O₄
• mdl: MFCD00597230
• 分子量: 216.193
• InChiKey: DLCJNIBLOSKIQW-UHFFFAOYSA-N

物化性质

• 熔点：
  189-191 °C
• 沸点：
  413.0±45.0 °C(Predicted)
• 密度：
  1.368±0.06 g/cm3(Predicted)
• 颜色/状态：
  White powder
• 溶解度：
  In water, 5.37X10+2 mg/L at 25 °C (est)
• 蒸汽压力：
  3.8X10-6 mm Hg at 25 °C (est)
• 碰撞截面：
  139.9 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  16
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  48.7
• 氢给体数：
  0
• 氢受体数：
  4

ADMET

代谢

玉带凤蝶（老虎凤蝶）是一种杂食性昆虫，很少遇到含有呋喃香豆素的植物，但它具有固有能力代谢这些高度有毒的异种化学物质低水平。在玉带凤蝶幼虫中，线性（花椒毒素，佛手柑素）和角形（白芷素，防风素）呋喃香豆素的代谢可以通过饮食中花椒毒素的存在诱导高达30倍。通过使用与三种昆虫P450s中保守氨基酸序列相对应的简并引物，家蝇（CYP6A1）、果蝇（CYP6A2）和凤蝶（CYP6B1），通过逆转录聚合酶链反应（RT-PCR）策略从玉带凤蝶幼虫中克隆花椒毒素诱导的P450转录物。编码高度保守的F--G-R-C-G P450特征基序的阳性克隆用于从玉带凤蝶花椒毒素诱导的cDNA文库中分离出全长CYP6B4v1 cDNA。序列比较表明，玉带凤蝶CYP6B4v1蛋白序列与凤蝶呋喃香豆素可诱导的CYP6B1v1和CYP6B3v1蛋白分别有63%和61%的同一性。Northern分析表明，CYP6B4和相关转录物在响应花椒毒素时高度诱导。通过杆状病毒介导在鳞翅目细胞系中表达CYP6B4v1蛋白，表明这种P450同工酶以高速率代谢异补骨脂素、帝皇素和佛手柑素，以中等速率代谢花椒毒素和补骨脂素，而仅以非常低的速率代谢白芷素、防风素和三甲沙林。

Papilio glaucus (tiger swallowtail) is a generalist that rarely encounters plants containing furanocoumarins yet is constitutively capable of metabolizing low levels of these highly toxic allelochemicals. In larvae of this species, metabolism of linear (xanthotoxin, bergapten), and angular (angelicin, sphondin), furanocoumarins can be induced up to 30-fold by the presence of xanthotoxin in their diet. Degenerate primers corresponding to conserved amino acid sequences in three insect P450s, Musca domestica (CYP6A1), Drosophila melanogaster (CYP6A2) and Papilio polyxenes (CYP6B1), were used to clone xanthotoxin-induced P450 transcripts from P. glaucus larvae by a reverse transcription-polymerase chain reaction (RT-PCR) strategy. Positive clones encoding the highly conserved F--G-R-C-G P450 signature motif were used to isolate a full-length CYP6B4v1 cDNA from a P. glaucus xanthotoxin-induced cDNA library. Sequence comparisons indicate the P. glaucus CYP6B4v1 protein sequence is 63% and 61% identical, respectively, to the P. polyxenes furanocoumarin-inducible CYP6B1v1 and CYP6B3v1 proteins. Northern analysis indicates that CYP6B4 and related transcripts are highly induced in response to xanthotoxin. Baculovirus-mediated expression of the CYP6B4v1 protein in lepidopteran cell lines demonstrates that this P450 isozyme metabolizes isopimpinellin, imperatorin, and bergapten at high rates, xanthotoxin and psoralen at intermediate rates and angelicin, sphondin, and trioxsalen only at very low rates.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

鉴定和使用：Sphondin 是 Heracleum maximum 根部的一个组成部分，这些根部通常被北美原住民用于治疗包括肺结核在内的呼吸系统疾病。人类研究：光致敏测试表明，sphondin 产生了弱光毒性效应。对 Heracleum laciniatum 中的补骨脂素的光接触过敏发生在两名志愿者身上，他们参与了植物匀浆和纯化补骨脂素光毒性的研究。案例1在第五次接触后出现了光过敏反应，案例2在第六次接触后出现。使用稀释溶液的测试表明对 sphondin、isobergapten 和 pimpinellin 过敏。动物研究：Sphondin 有效抑制了小鼠香豆素7-羟基化酶（COH）活性。当以0.05-15.0 uM 的浓度测试时，sphondin 显示出抗增殖活性，并在测试对 B16F10 黑色素瘤细胞时引起了 G2/M 期阻滞。

IDENTIFICATION AND USE: Sphondin is a component of Heracleum maximum roots, these roots are commonly used by the indigenous peoples of North America for the treatment of respiratory ailments including tuberculosis. HUMAN STUDIES: Photoepicutaneous testing showed weak phototoxic effects from sphondin. Photocontact allergy to psoralens in Heracleum laciniatum occurred in two persons volunteering for investigations into phototoxicity of plant homogenates and purified psoralens. Photoallergy was noted following the fifth exposure in case 1, and the sixth in case 2. Testing with diluted solutions demonstrated allergy to sphondin, isobergapten and pimpinellin. ANIMAL STUDIES: Sphondin effectively inhibited mouse coumarin 7-hydroxylase (COH) activity. Sphondin showed anti-proliferative activity and caused G2/M arrest at concentrations of 0.05-15.0 uM when tested against B16F10 melanoma cells.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

Sphondin对人体肺上皮细胞系（A549）中IL-1b诱导的COX-2蛋白表达和PGE2释放具有抑制作用。许多呋喃香豆素的作用机制基于它们与DNA和其他细胞组分（如RNA、蛋白质以及膜中的一些蛋白质，如磷脂酶A2和C、钙依赖性和cAMP依赖性蛋白激酶和表皮生长因子）形成光加合物的能力。呋喃香豆素在DNA碱基对之间插入，并在紫外线A照射后形成环加合物。

Sphondin possesses an inhibitory effect on IL-1b-induced COX-2 protein expression and PGE2 release in human pulmonary epithelial cell line (A549). The mechanism of action many furocoumarins is based on their ability to form photoadducts with DNA and other cellular components such as RNA, proteins, and several proteins found in the membrane such as phospholipases A2 and C, Ca-dependent and cAMPdependent protein-kinase and epidermal growth factor. Furocoumarins intercalate between base pairs of DNA and after ultraviolet-A irradiation, giving cycloadducts. (L579).

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 致癌物分类

未列入国际癌症研究机构(IARC)名录。IARC评估了其他呋喃香豆素类物质，将8-甲氧基补骨脂素归类为对人类致癌(第1组)，5-甲氧基补骨脂素归类为可能对人类致癌(第2A组)，以及其他某些呋喃香豆素类物质归类为对人类致癌性无法分类(第3组)。(L135)

Not listed by IARC. IARC has assessed other furocoumarins, classifying 8-methoxypsoralen as carcinogenic to humans (Group 1), 5-methoxypsoralen as possibly carcinogenic to humans (Group 2A), and certain other furocoumarins as not being classifiable as to their carcinogenicity to humans (Group 3). (L135)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 健康影响

呋喃香豆素中的8-甲氧基补骨脂素对人类具有致癌性，5-甲氧基补骨脂素也可能具有致癌性（L135）。一些来自小鼠研究的证据表明，当与UVA辐射暴露结合时，其他呋喃香豆素也具有致癌性（A15105）。SKLM认为，食用含有典型量呋喃香豆素的食物，其风险显著低于光毒性剂量范围，因此导致皮肤癌的额外风险微不足道。然而，某些食物，特别是芹菜和欧防风，可能会因储存、加工和生产条件而导致呋喃香豆素浓度显著增加，因此不能排除食用光毒性剂量的可能性（L2157）。已知呋喃香豆素光化学疗法会诱导多种副作用，包括红斑、水肿、色素沉着过度和皮肤过早老化。呋喃香豆素的所有光生物效应都源于其光化学反应。因为许多饮食或水溶性呋喃香豆素是细胞色素P450的强抑制剂，所以当与其他药物一起服用时，它们也会引起不良反应。这是白癜风患者发生光毒性的原因（L579）。

The furocoumarin 8-methoxypsoralen is carcinogenic to humans, and possibly 5-methoxypsoralen as well (L135). There is some evidence from mouse studies that other furocoumarins are carcinogenic when combined with exposure to UVA radiation (A15105). The SKLM regards the additional risk of skin cancer arising from the consumption of typical quantities of furocoumarin-containing foods, which remain significantly below the range of phototoxic doses, as insignificant. However, the consumption of phototoxic quantities cannot be ruled out for certain foods, particularly celery and parsnips, that may lead to significant increases in furocoumarin concentrations, depending on the storage, processing and production conditions. (L2157) Furocoumarin photochemotherapy is known to induce a number of side-effects including erythema, edema, hyperpigmentation, and premature aging of skin. All photobiological effects of furocoumarins result from their photochemical reactions. Because many dietary or water soluble furocoumarins are strong inhibitors of cytochrome P450s, they will also cause adverse drug reactions when taken with other drugs. Cause of phototoxicity in patient with vitiligo. (L579)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 相互作用

在浓度高达6.7 ppm时，8-甲氧基补骨脂素、花椒毒素和阿加宁对埃及伊蚊的一龄幼虫不具有毒性。用长波长紫外线照射敏感化的幼虫并不总是产生即时的毒性增强效果，但延迟效应非常明显。这些效应从一龄幼虫到成虫的整个发育过程中都可以观察到。当幼虫在没有光敏剂的情况下被照射，或者当它们被放置在已经用同样的光源照射过的光敏剂溶液中时，没有发现不良反应。8-甲氧基补骨脂素的 phototoxicity 略高于其同分异构体花椒毒素。最近有报道称阿加宁会与DNA组分发生光诱导环化反应，但在所使用的浓度范围内，其 phototoxicity 极小。

At concentrations up to 6.7 ppm, 8-methoxypsoralen, sphondin, and khellin are not toxic to first-instar larvae of the mosquito Aedes aegypti. The irradiation of sensitized larvae with long-wavelength ultraviolet light did not always produce any immediate toxicity enhancement, but delayed effects were clearly visible. These were observed over the development of the organisms from first-instar larvae to adults. No adverse effects were noted when larvae were irradiated in the absence of sensitizers, or when they were placed in solutions of sensitizers which had been previously irradiated with the same light sources. 8-Methoxypsoralen was slightly more phototoxic than its isomer sphondin. Khellin, recently reported to undergo photoinduced cyclization with DNA components, showed minimal phototoxicity in the concentration range used.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335

制备方法与用途

生物活性

Sphondin 可从 Heracleum laciniatum 中分离，对 IL-1β 诱导的 A549 细胞中 COX-2 蛋白和 PGE₂ 释放水平的升高具有抑制作用。

靶点

| COX-2 |

体外研究

Sphondin（浓度为 10-50 μM）预处理 A549 细胞可浓度依赖性地减弱 IL-1β 引起的 COX-2 蛋白表达和 PGE₂ 分泌。

化学性质

类白色针状结晶，可溶于甲醇、乙醇、DMSO 等有机溶剂，来源于牛尾独活。

用途

镇痛、抗炎、抗过敏、平滑肌解痉。

反应信息

• 作为反应物：
  描述：

  6-甲氧基当归素 在 sodium hydroxide 、 氯仿 、 双氧水 、 臭氧 作用下， 生成 秦皮素
  参考文献：
  名称：

  Spaeth; Schmid, Chemische Berichte, 1941, vol. 74, p. 595,598

  摘要：

  DOI：
• 作为产物：
  描述：

  6-phenylmethoxyfuro[2,3-h]chromen-2-one 在 palladium dihydroxide 氢气 、 potassium carbonate 作用下， 以 甲醇 、 乙酸乙酯 为溶剂， 反应 6.0h， 生成 6-甲氧基当归素
  参考文献：
  名称：

  Synthesis and antifungal activity of coumarins and angular furanocoumarins

  摘要：

  Angelicin, a naturally occurring furanocoumarin, that showed antifungal activity, was considered as a lead structure for a group of synthetic coumarins. Antifungal activities of the synthesized coumarins and angelicin derivatives were reported against Candida albicans, Cryptococcus neoformans, Saccharomyces cerevisiae and Aspergillus niger. Human cell line cytotoxicity of several coumarins was evaluated against KB cells. Angelicin and several potent antifungals showed to be non-toxic in this assay.

  DOI：

  10.1016/s0968-0896(99)00138-8

文献信息

• Ring-closing-metathesis-based synthesis of annellated coumarins from 8-allylcoumarins
  作者：Christiane Schultze、Bernd Schmidt

  DOI：10.3762/bjoc.14.278

  日期：——

  conveniently accessible through a microwave-promoted tandem Claisen rearrangement/Wittig olefination/cyclization sequence. They serve as a versatile platform for the annellation of five- to seven-membered rings using ring-closing olefin metathesis (RCM). Furano-, pyrano-, oxepino- and azepinocoumarins were synthesized from the same set of precursors using Ru-catalyzed double bond isomerizations and RCM in a defined

  可通过微波促进的串联克莱森重排/维蒂希烯化/环化序列方便地获得8-烯丙基香豆素。它们是使用闭环烯烃复分解（RCM）进行五元至七元环环合的通用平台。使用Ru催化的双键异构化和RCM按定义的顺序，从同一组前体中合成呋喃并，吡喃并，氧杂环丁烷和氮杂环庚烷香豆素。一类产品吡喃并[2,3-f]亚甲基-2,8-二酮无法通过丙烯酸酯的直接RCM获得，但可通过辅助串联催化RCM /烯丙基氧化序列从类似的烯丙基醚获得。
• A convenient synthesis of psoralens
  作者：Stefano Chimichi、Marco Boccalini、Barbara Cosimelli、Giampietro Viola、Daniela Vedaldi、Francesco Dall'Acqua

  DOI：10.1016/s0040-4020(02)00441-6

  日期：2002.6

  An efficient synthesis (yields >70%) of linear 7H-furo[3,2-g]chromen-7-one derivatives (psoralens or furocoumarins) has been carried out starting from ring-substituted 2-(coumarin-7-yl)oxyaldehydes; moreover, the phototoxicity of these compounds has been tested on a cultured cell line of murine fibroblast.

  从环取代的2-（香豆素-7-基）开始，已经进行了线性7 H-呋喃[3,2 - g ] chromen-7-one衍生物（补骨脂素或呋喃香豆素）的有效合成（收率> 70％）。）乙醛; 此外，已经在鼠成纤维细胞的培养细胞系上测试了这些化合物的光毒性。
• ISOTHIOCYANATE FUNCTIONAL SURFACTANT AND ASSOCIATED METHOD OF USE
  申请人：Silver Michael E.

  公开号：US20170037000A1

  公开（公告）日：2017-02-09

  An isothiocyanate functional surfactant, wherein the protonated form of said surfactant is represented by the following chemical structure: wherein X includes an integer ranging from approximately 1 to approximately 25, and wherein Y includes an integer ranging from approximately 6 to approximately 25.

  一种异硫氰酸酯功能表面活性剂，其中所述表面活性剂的质子化形式由以下化学结构表示：其中X包括从大约1到大约25的整数，Y包括从大约6到大约25的整数。
• Isothiocyanate functional surfactant and associated method of use
  申请人：Silver Michael E.

  公开号：US10308600B2

  公开（公告）日：2019-06-04

  A method for treating phytophotodermatitis including the steps of applying an isothiocyanate functional surfactant to an area affected by phytophotodermatitis, wherein said isothiocyanate functional surfactant comprises at least one isothiocyanate functional group associated with an aliphatic and/or aromatic carbon atom of the isothiocyanate functional surfactant.

  一种治疗植物皮炎的方法，包括以下步骤：将异硫氰酸盐官能团表面活性剂用于受植物皮炎影响的区域，其中所述异硫氰酸盐官能团表面活性剂包括至少一个与异硫氰酸盐官能团表面活性剂的脂肪族和/或芳香族碳原子相关联的异硫氰酸盐官能团。
• Bastian; Rene; Buisson, European Journal of Medicinal Chemistry, 1981, vol. 16, # 6, p. 563 - 568
  作者：Bastian、Rene、Buisson、et al.

  DOI：——

  日期：——

表征谱图