金诺芬

• 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
• 中文名称: 金诺芬
• 中文别名: (1-硫-Β-D-吡喃葡糖络)(三乙基膦)金-2,3,4,6-四乙酸酯；醋硫葡金；2,3,4,6-四乙酰氧基-1-硫代-beta-D-吡喃葡萄糖(三乙基磷)金盐
• 英文名称: auranofin
• 英文别名: (2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranosato-S)-(triethylphosphine) gold；Ridaura；MMV688978；(1-thio-β-D-glucopyranose-2,3,4,6-tetraacetato-S)(triethylphosphine)gold(I)；(2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranosato)(triethylphosphine) gold(I)；[(3,4,5-triacetyloxy-6-acteyloxymethyl,oxane-2-thio-late)Au(triethyl-phosphanium)]；(2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranosato)(triethylphosphan)gold；gold(1+);(2S,3R,4S,5R,6R)-3,4,5-triacetyloxy-6-(acetyloxymethyl)oxane-2-thiolate;triethylphosphane
• 化学式: C₂₀H₃₄AuO₉PS
• 分子量: 678.491
• InChiKey: AUJRCFUBUPVWSZ-XTZHGVARSA-M

计算性质

• 辛醇/水分配系数(LogP)：
  2.14
• 重原子数：
  32
• 可旋转键数：
  12
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  115
• 氢给体数：
  0
• 氢受体数：
  10

ADMET

代谢

代谢如此迅速，以至于在血液中未检测到完整的分子。

Metabolized so rapidly that the intact molecule has not been detected in blood.

来源:Hazardous Substances Data Bank (HSDB)

代谢

对于接受金钠硫代苹果酸的患者来说，尿液中主要的金物种是[Au(CN)2]-，这也同样出现在血液中的低分子量渗入物中。同样，这种化合物也被识别出在接受金诺芬治疗的患者的尿液和血液中。

For a patient receiving gold sodium thiomalate the principal gold species in the urine is [Au(CN)2]-, which is also seen in a low molecular weight infiltrate of the blood. The same compound is also identified in the urine and blood of a patient taking auranofin

来源:Hazardous Substances Data Bank (HSDB)

代谢

金诺芬（Auranofin），2,3,4,6-四-O-乙酰-1-硫-β-D-吡喃葡萄糖苷-S-（三乙基膦）-金(I)，在与仓鼠或大鼠肠道壁接触时被代谢，产生去乙酰化形式的药物。这个产物，1-硫-β-D-吡喃葡萄糖苷-S-（三乙基膦）-金(I)，在仓鼠或大鼠肠道反转实验中穿过了肠道壁...

Auranofin, 2,3,4,6-tetra-O-acetyl-1-thio-beta-D-glucopyranosato-S-(triethylphosphine)- gold(I), ...metabolized in contact with hamster or rat gut wall to yield the deacetylated form of the drug. This product, 1-thio-beta-D-glucopyranosato-S-(triethylphosphine)-gold(I), passed through hamster or rat intestinal wall in an everted gut experiment...

来源:Hazardous Substances Data Bank (HSDB)

代谢

从红细胞（RBCs）中暴露于10-100微摩尔奥罗诺金的金流出，三乙磷(2,3,4,6-四-O-乙酰-1-beta-D-葡萄糖苷-S-)金(I)进行了研究。全血中的红细胞被允许积累金，然后被放置在新鲜的血浆或缓冲盐溶液中。[14C]谷胱甘肽，通过原位标记生成，也流出并与白蛋白和金结合，提供了第一个直接证据，表明白蛋白-金-谷胱甘肽复合物（AlbSAuSG）可能是奥罗诺金形成后的循环代谢物，在奥罗诺金的两个原始配体被取代后形成。

The efflux of gold from red blood cells (RBCs) exposed to 10-100 microM auranofin, triethylphosphine(2,3,4,6-tetra-O-acetyl- 1-beta-D-gludopyranosato-S-)gold(I) was studied. RBCs in whole blood were allowed to accumulate gold, and then were place in fresh plasma or buffered saline solution. ...[14C]Glutathione, generated by in situ labeling, also effluxed and associated with the albumin and gold, providing the first direct evidence that the albumin-gold-glutathione complex (AlbSAuSG) may be a circulating metabolite of auranofin formed after both of the original ligands of auranofin are displaced.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 药物性肝损伤

金诺芬

Compound:auranofin

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

药物性肝损伤标注：低药物性肝损伤关注

DILI Annotation:Less-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重程度等级：3

Severity Grade:3

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

标签部分：警告和预防措施

Label Section:Warnings and precautions

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

参考文献：M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. 美国食品药品监督管理局批准的药物标签用于研究药物诱导的肝损伤，《药物发现今日》，16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007 M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank：按人类发展药物诱导肝损伤风险排名的最大参考药物清单。《药物发现今日》2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

References:M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007 M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

活体中，来自金诺芬的金大约有60%与血清蛋白结合。在与血清蛋白结合的金中，82%与白蛋白结合，其余与α1-、α2-和β-球蛋白结合，可能还包括IgG。血清中来自金诺芬的自由金的比例不到1-2%；使用金诺芬达到的自由金血清浓度似乎与使用金钠硫代硫酸盐达到的浓度相似。

In vivo, gold from auranofin is approximately 60% bound to serum proteins. Of the gold bound to serum proteins, 82% is bound to albumin and the remainder to alpha1-, alpha2-, and beta-globulins and possibly to IgG. Less than 1-2% of gold from auranofin in serum is present as free gold; serum concentrations of free gold attained with auranofin appear to be similar to those attained with gold sodium thiomalate.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在动物口服多剂量的金诺芬后，金元素在肾脏中的浓度最高；金也分布到脾脏、肺、肾上腺和肝脏，心脏、睾丸、消化道、肌肉、眼睛、脂肪和大脑中的浓度较低。在动物（可能在人类中也是如此），金诺芬中的少量金分布到胆汁中。类风湿性关节炎患者接受金诺芬治疗的关节滑液中的金浓度远低于接受parenteral金化合物治疗的患者，但在金诺芬治疗期间，血液与关节滑液中的金浓度比值与parenteral金治疗期间相似（大约1.7:1）。初步数据显示，在金诺芬治疗期间，皮肤中几乎没有或没有金积累，这与parenteral金化合物治疗期间发生的积累形成对比。在金诺芬治疗期间，头发或指甲几乎没有或没有金积累，并且到目前为止，即使总累积剂量高达6.1克，也未检测到角膜或晶状体中金的积累。

Following oral administration of multiple doses of auranofin in animals, gold is distributed in highest concentrations into the kidneys; gold is also distributed into the spleen, lungs, adrenals, and liver, with lower concentrations being distributed into the heart, testes, GI tract, muscle, eyes, fat, and brain. In animals (and possibly in humans), small amounts of gold from auranofin are distributed into bile. Synovial fluid gold concentrations in rheumatoid arthritis patients receiving auranofin are much lower than those in patients receiving therapy with parenteral gold compounds, but the ratio of blood-to-synovial fluid gold concentrations during auranofin therapy is similar to that during parenteral gold therapy (approximately 1.7:1). Preliminary data suggest that little or no gold cumulates in skin during auranofin therapy, in contrast to the accumulation that occurs during therapy with parenteral gold compounds. Little or no gold accumulation occurs in hair or nails during auranofin therapy, and accumulation of gold in the cornea or lens during therapy with the drug has not been detected to date with total cumulative doses as high as 6.1 g.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在健康成年人单次口服6毫克金诺芬后，平均血金峰值浓度为0.025微克/毫升（范围：0.014-0.046微克/毫升），发生在2小时。在类风湿性关节炎患者多次口服给药后，通常在8-12周内达到稳态血金浓度，尽管在某些患者中可能需要13-16周的时间。虽然个体间的差异相当大，但一旦在金诺芬治疗期间达到稳态血金浓度，继续给药时血金浓度在个体内的差异似乎最小。

Following oral administration of a single 6-mg dose of auranofin in healthy adults, mean peak blood gold concentrations of 0.025 ug/mL (range: 0.014-0.046 ug/mL) occurred at 2 hours. Following oral administration of multiple doses of the drug in patients with rheumatoid arthritis, steady-state blood gold concentrations are usually attained after 8-12 weeks, although periods of 13-16 weeks may be necessary in some patients. While there appears to be considerable interindividual variation, once steady-state blood gold concentrations are attained during auranofin therapy, there appears to be minimal intraindividual variation in blood gold concentration with continued dosing.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

动物研究的结果表明，奥瑞诺金的配体几乎被完全吸收；由于只有很少一部分的金被吸收，因此认为该药物在胃肠道中其配位键经历了广泛的断裂。一些实验数据表明，奥瑞诺金在胃肠道粘膜上松散且可逆地吸附。其他实验数据表明，奥瑞诺金的金含形态可能经历跨粘膜吸收，可能的初始代谢过程是在胃肠道粘膜内去乙酰化。

Results of animal studies indicate that the ligands of auranofin are almost completely absorbed; since a much smaller fraction of the gold is absorbed, the drug is believed to undergo extensive disruption at its coordination bonds within the GI tract. Some experimental data suggest that auranofin is loosely and reversibly adsorbed onto GI mucosa. Other experimental data suggest that gold-containing forms of auranofin may undergo transmucosal absorption, possibly with the initial metabolic process being deacetylation within the GI mucosa.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  金诺芬 、 美司坦 生成
  参考文献：
  名称：

  固相中金（I）-膦配合物的配体交换/加扰研究，通过DESI-MS分析。

  摘要：

  仅少数分析技术可用于表征机械化学合成反应产物。我们在这里证明DESI-MS是用于此目的的强大技术，将基于MS的测定的选择性与环境电离方法的简单性和原位分析能力相结合。在这项工作中，我们报告金质药物金诺芬及其前体三乙基膦氯化金（I）与固态的含硫醇氨基酸经历了一系列复杂的配体交换/加扰反应。通过固相反应的DESI-MS分析容易地表征产物，清楚地显示出配体交换和加扰，并且通过固态13 C-NMR独立地确认。硫代葡萄糖和三乙基膦部分与半胱氨酸及其衍生物交换，而谷胱甘肽仅取代了2,3,4,6-四-邻-乙酰基-β-1-D-吡喃葡萄糖。结论是配体交换和加扰反应可以在固态下进行，通过机械化学合成可以方便地以良好的收率（> 98％）制备本研究报道的一些独特产品，如（ L-半胱氨酸-S）-三乙基膦金（I），来自氯化三乙基膦金（I）和L-半胱氨酸。

  DOI：

  10.1007/s13361-019-02319-y
• 作为产物：
  描述：

  1-硫代-beta-D-葡萄糖五乙酸酯 在 4,4'-二羟基二苯硫醚 、 一水合肼 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 5.2h， 生成 金诺芬
  参考文献：
  名称：

  1-糖基硫代乙酸酯的改进合成及其在硫代葡萄糖苷格列净类似物合成中的应用

  摘要：

  我们报道的1-硫代糖苷相对绿色合成由per-的直接的反应Ó于EtOAc -acetylated葡糖与KSAc。此外，还开发了合成过氧乙酰化糖基二硫化物和糖基 1-硫醇的高效方法。在此基础上，金诺芬的合成得到改进，并以高产率高效合成了两种硫代葡萄糖苷格列净类似物（可能是 SGLT 抑制剂）。

  DOI：

  10.1002/ejoc.202100357
• 作为试剂：
  描述：

  1,2,3,4,6-alpha-D-葡萄糖五乙酸酯 在 甲醇 、 金诺芬 、 三氟化硼乙醚 、 钯 、 三乙胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 乙酸乙酯 为溶剂， 反应 13.03h， 生成
  参考文献：
  名称：

  一种全酰基保护的1-硫代葡萄糖、葡萄糖1-硫醇的制备方法及其应用

  摘要：

  本发明属于医药和糖化学合成技术领域，尤其涉及一种全酰基保护的1‑硫代葡萄糖、葡萄糖1‑硫醇的制备方法及其应用。制备方法是将全乙酰基保护的葡萄糖和硫代乙酸钾在有机溶剂中，以三氟化硼乙醚催化在常温至50℃反应4‑8小时，即可制得全乙酰保护的1‑硫代葡萄糖；制得的全乙酰保护的1‑硫代葡萄糖溶于二甲基甲酰胺后，用水合肼脱除硫乙酰基即可制得全乙酰保护的葡萄糖1‑硫醇；用全乙酰保护的葡萄糖1‑硫醇可进一步制得金诺芬和格列净硫代糖苷类似物。本发明方法反应条件温和，操作简便，合成成本低，相对绿色，产率高，金诺芬是治疗风湿性关节炎的药，而格列净硫代糖苷类似物是潜在的治疗2型糖尿病的药物。

  公开号：

  CN112538099B

文献信息

• Synthesis and Structure–Activity Relationship Study of Antimicrobial Auranofin against ESKAPE Pathogens
  作者：Bin Wu、Xiaojian Yang、Mingdi Yan

  DOI：10.1021/acs.jmedchem.9b00550

  日期：2019.9.12

  including multidrug resistant strains. It is, however, inactive toward Gram-negative bacteria, for which we are in dire need of new therapies. In this work, 40 auranofin analogues were synthesized by varying the structures of the thiol and phosphine ligands, and their activities were tested against ESKAPE pathogens. The study identified compounds that exhibited bacterial inhibition (MIC) and killing

  FDA批准的关节炎药物金诺芬（Auranofin）最近已被重新用作潜在的抗菌药物。它对许多革兰氏阳性细菌（包括耐多药菌株）表现良好。但是，它对革兰氏阴性细菌没有活性，因此我们急需新疗法。在这项工作中，通过改变硫醇和膦配体的结构合成了40种金诺芬类似物，并测试了它们对ESKAPE病原体的活性。该研究鉴定出的化合物具有比金诺芬高65倍的细菌抑制（MIC）和杀灭（MBC）活性，从而使它们对革兰氏阴性病原体有效。硫醇和膦结构都影响类似物的活性。三甲基膦和三乙基膦配体分别对革兰氏阴性菌和革兰氏阳性菌具有最高的活性。我们的SAR研究表明，巯基配体也非常重要，其结构可以调节AuI复合物对革兰氏阴性细菌和革兰氏阳性细菌的活性。而且，这些类似物具有的哺乳动物细胞毒性与金诺芬相似或更低。
• [EN] GOLD COMPOSITIONS AND METHODS OF USE THEREOF<br/>[FR] COMPOSITIONS D'OR ET LEURS PROCÉDÉS D'UTILISATION
  申请人：UNIV MASSACHUSETTS

  公开号：WO2020037231A1

  公开（公告）日：2020-02-20

  Gold compounds and pharmaceutically acceptable salts thereof are disclosed. Certain compounds and salts are active as antibacterial, antifungal, and/or anti-parasitic agents. The disclosure provides pharmaceutical compositions containing the gold compounds. Methods of using the gold compounds to treat bacterial infections are disclosed.

  金化合物及其药用可接受盐已被披露。某些化合物和盐作为抗菌、抗真菌和/或抗寄生虫剂具有活性。该披露提供含有金化合物的药物组合物。还披露了使用金化合物治疗细菌感染的方法。
• An efficient approach to chloro(organophosphine) gold(<scp>i</scp>) complexes for the synthesis of auranofin
  作者：Junchang Wang、Xuemeng Mi、Jiazhe Wang、You Yang

  DOI：10.1039/c6gc02908f

  日期：——

  A practical and efficient synthesis of chloro(organophosphine) gold(I) complexes is reported. Employment of 4,4'-dihydroxydiphenyl sulfide as a safe and non-irritating reductant is highlighted for the generation of Au(I)-S intermediates, which...

  报道了一种实用有效的氯（有机膦）金（Ⅰ）配合物的合成方法。强调了使用4,4'-二羟基二苯硫醚作为安全且无刺激性的还原剂，用于生成Au（I）-S中间体，该中间体...
• Selective S-deacetylation inspired by native chemical ligation: practical syntheses of glycosyl thiols and drug mercapto-analogues
  作者：Penghua Shu、Jing Zeng、Jinyi Tao、Yueqi Zhao、Guangmin Yao、Qian Wan

  DOI：10.1039/c5gc00084j

  日期：——

  Highly efficient selective S-deacetylations were achieved by simple transthioesterification under mild basic conditions.

  通过在温和的碱性条件下进行简单的硫代酯基转移，即可实现高效的选择性S-脱乙酰基作用。
• Anti-arthritic compositions containing gold salts and organophosphonates
  申请人：THE PROCTER & GAMBLE COMPANY

  公开号：EP0054997A1

  公开（公告）日：1982-06-30

  Compositions comprising pharmaceutically-acceptable gold salts and organophosphonates, especially the geminal diphosphonates, useful in the treatment of arthritic conditions, are disclosed. The method of treating arthritic conditions using these compositions is also disclosed

  本发明公开了由药学上可接受的金盐和有机膦酸盐（尤其是二膦酸盐）组成的组合物，可用于治疗关节炎。还公开了使用这些组合物治疗关节炎的方法