(2,3,4,6-tetra-O-acetyl-1-thio-β-D-galactopyranosato)(triethylphosphine) gold(I) | 99395-46-7

• 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: (2,3,4,6-tetra-O-acetyl-1-thio-β-D-galactopyranosato)(triethylphosphine) gold(I)
• 英文别名: (2,3,4,6-tetra-O-acetyl-1-thio-β-D-galacotopyranosato)(triethylphosphine)gold(I)；auranofin；2,3,4,6-tetra-O-acetyl-1-thio(triethyIphosphine)gold-β-D-galactopyranoside；gold(1+);(2S,3R,4S,5S,6R)-3,4,5-triacetyloxy-6-(acetyloxymethyl)oxane-2-thiolate;triethylphosphane
• CAS: 99395-46-7
• 化学式: C₂₀H₃₄AuO₉PS
• 分子量: 678.491
• InChiKey: AUJRCFUBUPVWSZ-JMYRMHIVSA-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

接受金钠硫代硫酸盐治疗的病人尿中的主要金物种是[Au(CN)2]-，这也出现在血液的低分子量浸润中。同样，服用金诺芬的病人体内尿液和血液中也可以检测到这种化合物。

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水中。... [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）可能是奥罗诺金在原始配体都被取代后形成的循环代谢物。

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

• 相互作用

...在之前表现出毒性反应的患者中，青霉胺毒性的发生率可能更高。停止使用金制剂和开始使用青霉胺之间的间隔并不影响毒性的发生率。金制剂治疗期间出现皮疹似乎不会影响青霉胺治疗期间皮疹的发展，但金制剂治疗期间出现蛋白尿或骨髓抑制的患者可能更有可能发展出类似的青霉胺副作用。

...there may be a higher incidence of penicillamine toxicity in patients who have previously shown toxic reactions. The interval between stopping the gold and starting the penicillamine did not influence incidence of toxicity. The development of a rash during gold treatment does not seem to influence the development of a rash during penicillamine treatment, but patients who have had proteinuria or bone-marrow depression during gold treatment may have an increased likelihood of developing a similar side effect with penicillamine.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

在一篇单一病例报告中，有建议称同时使用Ridaura（金诺芬）和苯妥英可能增加了苯妥英的血药水平。

In a single-patient report, there is the suggestion that concurrent administration of Ridaura /auranofin/ and phenytoin may have increased phenytoin blood levels.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

尚未有使用螯合剂等手段治疗Ridaura（金诺芬）过量的经验。然而，它们已用于注射用金制剂，并可以考虑用于Ridaura（金诺芬）过量。

There has been no experience with treating Ridaura overdosage with modalities such as chelating agents. However, they have been used with injectable gold and may be considered for Ridaura /(auranofin)/ overdosage.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

在急性过量情况下，建议立即进行催吐或洗胃，并给予适当的支持性治疗。

In case of acute overdosage, immediate induction of emesis or gastric lavage and appropriate supportive therapy is recommended.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

与治疗类风湿性关节炎的金盐疗法相关的肺毒性...如果正确处理，通过简单中断金盐治疗或使用皮质类固醇，预后良好，大多数情况下可以完全治愈。报告了一例对皮质类固醇治疗反应良好的病例，并分析了与类风湿性关节炎相关的肺纤维化的鉴别诊断。/金盐/

Pulmonary toxicity associated with gold salt treatment of rheumatoid arthritis...has a good prognosis if treated properly with the simple interruption of gold salts or with corticosteroids, with complete cure in the majority of cases. A case with good response to corticosteroid therapy is reported and the differential diagnosis with pulmonary fibrosis associated with rheumatoid arthritis is analyzed. /Gold salt/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在活体中，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，有82%与白蛋白结合，其余与α1-、α2-和β-球蛋白结合，可能还与IgG结合。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硫代酸钠达到的浓度相似。

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，较低浓度的金分布到心脏、睾丸、胃肠道、肌肉、眼睛、脂肪和大脑。在动物（可能在人类中也是如此），少量来自金诺芬的金元素会分布到胆汁中。类风湿性关节炎患者接受金诺芬治疗时，滑液中的金浓度远低于接受注射金化合物治疗的患者，但在金诺芬治疗期间，血液与滑液金浓度的比例与注射金治疗期间相似（大约为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累积，这与注射金化合物治疗期间发生的累积相反。在金诺芬治疗期间，头发或指甲几乎没有或没有金累积，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累积。

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

• 作为产物：
  描述：

  三乙基膦 在 potassium carbonate 作用下， 以 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 3.0h， 生成 (2,3,4,6-tetra-O-acetyl-1-thio-β-D-galactopyranosato)(triethylphosphine) gold(I)
  参考文献：
  名称：

  抗菌素金诺芬抗ESKAPE病原菌的合成及构效关系研究。

  摘要：

  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。

  DOI：

  10.1021/acs.jmedchem.9b00550

文献信息

• [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。
• ——
  作者：HILL D. T.、 SUTTON B. M.、 LANTOS I.、 WALES N.、 PENN H.

  DOI：——

  日期：——
• ——
  作者：HILL D. T.、 SUTTON B. M.、 LANTOS I.、 WALES N.、 PENN H.

  DOI：——

  日期：——
• 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。