光辉霉素 | 18378-89-7

• 物质功能分类: 原料药 - 抗肿瘤药 - 抗生素类抗肿瘤药
• 分子结构分类: 有机化合物 - 有机氧化合物
• 中文名称: 光辉霉素
• 中文别名: 光神霉素；普卡酶素；普卡霉素；金霉酸
• 英文名称: mithramycin
• 英文别名: mithramycin A；plicamycin；aureolic acid；(2S,3S)-2-[(2S,4R,5R,6R)-4-[(2S,4R,5S,6R)-4-[(2S,4S,5R,6R)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy-5-hydroxy-6-methyloxan-2-yl]oxy-5-hydroxy-6-methyloxan-2-yl]oxy-3-[(1S,3S,4R)-3,4-dihydroxy-1-methoxy-2-oxopentyl]-6-[(2S,4R,5R,6R)-4-[(2S,4R,5S,6R)-4,5-dihydroxy-6-methyloxan-2-yl]oxy-5-hydroxy-6-methyloxan-2-yl]oxy-8,9-dihydroxy-7-methyl-3,4-dihydro-2H-anthracen-1-one
• CAS: 18378-89-7
• 化学式: C₅₂H₇₆O₂₄
• 分子量: 1085.16
• InChiKey: CFCUWKMKBJTWLW-BKHRDMLASA-N

物化性质

• 熔点：
  180-183 °C
• 比旋光度：
  D20 -51° (c = 0.4 in ethanol)
• 沸点：
  761.72°C (rough estimate)
• 密度：
  1.1576 (rough estimate)
• 溶解度：
  可溶于DMSO（高达20mg/ml）或乙醇（高达10mg/ml）
• 物理描述：
  Solid
• 颜色/状态：
  YELLOW, CRYSTALLINE POWDER SHOWING BIREFRINGENCE
• 气味：
  ODORLESS
• 稳定性/保质期：

  HYGROSCOPIC, DECOMP SLOWLY IN LIGHT, & DECOMP IN HEAT

• 旋光度：
  Specific optical rotation at 20 °C for D (sodium) line = -51 deg (c = 0.4 in ethanol)
• 解离常数：
  pKa1 = 6.9; pKa2 = 7.7 (naphthalene hydroxyls) (est)

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  76
• 可旋转键数：
  15
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.77
• 拓扑面积：
  358
• 氢给体数：
  11
• 氢受体数：
  24

ADMET

毒理性

• 肝毒性

使用plicamycin进行化疗会导致几乎所有治疗超过1到2天并在治疗期间接受监测的患者出现血清酶水平升高。血清ALT、AST和LDH值在首次输注后的3天内开始上升，并在7到10天内达到峰值，水平为正常上限（ULN）的5到500倍。然而，这些升高是暂时的，在1到3周内会解决，并且很少伴有症状或黄疸。在这些发作期间进行的肝脏活检通常显示中央小叶坏死和充血。随着治疗的重复进行，升高的情况通常以相同或更低的程度继续发生。曾有一例报告，一名患者因非恶性高钙血症接受全程剂量的plicamycin治疗4天后，出现了急性肝衰竭，这提示可能是缺血性肝炎或窦状阻塞综合征。除此之外，尽管血清酶升高程度从中等到严重，但它们是暂时的并且是无害的。

Chemotherapy with plicamycin causes serum enzyme elevations in almost all patients who are treated for more than 1 or 2 days and who are monitored during therapy. Serum ALT, AST and LDH values begin to rise within 3 days of the first infusion and peak within 7 to 10 days at levels of 5 to 500 times the upper limit of the normal range (ULN). The elevations, however, are transient and resolve within 1 to 3 weeks and are rarely associated with symptoms or jaundice. Liver biopsies taken during these episodes usually demonstrate centrolobular necrosis and congestion. With repeated courses, elevations continue to occur generally to the same or lesser degree. A single instance of acute liver failure arising within days of therapy that was suggestive of ischemic hepatitis or sinusoidal obstruction syndrome has been reported in a patient treated with full doses of plicamycin for 4 days for nonmalignant hypercalcemia. Otherwise, the serum enzyme elevations, despite being moderate to severe, are transient and benign.

来源:LiverTox

毒理性

• 相互作用

普卡霉素引起的低凝血酶原血症可能会增加香豆素类和茚满二酮衍生物抗凝剂的活动性，并可能增加接受肝素或溶栓药物治疗的患者的出血风险；不推荐同时使用。

Plicamycin-induced hypoprothrombinemia may increase the activity of coumarin- and indandione-derivative anticoagulants and may increase the risk of bleeding in patient receiving heparin or thrombolytic agents; concurrent use is not recommended.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

同时使用非甾体抗炎药、阿司匹林、右旋糖酐、双嘧达莫、磺吡酮或丙戊酸与普卡霉素可能会增加出血风险，因为这些药物单独或与普卡霉素联合使用时，可能会通过增加或协同作用降低血液凝固能力，即抑制血小板聚集，同时普卡霉素和大剂量阿司匹林可能会诱导低凝血酶原血症；此外，阿司匹林、非甾体抗炎药或磺吡酮的胃肠道溃疡性或出血潜力可能会增加接受普卡霉素治疗患者的出血风险。

Concurrent use /of nonsteroidal anti-inflammatory drugs, aspirin, dextran, dipyridamole, sulfinpyrazone, or valproic acid/ with plicamycin may increase the risk of hemorrhage because of additive or multiple actions, which may decrease the blood-clotting ability, ie, inhibition of platelet aggregation, by these medications and/or plicamycin combined with induction of hypoprothrombinemia by plicamycin and large dose of aspirin; in addition, the gastrointestinal ulcerative or hemorrhagic potential of aspirin, the nonsteroidal anti-inflammatory drugs, or sulfinpyrazone may increase the risk of hemorrhage in plicamycin-treated patients.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

同时使用其他骨髓抑制药、肝毒性药物或肾毒性药物可能会增加中毒的风险。

Concurrent use /of other bone marrow depressants, hepatotoxic medications, or nephrotoxic medications/ may increase the potential for toxicity.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

维生素D的同时使用，包括钙化二醇和钙三醇，可能会拮抗plicamycin作为钙通道阻滞剂时的效果。

Concurrent use /of vitamin D, including calcifediol and calcitriol/ may antagonize the effect of plicamycin when used as a calcium antagonist.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

• 消除途径

用3H标记的plicamycin在小鼠中的放射自显影研究表明，同位素的最大浓度出现在肝脏的库普弗细胞和肾小管的细胞中。Plicamycin在最初的2小时内迅速从血液中清除，排泄也很快。67%的排泄发生在4小时内，75%在8小时内，而90%在注射后的第一个24小时内回收。

Radioautography studies with 3H-labeled plicamycin in mice show that the greatest concentrations of the isotope are in the Kupffer cells of the liver and cells of the renal tubules. Plicamycin is rapidly cleared from the blood within the first 2 hours and excretion is also rapid. 67% percent of measured excretion occurs within 4 hours, 75% within 8 hours, and 90% is recovered in the first 24 hours after injection.

来源:DrugBank

吸收、分配和排泄

不知道plicamycin是否会分泌在母乳中。

It is not known whether plicamycin is excreted in breast milk.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

作用持续时间：单次给药后7至10天。

Duration of action: 7 to 10 days with a single dose.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

首次给药后72小时达到最大效果。

Time to peak effect: 72 hours with a single dose.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

作用开始时间：用于治疗高钙血症时，通常在给药后24至48小时内血浆钙含量会降低。

Onset of action: When used for hypercalcemia, a reduction in plasma calcium usually occurs within 24 to 48 hours following administration.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  6.1(b)
• 危险品标志：
  Xn
• 安全说明：
  S22,S28A,S36/37/39,S38,S45
• 危险类别码：
  R22
• WGK Germany：
  3
• 海关编码：
  29419090
• 危险品运输编号：
  UN 3249
• RTECS号：
  PZ2800000
• 包装等级：
  III
• 危险类别：
  6.1(b)

制备方法与用途

生物活性

Plicamycin 是一种选择性特异性 Sp1 转录因子抑制剂。通过降低 Sp1 蛋白表达，Plicamycin 抑制癌细胞生长。

靶点

• Sp1 transcription factor：锌指转录因子，调节多种细胞功能并促进肿瘤进展，通过控制与细胞周期、凋亡和 DNA 损伤相关的基因的表达实现。Sp1 与 GC 富集区启动子结合，并与通用转录装置及多个信号通路中的共激活复合物相互作用。

体外研究

Plicamycin (Mith) 通过诱导蛋白酶体依赖性降解减少 Sp1 蛋白，从而通过 DR5/caspase-8/Bid 信号通路抑制宫颈癌生长。为了评估 Plicamycin 对宫颈癌细胞的抗增殖效果，在不同浓度下培养两种遗传背景不同的宫颈癌细胞系，经过 48 小时后发现 Plicamycin 浓度依赖性地抑制了 HEp-2 和 KB 细胞的增长。通过 DAPI 染色观察核浓缩和裂解来定性估计凋亡细胞死亡，Plicamycin 导致显著的 DNA 裂解。

体内研究

在异种移植模型中，Plicamycin (0.2 mg/kg/日) 显示出抗肿瘤活性，并观察到肿瘤体积和重量减少。治疗组小鼠体重无显著下降，表明 Plicamycin 相关毒性较低。Plicamycin 还增加了肿瘤异种移植物中的 TUNEL 阳性细胞数量，在各个器官中未见明显系统毒性。

用途

• 抗癌抗生素，对多种动物肿瘤有较强的抑制作用。
• 其作用机制是与 DNA 结合，抑制转录和蛋白质合成，抑制 RNA 的合成，并作用于细胞增殖的各个时期。
• 在多药耐药 (MDR) 表现型中，Plicamycin 是 Pgp 的底物。
• 用于流式细胞术中的荧光染色 DNA，适用于检测 DNA。

反应信息

• 作为反应物：
  描述：

  光辉霉素 在 羟胺 、 三氟乙酸 作用下， 以 甲醇 为溶剂， 以33%的产率得到C₅₂H₇₇NO₂₄
  参考文献：
  名称：

  Mithramycin 2′-Oximes with Improved Selectivity, Pharmacokinetics, and Ewing Sarcoma Antitumor Efficacy

  摘要：

  Mithramycin A (MTM) inhibits the oncogenic transcription factor EWS-FLI1 in Ewing sarcoma, but poor pharmacokinetics (PK) and toxicity limit its clinical use. To address this limitation, we report an efficient MTM 2'-oxime (MTM_ox) conjugation strategy for rapid MTM diversification. Comparative cytotoxicity assays of 41 MTM_ox analogues using E-twenty-six (ETS) fusion-dependent and ETS fusion-independent cancer cell lines revealed improved ETS fusion-independent/dependent selectivity indices for select 2'-conjugated analogues as compared to MTM. Luciferase-based reporter assays demonstrated target engagement at low nM concentrations, and molecular assays revealed that analogues inhibit the transcriptional activity of EWS-FLI1. These in vitro screens identified MTM_ox32E (a Phe-Trp dipeptide-based 2'-conjugate) for in vivo testing. Relative to MTM, MTM_ox32E displayed an 11-fold increase in plasma exposure and improved efficacy in an Ewing sarcoma xenograft. Importantly, these studies are the first to point to simple C3 aliphatic side-chain modification of MTM as an effective strategy to improve PK.

  DOI：

  10.1021/acs.jmedchem.0c01526
• 作为产物：
  描述：

  mithramycin DK 在 ketoreductase MtmW 作用下， 生成 光辉霉素
  参考文献：
  名称：

  Molecular Insight into Substrate Recognition and Catalysis of Baeyer–Villiger Monooxygenase MtmOIV, the Key Frame-Modifying Enzyme in the Biosynthesis of Anticancer Agent Mithramycin

  摘要：

  Baeyer-Villiger monooxygenases (BVMOs) have been shown to play key roles for the biosynthesis of important natural products. MtmOIV, a homodimeric FAD- and NADPH-dependent BVMO, catalyzes the key frame-modifying steps of the mithramycin biosynthetic pathway, including an oxidative C-C bond cleavage, by converting its natural substrate premithramycin B into mithramycin DK, the immediate precursor of mithramycin. The drastically improved protein structure of MtmOIV along with the high-resolution structure of MtmOIV in complex with its natural substrate premithramycin B are reported here, revealing previously undetected key residues that are important for substrate recognition and catalysis. Kinetic analyses of selected mutants allowed us to probe the substrate binding pocket of MtmOIV and also to discover the putative NADPH binding site. This is the first substrate-bound structure of MtmOIV providing new insights into substrate recognition and catalysis, which paves the way for the future design of a tailored enzyme for the chemo-enzymatic preparation of novel mithramycin analogues.

  DOI：

  10.1021/cb400399b

文献信息

• [EN] ACC INHIBITORS AND USES THEREOF<br/>[FR] INHIBITEURS DE L'ACC ET UTILISATIONS ASSOCIÉES
  申请人：GILEAD APOLLO LLC

  公开号：WO2017075056A1

  公开（公告）日：2017-05-04

  The present invention provides compounds I and II useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.

  本发明提供了化合物I和II，这些化合物可用作乙酰辅酶A羧化酶（ACC）的抑制剂，以及它们的组合物和使用方法。
• [EN] COMPOUNDS AND COMPOSITIONS COMPRISING CDK INHIBITORS AND METHODS FOR THE TREATMENT OF CANCER<br/>[FR] COMPOSÉS ET COMPOSITIONS COMPRENANT DES INHIBITEURS DES CDK ET MÉTHODES DE TRAITEMENT DU CANCER
  申请人：UNIV GEORGIA STATE RES FOUND

  公开号：WO2010129858A1

  公开（公告）日：2010-11-11

  Disclosed herein are compounds suitable for use as antitumor agents, methods for treating cancer wherein the disclosed compounds are used in making a medicament for the treatment of cancer, methods for treating a tumor comprising, administering to a subject a composition comprising one or more of the disclosed cytotoxic agents, and methods for preparing the disclosed antitumor agents.

  本文披露了适用作抗肿瘤药剂的化合物，用于治疗癌症的方法，其中所披露的化合物用于制备治疗癌症的药物，治疗肿瘤的方法包括向受试者施用包含一种或多种所披露的细胞毒性药剂的组合物，以及制备所披露的抗肿瘤药剂的方法。
• Cobalamin conjugates for anti-tumor therapy
  申请人：Weinshenker M. Ned

  公开号：US20050054607A1

  公开（公告）日：2005-03-10

  The present invention provides a cobalamin-drug conjugate suitable for the treatment of tumor related diseases. Cobalamin is indirectly covalently bound to an anti-tumor drug via a cleavable linker and one or more optional spacers. Cobalamin is covalently bound to a first spacer or the cleavable linker via the 5′-OH of the cobalamin ribose ring. The drug is bound to a second spacer of the cleavable linker via an existing or added functional group on the drug. After administration, the conjugate forms a complex with transcobalamin (any of its isoforms). The complex then binds to a receptor on a cell membrane and is taken up into the cell. Once in the cell, an intracellular enzyme cleaves the conjugate thereby releasing the drug. Depending upon the structure of the conjugate, a particular class or type of intracellular enzyme affects the cleavage. Due to the high demand for cobalamin in growing cells, tumor cells typically take up a higher percentage of the conjugate than do normal non-growing cells. The conjugate of the invention advantageously provides a reduced systemic toxicity and enhanced efficacy as compared to a corresponding free drug.

  本发明提供了一种适用于治疗肿瘤相关疾病的钴胺素-药物结合物。钴胺素通过可切割的连接剂间接共价结合到抗肿瘤药物上，还可以通过一个或多个可选的间隔物。钴胺素通过其核糖环的5'-OH与第一间隔物或可切割连接剂共价结合。药物通过其现有或添加的功能基团与可切割连接剂的第二间隔物结合。在给药后，结合物与转钴胺素（其任何同工异构体）形成复合物。然后，该复合物结合到细胞膜上的受体并被细胞摄取。一旦进入细胞，细胞内酶将切割结合物，从而释放药物。根据结合物的结构，特定类别或类型的细胞内酶影响切割。由于生长细胞对钴胺素的需求量较高，肿瘤细胞通常摄取结合物的比例高于正常非生长细胞。本发明的结合物与相应的游离药物相比，具有较低的全身毒性和增强的疗效。
• [EN] 2-QUINOLONE DERIVED INHIBITORS OF BCL6<br/>[FR] INHIBITEURS DE BCL6 DÉRIVÉS DE 2-QUINOLONE
  申请人：CANCER RESEARCH TECH LTD

  公开号：WO2018215798A1

  公开（公告）日：2018-11-29

  The present invention relates to compounds of formula I that function as inhibitors of BCL6(B- cell lymphoma 6) activity: Formula I wherein X1, X2, X3, R1, R2, R3, R4 and R5 are each as defined herein. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer,as well as other diseases or conditions in which BCL6 activity is implicated.

  本发明涉及作为BCL6（B细胞淋巴瘤6）活性抑制剂的I式化合物：式中X1、X2、X3、R1、R2、R3、R4和R5分别如本文所定义。本发明还涉及制备这些化合物的方法，包括含有它们的药物组合物，以及它们在治疗增生性疾病（如癌症）以及其他BCL6活性所涉及的疾病或病况中的用途。
• [EN] SUBSTITUTED N-HETEROCYCLIC CARBOXAMIDES AS ACID CERAMIDASE INHIBITORS AND THEIR USE AS MEDICAMENTS<br/>[FR] CARBOXAMIDES N-HÉTÉROCYCLIQUES SUBSTITUÉS UTILISÉS EN TANT QU'INHIBITEURS DE LA CÉRAMIDASE ACIDE ET LEUR UTILISATION EN TANT QUE MÉDICAMENTS
  申请人：BIAL BIOTECH INVEST INC

  公开号：WO2021055627A1

  公开（公告）日：2021-03-25

  The invention provides substituted N-heterocyclic carboxamides and related compounds, compositions containing such compounds, medical kits, and methods for using such compounds and compositions to treat a medical disorder, e.g., cancer, lysosomal storage disorder, neurodegenerative disorder, inflammatory disorder, in a patient.

  这项发明提供了替代的N-杂环羧酰胺和相关化合物，含有这些化合物的组合物，医疗工具包，以及使用这些化合物和组合物治疗患者的医疗疾病（例如癌症、溶酶体贮积症、神经退行性疾病、炎症性疾病）的方法。