新生霉素 | 303-81-1

• 物质功能分类: 原料药 - 抗生素类药物 - 其它抗生素类药
• 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: 新生霉素
• 英文名称: novobiocin
• 英文别名: [(3R,4S,5R,6R)-5-hydroxy-6-[4-hydroxy-3-[[4-hydroxy-3-(3-methylbut-2-enyl)benzoyl]amino]-8-methyl-2-oxochromen-7-yl]oxy-3-methoxy-2,2-dimethyloxan-4-yl] carbamate
• CAS: 303-81-1
• 化学式: C₃₁H₃₆N₂O₁₁
• 分子量: 612.634
• InChiKey: YJQPYGGHQPGBLI-KGSXXDOSSA-N

物化性质

• 熔点：
  170-172 °C
• 比旋光度：
  D24 -63.0° (c = 1 in ethanol)
• 沸点：
  657.29°C (rough estimate)
• 密度：
  1.3448
• 溶解度：
  可溶于DMSO（少许）、甲醇（少许）
• 物理描述：
  Solid
• 颜色/状态：
  Pale yellow orthorhombic crystals from ethanol
• 蒸汽压力：
  4.9X10-27 mm Hg at 25 °C (est)
• 旋光度：
  Specific optical rotation at 24 °C for D (sodium) line = -63.0 deg (c = 1 in ethanol)
• 解离常数：
  pKa1 = 4.3 (coumarin hydroxyl)

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  44
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  196
• 氢给体数：
  5
• 氢受体数：
  11

ADMET

毒理性

• 人类毒性摘录

/症状和体征/ 在第一阶段临床试验中，难治性癌症病人在第1、3和5天接受VP-16治疗。在给予VP-16之前60分钟，给予止吐药，包括昂丹司琼和地塞米松。VP-16前30分钟口服新生霉素，并根据标准剂量递增设计，在连续的患者组中递增剂量。治疗周期每4周重复一次。在第一个治疗周期中，通过高效液相色谱法测定新生霉素的血浆浓度。33名患者共治疗了69个周期。11名患者以VP-16的起始剂量120 mg/m2开始治疗，其中3名患者出现中性粒细胞减少性发热。VP-16的剂量降至100 mg/平方米，并额外招募了22名患者。新生霉素的剂量范围为3至9克。当新生霉素剂量至少为5.5克时，血浆浓度至少为150 uM可维持24小时。剂量限制性毒性包括中性粒细胞减少性发热和可逆性高胆红素血症。在其他新生霉素试验中，恶心是一个限制性毒性，但通过使用血清素能抗吐药得到了很好的控制。腹泻在大多数患者中常见但轻微。在之前接受过治疗的患者中，推荐的新生霉素剂量为每天7克/平方米。新生霉素似乎不会增加VP-16对骨髓或胃肠道粘膜的毒性。在总体而非游离药物水平上，容易实现与体外调节VP-16所需水平相当的新生霉素血浆浓度。

/SIGNS AND SYMPTOMS/ Patients with refractory cancer were treated with VP-16 on days 1, 3, and 5 /in a Phase 1 Clinical Trial/. Antiemetics, consisting of ondansetron and dexamethasone, were given 60 minutes before the VP-16 was administered. Novobiocin was given orally 30 minutes before the VP-16, and the dose was escalated in successive groups of patients according to a standard dose escalation design. Treatment cycles were repeated every 4 weeks. Plasma concentrations of novobiocin were determined during the first treatment cycle by high-performance liquid chromatography. Thirty-three patients were treated for a total of 69 cycles. Eleven patients were treated with a starting dose of VP-16 of 120 mg/m2, and three of these patients experienced neutropenic fever. The dose of VP-16 was reduced to 100 mg/sq m, and an additional 22 patients were enrolled. The dose of novobiocin ranged from 3 to 9 g. At a novobiocin dose of at least 5.5 g, plasma concentrations of at least 150 uM were sustained for 24 hours. Dose-limiting toxicities consisted of neutropenic fever and reversible hyperbilirubinemia. Nausea, which was a limiting toxicity in other trials of novobiocin, was well controlled with the use of serotonergic antiemetics. Diarrhea was common but mild in most patients. In previously treated patients, the recommended dose of novobiocin in this schedule is 7 g/sq m/day. Novobiocin does not appear to augment the toxicity of VP-16 to the bone marrow or the gastrointestinal mucosa. Plasma concentrations of novobiocin equivalent to the levels required to modulate VP-16 in vitro are readily achievable for total but not unbound free drug.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 人类毒性摘录

/症状和体征/ 抗肿瘤药物耐药性是改善人类大多数成人癌症治疗的主要障碍。新生霉素是一种抗生素，可以抑制真核拓扑异构酶II酶，通过形成致命的DNA-DNA链间交联，增加了几种烷化剂的体外细胞毒性，可能是通过减少药物单加合物的修复。在体内治疗的鼠类肿瘤中，新生霉素显著增强了烷化剂的细胞毒性，而未伴随宿主毒性的增加。在这种背景下，进行了一项新生霉素和环磷酰胺的I期临床试验，用于治疗难治性癌症患者。新生霉素口服给药96小时；在48小时时给予750 mg/m2的静脉环磷酰胺。34名患者接受了65个疗程。在这项试验中，新生霉素的剂量限制性毒性是呕吐。最大耐受剂量是6克/天。34名患者中有6名出现III级或IV级骨髓抑制，但未观察到剂量递增效应。三名患者出现过敏反应，但完全缓解。没有发生其他显著毒性。尽管没有观察到血清新生霉素水平的剂量依赖性效应，但在大于或等于4克/天的19名患者中，有18名在稳态下血清水平大于或等于100微克/毫升，这个水平与体外使用的水平和体内观察到的水平相对应，其中小鼠的新生霉素半衰期为82分钟，远小于人类观察到的6.0小时。在30名可评估的患者中，有2名患者部分响应。另外四名患者病情稳定。六名患者中有四名在环磷酰胺联合治疗期间出现疾病进展。新生霉素在接受环磷酰胺治疗的患者中耐受性良好，血药水平处于药物增强范围内。预计将对环磷酰胺难治性患者进行II期临床试验。

/SIGNS AND SYMPTOMS/ Antineoplastic drug resistance is a major obstacle to improved treatment of most adult cancers in humans. Novobiocin, an antibacterial agent which inhibits the eukaryotic topoisomerase II enzyme, increases the cytotoxicity of several alkylating agents in vitro by the formation of lethal DNA-DNA interstrand cross-links, perhaps by decreasing the repair of drug monoadducts. In murine tumors treated in vivo novobiocin markedly potentiates alkylating agent cytotoxicity without concomitant increases in host toxicity. With this background, a Phase I trial of novobiocin and cyclophosphamide was performed in refractory cancer patients. Novobiocin was given p.o. for 96 h; 750 mg/m2 of i.v. cyclophosphamide was administered at 48 hr. Thirty-four patients received 65 courses. The dose-limiting toxicity of novobiocin in this trial was vomiting. The maximum tolerated dose was 6 g/day. Six of 34 patients had Grade III or IV mylosuppression but no dose escalation effect was noted. Three patients developed allergic reactions which resolved completely. No other significant toxicity occurred. While no dose-dependent effect on serum novobiocin levels occurred, 18 of 19 patients treated at greater than or equal to 4 g daily had serum levels greater than or equal to 100 ug/ml at steady state, a level which corresponds to levels used in vitro and seen in vivo where the murine novobiocin half-life of 82 min is far less than that seen in humans (6.0 hr). Two of 30 evaluable patients had partial responses. Four other patients had stable disease. Four of six had prior disease progression on cyclophosphamide combination therapy. Novobiocin is well tolerated in patients receiving cyclophosphamide and blood levels are in the drug-potentiating range. Phase II trials in cyclophosphamide refractory patients are anticipated.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 非人类毒性摘录

/遗传毒性/ 抗微生物剂萘啶酸和新生霉素都是DNA旋转酶的抑制剂，它们优先抑制DNA修复缺陷的大肠杆菌、沙门氏菌鼠伤寒亚种和枯草杆菌的生长。另一方面，即使在考虑到这些化合物的代谢特性的条件下进行测试，这些试剂对鼠伤寒沙门氏菌和大肠杆菌也没有表现出明显的致突变性。

/GENOTOXICITY/ The antimicrobial agents nalidixic acid and novobiocin, both inhibitors of DNA gyrase, preferentially inhibit the growth of DNA repair-deficient Escherichia coli, Salmonella typhimurium and Bacillus subtilis. On the other hand, these agents exhibit no demonstrable mutagenicity for S. typhimurium and E. coli even when tested under conditions designed to take the metabolic properties of these agents into consideration.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 蛋白质结合

百分之九十五

95%

来源:DrugBank

吸收、分配和排泄

• 吸收

口腔生物利用度可以忽略不计。

Oral bioavailability is negligible.

来源:DrugBank

吸收、分配和排泄

在I期临床试验中，难治性癌症患者在第1、3和5天接受了VP-16治疗。在给予VP-16之前60分钟，给予止吐药，包括昂丹司琼和地塞米松。在VP-16之前30分钟口服新生霉素，并根据标准剂量递增设计，在连续的患者组中递增剂量。治疗周期每4周重复一次。在第一个治疗周期中，通过高效液相色谱法测定新生霉素的血浆浓度。33名患者共接受了69个周期的治疗。11名患者起始剂量为120 mg/平方米的VP-16治疗，其中3名患者出现中性粒细胞减少性发热。将VP-16的剂量减少到100 mg/m²，并额外招募了22名患者。新生霉素的剂量范围为3至9克。当新生霉素剂量至少为5.5克时，血浆浓度至少为150 uM可以维持24小时。

Patients with refractory cancer were treated with VP-16 on days 1, 3, and 5 /in a Phase 1 Clinical Trial/. Antiemetics, consisting of ondansetron and dexamethasone, were given 60 minutes before the VP-16 was administered. Novobiocin was given orally 30 minutes before the VP-16, and the dose was escalated in successive groups of patients according to a standard dose escalation design. Treatment cycles were repeated every 4 weeks. Plasma concentrations of novobiocin were determined during the first treatment cycle by high-performance liquid chromatography. Thirty-three patients were treated for a total of 69 cycles. Eleven patients were treated with a starting dose of VP-16 of 120 mg/sq m, and three of these patients experienced neutropenic fever. The dose of VP-16 was reduced to 100 mg/m2, and an additional 22 patients were enrolled. The dose of novobiocin ranged from 3 to 9 g. At a novobiocin dose of at least 5.5 g, plasma concentrations of at least 150 uM were sustained for 24 hours.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• WGK Germany：
  3
• 海关编码：
  2941906000

制备方法与用途

作用机制

新生霉素的抗菌作用与青霉素和红霉素相似，对葡萄球菌、肺炎球菌、白喉杆菌及脑膜炎球菌等有很强的抑制效果。耐青霉素G的金葡菌对新生霉素仍敏感，但革兰阴性杆菌中除嗜血杆菌外大多不敏感。新生霉素对真菌、立克次体、病毒和原虫等无作用。该药物主要通过抑制细菌蛋白质和核酸的合成起抑菌作用，在高浓度时也可表现出杀菌效果。然而，细菌对新生霉素易产生耐药性。

药代动力学

口服后，新生霉素在2～4小时内血浓度达到峰值，并能维持12小时之久。其血半寿期约为3小时，与血清蛋白结合率高达95%。体内广泛分布，尤其在肝、胆汁中浓度较高，胆汁浓度约为血浓度的2～8倍。约有三分之一的药物通过粪便排出，仅有2～3%经尿液排泄。乳汁中的新生霉素浓度可达到血浓度的6～25%。

不良反应

新生霉素可能引起多种副作用，最常见的包括皮疹和胃肠道症状，如恶心、呕吐、腹泻等。其他不良反应还包括药物热、黄疸、白细胞减少和粒细胞减少等，偶尔还可能出现头晕、视力模糊、过敏性肺炎或心肌炎、血管神经性水肿、血尿及肝功能损害等症状。

由于上述缺点，目前该药已较少用于临床治疗，仅限于对常用抗菌药物耐药的葡萄球菌感染。适用于软组织感染、脓皮病、中耳炎和支气管炎、肺炎等。为防止细菌产生耐药性，常与其他抗生素如氨基糖甙类、利福平或磺胺药合用。

静滴时不宜与碱性抗生素（如链霉素、红霉素）联合使用，以免形成不溶于水的盐类。新生霉素可通过口服、肌内注射或静脉滴注给药。成人每日剂量为1～2g，分3～4次口服；儿童剂量为每日25～50mg/kg，分次口服。肌内注射和静脉注射较少使用，剂量为每日20～30mg/kg，静脉注射时需用注射用水或生理盐水溶解。

肝功能不全者应慎用此药。

反应信息

• 作为反应物：
  描述：

  新生霉素 在 Schwartz's reagent 作用下， 以 乙二醇二甲醚 为溶剂， 反应 18.0h， 以6.8 mg的产率得到DHN1
  参考文献：
  名称：

  作为潜在的热休克蛋白90抑制剂的新霉素类似物的合成和生物学评估

  摘要：

  最近的研究表明，新霉素（NB）是具有证明的DNA回旋酶抑制作用的古默霉素（CA）家族的一种抗生素，通过与C-内的一个假定的ATP结合位点弱结合来抑制热休克蛋白90（HSP90）。总站。为了开发靶向该位点的更有效的HSP90抑制剂并定义此类化合物的结构-活性关系（SAR），我们合成了27种从NB和CA开始的3-amido-7-noviosylcoumarin类似物。使用几种生物学测定法评估了这些物质对HSP90抑制的证据，包括抑制细胞增殖和细胞周期阻滞，诱导热休克反应，抑制体外萤光素酶重新折叠以及消耗HSP90客户蛋白c-erbB-2 /。 HER-2 / neu（HER2）。这项SAR研究表明，通过除去NB / C-3上的吲哚-2-甲酰胺基团取代C-3上的4-羟基-异戊基苯甲酰胺基，可以显着提高生物活性。组从香豆素环。如化合物所示，香豆素部分中的4-羟基甲基化可适度提高生物活性11和13。

  DOI：

  10.1016/j.bmc.2013.06.042
• 作为产物：
  描述：

  (3R,4S,5R,6R)-6-((3-(4-((tert-butyldimethylsilyl)oxy)-3-(3-methylbut-2-en-1-yl)benzamido)-4-hydroxy-8-methyl-2-oxo-2H-chromen-7-yl)oxy)-5-hydroxy-3-methoxy-2,2-dimethyltetrahydro-2H-pyran-4-yl carbamate 在 水 、 溶剂黄146 、 四甲基胍 作用下， 以 四氢呋喃 、 乙腈 为溶剂， 以58%的产率得到新生霉素
  参考文献：
  名称：

  CHEMOSELECTIVE ENRICHMENT FOR COMPOUND ISOLATION

  摘要：

  通过形成聚合硅氧烷醚，可以实现对含有脂肪烃羟基和芳香族羟基化合物的化学选择性分离。本文描述了从聚合硅氧烷试剂中选择性释放含有脂肪烃羟基和芳香族羟基化合物的化学选择性。

  公开号：

  US20140107328A1

文献信息

• [EN] ERK INHIBITORS<br/>[FR] INHIBITEURS D'ERK
  申请人：MERCK SHARP & DOHME

  公开号：WO2016100050A1

  公开（公告）日：2016-06-23

  The present invention provides a compound of Formula (I) or the pharmaceutically acceptable salts, esters, and prodrugs thereof, which are ERK2 inhibitors. The invention also provides a pharmaceutical composition comprising an effective amount of at least one compound of Formula (I) and a pharmaceutically acceptable carrier. The invention also provides a pharmaceutical composition comprising an effective amount of at least one compound of Formula (I) and an effective amount of at least one other pharmaceutically active ingredient (such as, for example, a chemotherapeutic agent), and a pharmaceutically acceptable carrier.

  本发明提供了一种化合物(I)或其药学上可接受的盐、酯和前药，这些化合物是ERK2抑制剂。该发明还提供了一种包括至少一种化合物(I)和药学上可接受的载体的有效量的药物组合物。该发明还提供了一种包括至少一种化合物(I)的有效量和至少一种其他药学活性成分的有效量（例如，化疗药物等）以及药学上可接受的载体的药物组合物。
• [EN] QUINOLONE DERIVATIVES AS ANTIBACTERIALS<br/>[FR] DÉRIVÉS DE QUINOLONE COMME ANTIBACTÉRIENS
  申请人：NOVARTIS AG

  公开号：WO2016020836A1

  公开（公告）日：2016-02-11

  This invention is in the field of medicinal chemistry and relates to compounds, and pharmaceutical compositions thereof, that inhibit bacterial gyrase. The compounds are useful as inhibitors of bacterial gyrase activity and bacterial infections, and have the structure of Formula (I) as further described herein. The invention further provides pharmaceutical compositions comprising a compound of Formula (I) and methods of using the compounds and compositions to treat bacterial infections.

  这项发明属于药物化学领域，涉及抑制细菌旋转酶的化合物及其制药组合物，这些化合物可用作抑制细菌旋转酶活性和细菌感染的药物，并具有如下所述的Formula (I)的结构。该发明还提供了包含Formula (I)化合物的药物组合物，以及使用这些化合物和组合物治疗细菌感染的方法。
• [EN] HETEROCYCLIC UREA COMPOUNDS<br/>[FR] COMPOSÉS HÉTÉROCYCLIQUES D'URÉE
  申请人：BIOTA EUROPE LTD

  公开号：WO2013091011A1

  公开（公告）日：2013-06-27

  The present invention provides a compound of the following formula, racemates, enantiomers and salts thereof. Also provided is the use of these compounds as antibacterials, compositions comprising them and processes for their manufacture.

  本发明提供了以下式的化合物，它们的外消旋体、对映体和盐。还提供了这些化合物作为抗菌剂的用途，包括它们的组合物和制造过程。
• PHOSPHONATED RIFAMYCINS AND USES THEREOF FOR THE PREVENTION AND TREATMENT OF BONE AND JOINT INFECTIONS
  申请人：Rose Yannick Stephane

  公开号：US20110263534A1

  公开（公告）日：2011-10-27

  The present invention relates to phosphonated Rifamycins, and methods of making and using such compounds. These compounds are useful as antibiotics for prophylaxis and/or the treatment of bone and joint infections, especially for the prophylaxis and/or treatment of osteomyelitis.

  本发明涉及磷酸化利福霉素以及制备和使用这类化合物的方法。这些化合物可用作预防和/或治疗骨骼和关节感染的抗生素，特别是用于预防和/或治疗骨髓炎。
• [EN] CONTROLLED-RELEASE TYROSINE KINASE INHIBITOR COMPOUNDS WITH LOCALIZED PK PROPERTIES<br/>[FR] COMPOSÉS INHIBITEURS DE TYROSINE KINASE À LIBÉRATION CONTRÔLÉE PRÉSENTANT DES PROPRIÉTÉS PHARMACOCINÉTIQUES LOCALISÉES
  申请人：ASCENDIS PHARMA ONCOLOGY DIV A/S

  公开号：WO2020254613A1

  公开（公告）日：2020-12-24

  The present invention relates to a water-insoluble controlled-release tyrosine kinase inhibitor ("TKI") compound for use in the treatment of a cell-proliferation disorder, wherein said water-insoluble controlled-release TKI compound releases one or more TKI drug, wherein the water-insoluble controlled-release TKI compound is administered by intra-tissue administration and wherein the total amount of TKI moieties and TKI drug molecules remaining locally in such tissue 3 days after said intra-tissue administration is at least 25% of the amount of TKI moieties or TKI drug molecules administered by said intra-tissue administration; and to related aspects.

  本发明涉及一种水不溶性控释酪氨酸激酶抑制剂（“TKI”）化合物，用于治疗细胞增殖紊乱，其中所述水不溶性控释TKI化合物释放一种或多种TKI药物，所述水不溶性控释TKI化合物通过组织内给药给予，并且在所述组织内给药后的第3天，所述组织中残留的TKI基团和TKI药物分子的总量至少为所述组织内给药给予的TKI基团或TKI药物分子总量的25％；以及相关方面。