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15-[[(6-deoxy-2,6-di-O-methyl-β-D-allopyranosyl)-oxy]methyl]-6-[[3,6-dideoxy-4-O-(2,6-dideoxy-3-C-methyl-α-L-ribo-hexapyranosyl)-3-(dimethylamino)-β-D-glucopyranosyl]oxy]-16-ethyl-4-hydroxy-5,9,13-trimethyl-2,10-oxo-oxocyclo-hexadeca-11,13-diene-7... | 1401-69-0

中文名称
——
中文别名
——
英文名称
15-[[(6-deoxy-2,6-di-O-methyl-β-D-allopyranosyl)-oxy]methyl]-6-[[3,6-dideoxy-4-O-(2,6-dideoxy-3-C-methyl-α-L-ribo-hexapyranosyl)-3-(dimethylamino)-β-D-glucopyranosyl]oxy]-16-ethyl-4-hydroxy-5,9,13-trimethyl-2,10-oxo-oxocyclo-hexadeca-11,13-diene-7...
英文别名
tylosin;Tylon;2-[(11E,13E)-6-[5-(4,5-dihydroxy-4,6-dimethyloxan-2-yl)oxy-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-16-ethyl-4-hydroxy-15-[(5-hydroxy-3,4-dimethoxy-6-methyloxan-2-yl)oxymethyl]-5,9,13-trimethyl-2,10-dioxo-1-oxacyclohexadeca-11,13-dien-7-yl]acetaldehyde
15-[[(6-deoxy-2,6-di-O-methyl-β-D-allopyranosyl)-oxy]methyl]-6-[[3,6-dideoxy-4-O-(2,6-dideoxy-3-C-methyl-α-L-ribo-hexapyranosyl)-3-(dimethylamino)-β-D-glucopyranosyl]oxy]-16-ethyl-4-hydroxy-5,9,13-trimethyl-2,10-oxo-oxocyclo-hexadeca-11,13-diene-7...化学式
CAS
1401-69-0
化学式
C46H77NO17
mdl
——
分子量
916.114
InChiKey
WBPYTXDJUQJLPQ-LLMNDNAOSA-N
BEILSTEIN
——
EINECS
——
  • 物化性质
  • 计算性质
  • ADMET
  • 安全信息
  • SDS
  • 制备方法与用途
  • 上下游信息
  • 反应信息
  • 文献信息
  • 表征谱图
  • 同类化合物
  • 相关功能分类
  • 相关结构分类

物化性质

  • 熔点:
    135-137°C
  • 比旋光度:
    D25 -46° (c = 2 in methanol)
  • 沸点:
    796.05°C (rough estimate)
  • 密度:
    1.1424 (rough estimate)
  • 溶解度:
    DMF:30mg/mL; DMSO:25mg/mL;乙醇:30mg/mL
  • 物理描述:
    Solid
  • 颜色/状态:
    Crystals from water
  • 蒸汽压力:
    1.98X10-34 mm Hg at 25 °C (est)
  • 稳定性/保质期:

    Stable under recommended storage conditions.

  • 旋光度:
    Specific optical rotation: -46 deg at 25 °C/D (c = 2 cm methanol)
  • 分解:
    When heated to decomposition it emits toxic fumes of /nitrogen oxide/.
  • 解离常数:
    pKa = 7.73

计算性质

  • 辛醇/水分配系数(LogP):
    1
  • 重原子数:
    64
  • 可旋转键数:
    13
  • 环数:
    4.0
  • sp3杂化的碳原子比例:
    0.85
  • 拓扑面积:
    239
  • 氢给体数:
    5
  • 氢受体数:
    18

ADMET

代谢
链霉菌属弗拉德菌的泰乐菌素生物合成(tyl)基因簇包含辅助基因,这些基因编码通常与初级代谢相关的功能。这些基因的破坏不会导致生存能力的丧失,因为基因组其他位置也存在着等效基因(可能用于“看家”目的)。tyl簇还包含两个编码在数据库中没有任何蛋白质相似性的产物的基因。两个辅助基因,metF(编码N5,N10-亚甲基四氢叶酸还原酶)和metK(编码S-腺苷酸合成酶),位于tyl簇中的一个“未知”基因(orf9)的两侧。在所有这三个基因都被破坏的弗拉德菌菌株中,泰乐菌素的产量降低了,尽管这种影响在补充了甘甜菜碱培养基中被掩盖了,因为甘甜菜碱可以向四氢叶酸池提供甲基。显然,将辅助基因招募到tyl簇的一个后果是增强了次级代谢期间转甲基的能力。
The tylosin-biosynthetic (tyl) gene cluster of Streptomyces fradiae contains ancillary genes that encode functions normally associated with primary metabolism. These can be disrupted without loss of viability, since equivalent genes (presumably used for 'housekeeping' purposes) are also present elsewhere in the genome. The tyl cluster also contains two genes that encode products unlike any proteins in the databases. Two ancillary genes, metF (encoding N5,N10-methylenetetrahydrofolate reductase) and metK, encoding S-adenosylmethionine synthase, flank one of the 'unknown' genes (orf9) in the tyl cluster. In a strain of S. fradiae in which all three of these genes were disrupted, tylosin production was reduced, although this effect was obscured in media supplemented with glycine betaine which can donate methyl groups to the tetrahydrofolate pool. Apparently, one consequence of the recruitment of ancillary genes into the tyl cluster is enhanced capacity for transmethylation during secondary metabolism.
来源:Hazardous Substances Data Bank (HSDB)
代谢
关于致病性诺卡氏菌对大环内酯类抗生素(沙链霉素泰乐菌素)的敏感性研究显示,大多数被检测的诺卡氏菌种类对这两种抗生素都有很高的耐药性,尽管N. nova(诺卡氏菌属的一个种)对此有一定的敏感性。N. asteroides IFM 0339(一种诺卡氏菌)通过在2'-OH位的糖基化或糖基化并还原20位的甲酰基团,将这些大环内酯类抗生素转化为无活性的代谢物。通过核磁共振(NMR)和质谱(MS)数据确定了代谢物的结构,分别为2'-[O-(beta-D-吡喃葡萄糖基)]沙链霉素(2),2'-[O-(beta-D-吡喃葡萄糖基)]泰乐菌素(5)和20-二氢-2'-[O-(beta-D-吡喃葡萄糖基)]泰乐菌素(4)。
Studies on the susceptibility of pathogenic Nocardia to macrolide antibiotics, chalcomycin and tylosin, showed that most of the Nocardia species examined were highly resistant to both antibiotics, although N. nova was moderately susceptible. N. asteroides IFM 0339 converted these macrolides into inactive metabolites by glycosylation at 2'-OH or glycosylation and reduction of the 20-formyl group. The structures of the metabolites were determined from NMR and MS data to be 2'-[O-(beta-D-glucopyranosyl)]chalcomycin (2), 2'-[O-(beta-D-glucopyranosyl)]tylosin (5) and 20-dihydro-2'-[O-(beta-D-glucopyranosyl)]tylosin (4).
来源:Hazardous Substances Data Bank (HSDB)
代谢
泰乐菌素是由 Streptomyces fradiae 通过聚酮代谢和三种脱氧己糖的合成相结合产生的,其中mycaminose是最先添加到聚酮苷元tylactone(原泰乐菌素)的。以前,破坏编码mycaminose与苷元结合的基因(tylMII)意外地消除了后者的积累,这提高了在S. fradiae中聚酮代谢与脱氧己糖生物合成之间存在联系的可能性。然而,当时,无法排除另一种解释,即对不参与mycaminose代谢的其他基因表达产生下游影响可能导致了这种现象。在这里,研究表明破坏四个特定参与mycaminose生物合成的基因(tylMI-III和tylB)中的任何一个都会引起类似的反应,这证实了mycaminosyl-tylactone的产生直接影响S. fradiae中的聚酮代谢。在类似条件下,当mycaminose生物合成被基因破坏特异性阻断时,通过外源添加糖基化的泰乐菌素前体可以恢复tylactone的积累。此外,还发现某些不属于泰乐菌素途径的其他大环内酯也具有定性相似的效应。比较刺激性大环内酯的结构将有助于研究其刺激机制。
Tylosin is produced by Streptomyces fradiae via a combination of polyketide metabolism and synthesis of three deoxyhexose sugars, of which mycaminose is the first to be added to the polyketide aglycone, tylactone (protylonolide). Previously, disruption of the gene (tylMII) encoding attachment of mycaminose to the aglycone unexpectedly abolished accumulation of the latter, raising the possibility of a link between polyketide metabolism and deoxyhexose biosynthesis in S. fradiae. However, at that time, it was not possible to eliminate an alternative explanation, namely, that downstream effects on the expression of other genes, not involved in mycaminose metabolism, might have contributed to this phenomenon. Here, it is shown that disruption of any of the four genes (tylMI--III and tylB) specifically involved in mycaminose biosynthesis elicits a similar response, confirming that production of mycaminosyl-tylactone directly influences polyketide metabolism in S. fradiae. Under similar conditions, when mycaminose biosynthesis was specifically blocked by gene disruption, accumulation of tylactone could be restored by exogenous addition of glycosylated tylosin precursors. Moreover, certain other macrolides, not of the tylosin pathway, were also found to elicit qualitatively similar effects. Comparison of the structures of stimulatory macrolides will facilitate studies of the stimulatory mechanism.
来源:Hazardous Substances Data Bank (HSDB)
代谢
在链霉菌Streptomyces fradiae中,有三种糖基转移酶参与泰乐菌素生物合成。首先添加到多酮糖苷元(泰乳糖酮)上的糖是麦卡米糖,编码麦卡米糖基转移酶的基因是orf2*(tylM2)。然而,有针对性的破坏orf2*基因并没有在通常有利于泰乐菌素生产的条件下导致泰乳糖酮的积累;相反,泰乳糖酮的合成实际上被彻底取消了。这部分可能是由于orf2*基因下游基因表达受到了极性效应的影响,特别是orf4*(ccr)基因,它编码肉桂酰辅酶A还原酶,这是一种为多酮代谢提供4碳延伸单元的酶。然而,这并不能完全解释现象,因为当orf2*基因被重新引入到破坏的菌株中时,泰乐菌素的生产恢复了约10%的野生型平。当泰乐菌素的糖基化前体被喂养给破坏的菌株时,它们被转化为泰乐菌素,证实了与泰乐菌素生物合成相关的三种糖基转移酶中有两种仍然完整。然而,有趣的是,在这种条件下也积累了泰乳糖酮,而且当泰乐菌素被添加到类似的发酵中时,积累的程度要小得多。因此,得出结论,糖基化的巨环内酯在S. fradiae中对多酮代谢产生了明显的正向效应。
Three glycosyltransferases are involved in tylosin biosynthesis in Streptomyces fradiae. The first sugar to be added to the polyketide aglycone (tylactone) is mycaminose and the gene encoding mycaminosyltransferase is orf2* (tylM2). However, targeted disruption of orf2* did not lead to the accumulation of tylactone under conditions that normally favor tylosin production; instead, the synthesis of tylactone was virtually abolished. This may, in part, have resulted from a polar effect on the expression of genes downstream of orf2*, particularly orf4* (ccr) which encodes crotonyl-CoA reductase, an enzyme that supplies 4-carbon extender units for polyketide metabolism. However, that cannot be the entire explanation, since tylosin production was restored at about 10% of the wild-type level when orf2* was re-introduced into the disrupted strain. When glycosylated precursors of tylosin were fed to the disrupted strain, they were converted to tylosin, confirming that two of the three glycosyltransferase activities associated with tylosin biosynthesis were still intact. Interestingly, however, tylactone also accumulated under such conditions and, to a much lesser extent, when tylosin was added to similar fermentations. It is concluded that glycosylated macrolides exert a pronounced positive effect on polyketide metabolism in S. fradiae.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
  • 毒性总结
鉴定和使用:泰乐菌素用于辅助治疗与鸡败血支原体相关的慢性呼吸道疾病。它也用于减少与火鸡败血支原体相关的传染性鼻窦炎的严重程度。在蜜蜂中,它用于控制美洲幼虫腐臭病(幼虫芽孢杆菌)。最后,泰乐菌素用于治疗和控制与猪螺旋体相关的猪痢疾。人类接触和毒性:农场工人和从事兽医医学的人报告了由泰乐菌素引起的接触性皮炎。动物研究:将泰乐菌素0.1毫升、52毫克或58毫克的Tylan 200注射液、泰乐菌素浓缩液或Tylan可溶性液分别放入兔子的一个眼睛中。Tylan 200注射液引起了非常轻微的结膜充血,在48小时内清除。泰乐菌素浓缩液在接触后1小时内引起了角膜混浊、轻微的角膜混浊、轻至中度的虹膜炎和中度的结膜炎。然而,所有刺激在14天内清除。Tylan可溶性液在1小时内引起了轻至中度的角膜混浊、明显的虹膜炎和中度结膜炎。在这项研究中,所有刺激在接触后7天内清除。雌性大鼠皮下注射泰乐菌素,剂量高达每天100毫克/千克体重,持续28天,没有毒理学影响。雄性和雌性大鼠在饮食中给予泰乐菌素碱,剂量为0、1000、5000和10000毫克/千克,持续1年。处理的大鼠在测试的7到12个月内表现出中度过度敏感和过度活跃,但没有因处理而导致的死亡。在给予5000和10000毫克/千克饮食的雌性中观察到淋巴细胞数量增加、中性粒细胞数量减少和尿液pH增加。显微镜检查显示,所有处理组的雌性垂体肿瘤略有增加:0、1000、5000和10000毫克/千克饮食分别为1、3、4和3个腺瘤,0、0、1和0个癌。在另一项大鼠研究中,雄性和雌性大鼠被喂食含有0、20000、50000、100000或200000毫克/千克饮食的泰乐菌素碱,持续2年。在两个最高剂量下,体重增加和食物摄入量减少。所有高剂量的大鼠在12个月内死亡,表现出高营养不良、淋巴器官萎缩/坏死的发病率。在一项为期2年的研究中,狗和混合品种的狗通过胶囊口服剂量为0、1、10或100毫克/千克体重/天的泰乐菌素碱。在研究进行153天后,通过添加更多剂量的雄性和雌性杂种狗(每天200或400毫克/千克体重)来扩展研究期。偶尔出现腹泻和呕吐的狗给予10-400毫克/千克体重/天。在两只狗在100毫克/千克体重/天和一只狗在400毫克/千克体重/天记录了暂时升高的酚酞保留时间。在尸检中,发现一只给予200毫克/千克体重/天的狗有轻度肾盂肾炎,一只给予400毫克/千克体重/天的狗有双侧肾病、轻度慢性肾盂肾炎和轻度慢性膀胱炎。泰乐菌素碱通过灌胃给予小鼠,剂量为0、100、500或1000毫克/千克体重/天,在妊娠的第7-12天。每组给予0或500毫克/千克体重/天的4只小鼠被允许分娩,其余在妊娠第18天被杀死。母体体重增加或胎儿发育没有处理相关的差异。在7周和9周的交付后代中没有发现不良影响。雌性大鼠在妊娠的第0-20天给予含有0、1000、10000或100000毫克/千克饮食的泰乐菌素碱,并在妊娠第20天杀死。在100000毫克/千克饮食中,母体和胎儿的体重下降,骨骼形成延迟。来自对照组和两个最高剂量组的部分雌性从妊娠第0天到出生后第21天进行处理并允许分娩。在100000毫克/千克饮食中,后代体重增加较低。泰乐菌素在小鼠淋巴瘤细胞的体外基因突变诱导试验中呈阳性,但在HGPRT+中国仓鼠卵巢细胞的体外基因突变诱导试验、中国仓鼠卵巢细胞的体外染色体损伤试验和体内小鼠骨髓的细胞遗传学损伤试验中呈阴性。生态毒理学研究:泰乐菌素对调查的淡绿藻在72小时暴露期间有毒。
IDENTIFICATION AND USE: Tylosin is used as an aid in the treatment of chronic respiratory disease associated with Mycoplasma gallisepticum in chickens. It is also used for the reduction in severity of effects of infectious sinusitis associated with Mycoplasma gallisepticum in turkeys. In honey bees, it is used for the control of American Foulbrood (Paenibacillus larvae). Finally, tylosin is used for the treatment and control of swine dysentery associated with Brachyspira hyodysenteriae. HUMAN EXPOSURE AND TOXICITY: Contact dermatitis caused by tylosin has been reported by farm workers and individuals employed in veterinary medicine. ANIMAL STUDIES: Tylosin was placed in one eye of rabbits in an amount of 0.1 mL, 52 mg or 58 mg of Tylan 200 Injection, Tylosin Concentrate or Tylan Soluble, respectively. Tylan 200 Injection caused very slight conjunctival hyperemia, which cleared within 48 hr. Tylosin Concentrate caused corneal dullness, slight corneal opacity, slight to moderate iritis and moderate conjunctivitis within 1 hr post-exposure. However, all irritation cleared within 14 days. Tylan Soluble caused slight to moderate corneal opacity, marked iritis and moderate conjunctivitis within 1 hr. In this study, all irritation cleared within 7 days post exposure. Female rats were treated subcutaneously with tylosin up to 100 mg/kg bw per day for 28 days without any toxicological effects. Male and female rats were administered tylosin base in the diet for 1 year at levels of 0, 1000, 5000 and 10,000 mg/kg. Treated rats appeared moderately hyperirritable and hyperactive from 7 to 12 months on test, but there was no mortality attributable to treatment. Increased numbers of lymphocytes, decreased numbers of neutrophils and increased urine pH were observed in females given 5000 and 10,000 mg/kg diet. Microscopic examination revealed a slight increase in pituitary tumors in females of all treated groups: 1, 3, 4 and 3 adenomas and 0, 0, 1 and 0 carcinomas at 0, 1000, 5000 and 10,000 mg/kg diet, respectively. In another rat study, male and female rats were fed diets containing 0, 20,000, 50,000, 100,000 or 200,000 mg tylosin base/kg diet for 2 years. Body weight gain and food intake were reduced at the two highest doses. All high-dose rats died within 12 months and exhibited high incidences of malnutrition and atrophy/necrosis of lymphoid organs. In a 2-year study, dogs and mixed-breed dogs were given oral doses of 0, 1, 10 or 100 mg tylosin base/kg bw per day by capsule. After this study had progressed for 153 days, it was expanded by adding further groups of male and female mongrel dogs given doses of 200 or 400 mg tylosin base/kg bw per day for the remainder of the study period. Occasional diarrhea and vomiting occurred in dogs given 10-400 mg/kg bw per day. Transient elevated bromosulfophthalein retention times were recorded in two dogs at 100 mg/kg bw per day and one dog at 400 mg/kg bw per day. At necropsy, mild pyelonephritis was found in one dog given 200 mg/kg bw per day, and bilateral nephrosis, mild chronic pyelonephritis and mild chronic cystitis were seen in one dog given 400 mg/kg bw per day. Tylosin base was given by gavage to mice at doses of 0, 100, 500 or 1000 mg/kg bw per day on gestation days 7-12. Four mice per group given 0 or 500 mg/kg bw per day were allowed to deliver, the remainder were killed on gestation day 18. There were no treatment-related differences in maternal body weight gains or development of fetuses. No adverse effects were noted in delivered offspring at 7 and 9 weeks. Female rats were given diets containing 0, 1000, 10,000 or 100,000 mg tylosin base/kg, dosed on gestation days 0-20 and killed on gestation day 20. At 100,000 mg/kg diet, body weight was depressed in dams and fetuses, and ossification was retarded. Some females from the control and the two highest dose groups were treated from gestation day 0 to postnatal day 21 and allowed to deliver. The body weight gain of offspring was lower at 100,000 mg/kg diet. Tylosin tested positive in an in vitro assay for the induction of gene mutations in mouse lymphoma cells but tested negative in an in vitro assay for the induction of gene mutations in HGPRT+ Chinese hamster ovary cells, an in vitro chromosomal damage assay in Chinese hamster ovary cells and an in vivo assay for cytogenetic damage in mouse bone marrow. ECOTOXICITY STUDIES: Tylosin was toxic in the freshwater green alga investigated over 72-hr exposures.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
  • 副作用
皮肤致敏剂 - 一种可以诱导皮肤产生过敏反应的制剂。
Skin Sensitizer - An agent that can induce an allergic reaction in the skin.
来源:Haz-Map, Information on Hazardous Chemicals and Occupational Diseases
毒理性
  • 相互作用
在肉鸡中研究了膨润土与泰乐菌素之间的相互作用,基于体内获得的药代动力学特征。同时口服膨润土和泰乐菌素显著降低了泰乐菌素的血浆平,减少了血浆浓度-时间曲线下的面积(AUC(0-∞))、最大血浆浓度(C(max))、达到最大血浆浓度的时间(T(max))和相对口服生物利用度。结果明确证明了泰乐菌素与膨润土的结合。因此,应避免同时给予泰乐菌素(在饮用或饲料中)和膨润土(作为霉菌毒素吸附剂混合在饲料中)。
The interaction between bentonite and tylosin was investigated in broiler chickens, based on pharmacokinetic characteristics obtained in vivo. Simultaneous oral administration of bentonite and tylosin significantly lowered plasma levels of tylosin and reduced the area under the plasma concentration-time curve (AUC(0-inf)), maximal plasma concentration (C(max)), time to maximal plasma concentration (T(max)) and relative oral bioavailability. The results prove unambiguously the binding of tylosin by bentonite. Simultaneous administration of tylosin (in the drinking water or feed) and bentonite (mixed in the feed as a mycotoxin binder) should therefore be avoided.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
  • 相互作用
在人身上,一些大环内酯类抗生素通过形成稳定的代谢中间体(MI)复合物与细胞色素P4503A(CYP3A)亚家族的酶发生临床相关的药物-药物相互作用。这种复合物的形成可能导致同时给药的药物的生物转化率降低。在以前的研究中,发现兽用抗生素替米考星也能在猪和 rats 中形成稳定的MI复合物。在目前的研究中,研究了一系列大环内酯类抗生素和替米考星在山羊和牛的微粒体组分以及表达牛CYP3A的细胞系中的CYP3A相对抑制活性和MI复合物形成。发现替米考星和三乙酰奥莱andomycin(TAO)是所有测试系统中的有效CYP450活性抑制剂红霉素和tilmicosin被发现是相对较弱的CYP450活性抑制剂,在微粒体中,它们在表达牛CYP3A4的细胞系中的活性相对较弱。泰乐菌素在微粒体中显示出是弱抑制剂,在细胞系中则不是,而螺旋霉素根本没有效果。通过光谱分析测量的MI复合物形成发生在TAO、替米考星红霉素泰乐菌素上,但tilmicosin和螺旋霉素则没有。尽管在体内还有其他因素发挥作用,但这些结果可能解释了潜在的药物-药物相互作用以及在这方面相关化合物之间的差异。
In humans, clinically relevant drug-drug interactions occur with some macrolide antibiotics via the formation of stable metabolic intermediate (MI) complexes with enzymes of the cytochrome P4503A (CYP3A) subfamily. The formation of such complexes can result in a decreased biotransformation rate of simultaneously administered drugs. In previous studies it was shown that the veterinary antibiotic tiamulin was also able to form a stable MI complex in pigs and rats. In the present study the relative CYP3A inhibiting potency and MI complex formation of a series of macrolide a