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达福普丁甲磺酸 | 112362-50-2

中文名称
达福普丁甲磺酸
中文别名
达福普汀
英文名称
dalfopristin
英文别名
RP54476;synercid;(6R,7S,10R,11R,12E,17E,19E,21S)-6-[2-(diethylamino)ethylsulfonyl]-21-hydroxy-11,19-dimethyl-10-propan-2-yl-9,26-dioxa-3,15,28-triazatricyclo[23.2.1.03,7]octacosa-1(27),12,17,19,25(28)-pentaene-2,8,14,23-tetrone
达福普丁甲磺酸化学式
CAS
112362-50-2
化学式
C34H50N4O9S
mdl
——
分子量
690.858
InChiKey
SUYRLXYYZQTJHF-VMBLUXKRSA-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:
    ~150°
  • 沸点:
    940.5±65.0 °C(Predicted)
  • 密度:
    1.27±0.1 g/cm3(Predicted)
  • 溶解度:
    DMSO:113.0(最大浓度 mg/mL);163.57(最大浓度 mM)乙醇:100.0(最大浓度 mg/mL);144.75(最大浓度 mM)
  • 颜色/状态:
    Slightly yellow to yellow powder
  • 蒸汽压力:
    8.83X10-29 mm Hg at 25 °C (est)

计算性质

  • 辛醇/水分配系数(LogP):
    2.2
  • 重原子数:
    48
  • 可旋转键数:
    7
  • 环数:
    3.0
  • sp3杂化的碳原子比例:
    0.62
  • 拓扑面积:
    185
  • 氢给体数:
    2
  • 氢受体数:
    11

ADMET

代谢
通过解转化为活性非共轭代谢物。
Converted to an active non-conjugated metabolite by hydrolysis.
来源:DrugBank
代谢
奎奴普丁和达福普丁转化为几种主要活性代谢物:奎奴普丁有2种结合型代谢物(与谷胱甘肽和半胱酸结合)和达福普丁有1种非结合型代谢物(通过解形成),这些代谢物与相应的母药也具有协同作用。这种转化是通过非酶促反应在体外发生的,与细胞色素P-450(CYP)和谷胱甘肽转移酶无关。
Quinupristin and dalfopristin are converted to several major active metabolites: 2 conjugated (with glutathione and cysteine) metabolites for quinupristin and one nonconjugated (formed by hydrolysis) metabolite for dalfopristin, which also act synergistically with the complementary parent drug. This conversion occurs in vitro by nonenzymatic reactions independent of cytochrome P-450 (CYP) and glutathione transferase enzymes.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
  • 相互作用
Synercid与硝苯地平(重复口服剂量)和咪达唑仑(静脉推注剂量)联合给药在健康志愿者中导致这些药物的血药浓度升高。硝苯地平咪达唑仑的Cmax分别增加了18%和14%(中位数值),AUC分别增加了44%和33%。
Concomitant administration of Synercid and nifedipine (repeated oral doses) and midazolam (intravenous bolus dose) in healthy volunteers led to elevated plasma concentrations of these drugs. The Cmax increased by 18% and 14% (median values) and the AUC increased by 44% and 33% for nifedipine and midazolam, respectively.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
  • 相互作用
体外药物相互作用研究已经证实,Synercid 显著抑制了细胞色素 P450 3A4 对环孢素 A、咪达唑仑硝苯地平特非那丁的代谢。此外,在接受 Synercid 7.5 mg/kg 每 8 小时一次,连续给药 2 天,并在第 3 天给予 300 mg 环孢素的 24 名受试者中,环孢素的 AUC(药时曲线下面积)增加了 63%,环孢素的 Cmax(最大血药浓度)增加了 30%,环孢素的半衰期增加了 77%,环孢素的清除率下降了 34%。当环孢素与 Synercid 联用时,应当进行环孢素的治疗平监测。
In vitro drug interaction studies have demonstrated that Synercid significantly inhibits cytochrome P450 3A4 metabolism of cyclosporin A, midazolam, nifedipine and terfenadine. In addition, 24 subjects given Synercid 7.5 mg/kg q8h for 2 days and 300 mg of cyclosporine on day 3 showed an increase of 63% in the AUC of cyclosporine, an increase of 30% in the Cmax of cyclosporine, a 77% increase in the half life of cyclosporine, and, a decrease of 34% in the clearance of cyclosporine. Therapeutic level monitoring of cyclosporine should be performed when cyclosporine must be used concomitantly with Synercid.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
  • 相互作用
Synercid和地高辛之间的药物相互作用不能排除,但通过CYP3A4酶抑制发生的可能性不大。Synercid在体外对Eubacterium lentum展示了活性(在两个菌株上进行测试时的MIC值为0.25 ug/mL)。地高辛部分由肠道中的细菌代谢,因此,基于Synercid抑制地高辛的肠道代谢(由Eubacterium lentum)的药物相互作用是可能的。
A drug interaction between Synercid and digoxin cannot be excluded but is unlikely to occur via CYP3A4 enzyme inhibition. Synercid has shown in vitro activity (MICs of 0.25 ug/mL when tested on two strains) against Eubacterium lentum. Digoxin is metabolized in part by bacteria in the gut and as such, a drug interaction based on Synercid's inhibition of digoxin's gut metabolism (by Eubacterium lentum) may be possible.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
  • 相互作用
一名21岁的女性肾移植受者,在接受每日150毫克口服环孢素后,开始接受静脉注射20毫克/千克/日的奎奴普丁/达福普丁治疗,两天后环孢素血药浓度升高。基线低谷环孢素平在80至105纳克/毫升之间。开始奎奴普丁/达福普丁治疗两天和三天后,低谷环孢素平分别升至261和291纳克/毫升。环孢素剂量降至每日100毫克,血药浓度恢复到基线平。停用奎奴普丁/达福普丁后,环孢素血药浓度降低,剂量恢复到之前的方案。
A case is presented in which a 21-yr-old woman who was receiving 150 mg/day oral cyclosporine after kidney transplantation developed elevated cyclosporine blood levels 2 days after starting treatment with intravenous injections of 20 mg/kg/day quinupristin/dalfopristin. Baseline trough cyclosporine levels ranged from 80 to 105 ng/ml. Two and 3 days after initiation of quinupristin/dalfopristin therapy, trough cyclosporine levels increased to 261 and 291 ng/ml, respectively. The cyclosporine dosage was decreased to 100 mg/day and the blood levels returned to baseline. After discontinuation of quinupristin/dalfopristin, the cyclosporine blood concentration decreased and the dosage was increased to the previous regimen.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
  • 解毒与急救
接受过量治疗的病人应仔细观察并给予支持性治疗。Synercid 不能通过腹膜透析或血液透析清除。
Patients who receive an overdose should be carefully observed and given supportive treatment. Synercid is not removed by peritoneal dialysis or by hemodialysis.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
奎奴普丁和达福普丁在大鼠乳汁中有分布...。
Quinupristin and dalfopristin is distributed into milk in rats ... .
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
喹努普里斯坦/达尔福普里斯坦的药代动力学已在接受放射性标记和未标记药物静脉输注的大鼠、猴子和人类中进行研究。在大鼠和猴子中,喹努普里斯坦和达尔福普里斯坦在血液中迅速消除,并在广泛组织中分布。然而,它们不会显著地穿透中枢神经系统或跨越胎盘,并且在停止给药后似乎不会在体内显著残留。喹努普里斯坦在大鼠和猴子中的血液消除半衰期分别约为0.6小时和0.5小时,而达尔福普里斯坦在大鼠和猴子中的半衰期分别约为0.6小时和0.2小时。两种化合物主要通过胆汁进入粪便消除;喹努普里斯坦主要以原形排泄,而达尔福普里斯坦在排泄前会广泛代谢。代谢物包括对达尔福普里斯坦具有微生物活性的普里斯坦霉素PIIA,以及对喹努普里斯坦具有微生物活性的谷胱甘肽和半胱酸结合衍生物。喹努普里斯坦和达尔福普里斯坦在人体内似乎以类似方式处理。静脉给药后,两种化合物都会迅速从血液中清除,喹努普里斯坦的消除半衰期约为1小时,达尔福普里斯坦的消除半衰期为0.4-0.5小时。喹努普里斯坦的药代动力学特征与剂量无关,达尔福普里斯坦和RP 12536共同考虑时也是如此。喹努普里斯坦/达尔福普里斯坦在人类非炎症性间质液中的血管外扩散已得到评估。
The pharmacokinetics of quinupristin/dalfopristin have been studied in rats, monkeys and humans following intravenous infusion of radiolabelled and unlabelled drug. In rats and monkeys quinupristin and dalfopristin undergo rapid elimination from the blood and wide tissue distribution. Nevertheless, they do not penetrate the central nervous system or cross the placenta to any significant degree and they do not appear to be subject to significant body retention following cessation of administration. The blood elimination half-life of quinupristin was approximately 0.6 hr in rats and 0.5 hr in monkeys, and that of dalfopristin was approximately 0.6 hr and 0.2 hr, respectively. Both compounds are primarily eliminated through the bile into the faeces; quinupristin is mainly excreted unchanged whereas dalfopristin is extensively metabolized beforehand. The metabolites include the microbiologically active pristinamycin PIIA for dalfopristin and the microbiologically active glutathione- and cysteine-conjugated derivatives for quinupristin. Quinupristin and dalfopristin appear to be handled in a similar manner by humans. Following intravenous administration both compounds are rapidly cleared from the blood with elimination half-lives of approximately 1 hr for quinupristin and 0.4-0.5 hr for dalfopristin. The pharmacokinetic profile of quinupristin is dose-independent and so is that of dalfopristin and RP 12536 when considered together. Extravascular diffusion of quinupristin/dalfopristin has been assessed in human non-inflammatory interstitial fluid.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
粪便排泄是亲本药物及其代谢物的主要消除途径(占剂量的75至77%)。尿液排泄约占quinupristin的15%和dalfopristin的19%。大鼠的预临床数据显示,大约80%的剂量通过胆汁排泄,并提示在人体中,胆汁排泄可能是粪便消除的主要途径。
Fecal excretion constitutes the main elimination route for both parent drugs and their metabolites (75 to 77% of dose). Urinary excretion accounts for approximately 15% of the quinupristin and 19% of the dalfopristin dose. Preclinical data in rats have demonstrated that approximately 80% of the dose is excreted in the bile and suggest that in man, biliary excretion is probably the principal route for fecal elimination.
来源:Hazardous Substances Data Bank (HSDB)

制备方法与用途

达福普汀(Dalfopristin)为链阳菌素普那霉素IIA的半合成衍生物,与奎奴普丁(Quinupristin)以70/30(w/w)比例组成的抗生素协同复合制剂于1999年9月首次上市,商品名为达福普汀-奎奴普丁。这种药物主要用于治疗成人致命性耐万古霉素屎肠球菌(VREF)菌血症相关感染、耐甲氧西林黄色葡萄球菌(MRSA)及化脓性链球菌引起的皮肤和软组织感染。

达福普汀(Dalfopristin)是ostreogyrcin A的半合成类似物。Quinupristin/Dalfopristin(Q/D)是一种亲本链霉菌素,其活性范围包括革兰氏阳性病原体,并对其他种类的抗菌化合物具有抗性的病原体。

靶点

体外研究

Quinupristin/Dalfopristin (Q/D) 是一种组合制剂,其中包含两种协同抗生素成分:30% 的链霉菌素B(Quinupristin)和70% 的链霉菌素A(Dalfopristin),比例为30:70。这种半合成的注射用链霉菌素是一种组合药物,由从pristinamycin衍生的成分组成:一种类型B链霉菌素(Quinupristin)和一种类型A链霉菌素(Dalfopristin)。

上下游信息

  • 下游产品
    中文名称 英文名称 CAS号 化学式 分子量

反应信息

  • 作为反应物:
    描述:
    达福普丁甲磺酸四氢呋喃 、 aq. phosphate buffer 为溶剂, 以99 %的产率得到蛎灰菌素A
    参考文献:
    名称:
    链霉素 A 衍生物作为线粒体翻译抑制剂抑制胶质母细胞瘤干细胞生长
    摘要:
    胶质母细胞瘤治疗的新治疗策略,尤其是处理肿瘤的胶质母细胞瘤干细胞 (GSC) 成分,是一项紧迫的医疗需求。最近,线粒体翻译抑制已被证明会影响 GSC 的生长、克隆形成和自我更新能力,因此成为一个有吸引力的治疗靶点。抑制线粒体核糖体功能的链阳菌素 B 和 A 抗生素奎奴普丁/达福普汀 (Q/D) 的组合在体外更有效地影响 GSC比护理替莫唑胺的标准。在这里,基于 Q/D 结合线粒体核糖体的冷冻电镜结构的对接计算已被用于开发一系列链阳霉素 A 衍生物。我们从达福普汀和维吉尼亚霉素 M1 支架开始获得了 22 个新的和已知的分子。进行结构-活性关系细化以评估这些化合物单独或与奎奴普汀组合抑制 GSC 生长和抑制线粒体翻译的能力。最后,定量超高效液相色谱-质谱法使我们能够评估其中一些衍生物的细胞渗透。其中,达福普汀和维吉尼亚霉素M1的氟衍生物(16 R )-1e和(16 R )-2e,分别,flopristin
    DOI:
    10.1016/j.ejmech.2022.114979
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文献信息

  • [EN] A CONJUGATE OF A CYTOTOXIC AGENT TO A CELL BINDING MOLECULE WITH BRANCHED LINKERS<br/>[FR] CONJUGUÉ D'UN AGENT CYTOTOXIQUE À UNE MOLÉCULE DE LIAISON CELLULAIRE AVEC DES LIEURS RAMIFIÉS
    申请人:HANGZHOU DAC BIOTECH CO LTD
    公开号:WO2020257998A1
    公开(公告)日:2020-12-30
    Provided is a conjugation of cytotoxic drug to a cell-binding molecule with a side-chain linker. It provides side-chain linkage methods of making a conjugate of a cytotoxic molecule to a cell-binding ligand, as well as methods of using the conjugate in targeted treatment of cancer, infection and immunological disorders.
    提供了一种将细胞毒性药物与一个侧链连接分子结合的共轭物。它提供了制备细胞毒性分子与细胞结合配体的共轭物的侧链连接方法,以及在靶向治疗癌症、感染和免疫性疾病中使用该共轭物的方法。
  • [EN] CROSS-LINKED PYRROLOBENZODIAZEPINE DIMER (PBD) DERIVATIVE AND ITS CONJUGATES<br/>[FR] DÉRIVÉ DE DIMÈRE DE PYRROLOBENZODIAZÉPINE RÉTICULÉ (PBD) ET SES CONJUGUÉS
    申请人:HANGZHOU DAC BIOTECH CO LTD
    公开号:WO2020006722A1
    公开(公告)日:2020-01-09
    A novel cross-linked cytotoxic agents, pyrrolobenzo-diazepine dimer (PBD) derivatives, and their conjugates to a cell-binding molecule, a method for preparation of the conjugates and the therapeutic use of the conjugates.
    一种新型的交联细胞毒剂,吡咯苯并二氮杂环二聚体(PBD)衍生物,以及它们与细胞结合分子的结合物,一种制备这些结合物的方法以及这些结合物的治疗用途。
  • [EN] TRICYCLIC TRIAZOLE COMPOUNDS THAT MODULATE HSP90 ACTIVITY<br/>[FR] COMPOSÉS TRIAZOLES TRICYCLIQUES MODULANT L'ACTIVITÉ HSP90
    申请人:SYNTA PHARMACEUTICALS CORP
    公开号:WO2009139916A1
    公开(公告)日:2009-11-19
    The present invention relates to substituted tricyclic triazole compounds and compositions comprising substituted tricyclic triazole compounds. The invention further relates to methods of inhibiting the activity of Hsp90 in a subject in need thereof and methods for preventing or treating hyperproliferative disorders, such as cancer, in a subject in need thereof comprising administering to the subject a compound of the invention, or a composition comprising such a compound.
    本发明涉及替代三环三唑化合物和包含替代三环三唑化合物的组合物。该发明还涉及在需要的受体中抑制Hsp90活性的方法,以及预防或治疗高增殖性疾病(如癌症)的方法,其中包括向受体施用本发明的化合物或包含这种化合物的组合物。
  • [EN] FUSED POLYCYCLIC 2-PYRIDINONE ANTIBACTERIAL COMPOUNDS<br/>[FR] COMPOSÉS ANTIBACTÉRIENS DE 2-PYRIDINONE POLYCYCLIQUE
    申请人:PTC THERAPEUTICS INC
    公开号:WO2016109706A1
    公开(公告)日:2016-07-07
    The present description relates to fused polycyclic 2-pyridinone compounds and forms and pharmaceutical compositions thereof and methods of using such compounds, forms or compositions thereof for treating or ameliorating a wild-type or drug-resistant form of N. gonorrhoeae or N. meningitides. A compound of Formula (la), Formula (lb) or Formula (Ic), or a form thereof, wherein the dashed lines represent one or more double bonds optionally present where allowed by available valences.
    本描述涉及融合的多环2-吡啶酮化合物及其形式和药物组合物,以及使用这些化合物、形式或组合物治疗或改善N. gonorrhoeae或N. meningitides的野生型或耐药型的方法。其中,化合物的化学式为(la)、(lb)或(Ic),或其形式,其中虚线代表一个或多个双键,根据可用的价键允许的情况下可选择地存在。
  • [EN] COMPOUNDS COMPRISING CLEAVABLE LINKER AND USES THEREOF<br/>[FR] COMPOSÉS COMPRENANT UN LIEUR CLIVABLE ET LEURS UTILISATIONS
    申请人:INTOCELL INC
    公开号:WO2019008441A1
    公开(公告)日:2019-01-10
    Provided are a compound including a cleavable linker, a use thereof, and an intermediate compound for preparing the same, and more particularly, the compound including a cleavable linker of the present invention may include an active agent (for example, a drug, a toxin, a ligand, a probe for detection, etc.) having a specific function or activity, a SO2 functional group which is capable of selectively releasing the active agent, and a functional group which triggers a chemical reaction, a physicochemical reaction and/or a biological reaction by external stimulation, and may further include a ligand (for example, oligopeptide, polypeptide, antibody, etc.) having binding specificity for a desired target receptor.
    提供了一种包括可切割连接物的化合物,其用途,以及用于制备该化合物的中间体化合物,更具体地,本发明的包括可切割连接物的化合物可能包括具有特定功能或活性的活性剂(例如,药物,毒素,配体,用于检测的探针等),能够选择性释放活性剂的SO2官能团,以及通过外部刺激触发化学反应,物理化学反应和/或生物反应的官能团,并且还可以包括具有与所需靶受体结合特异性的配体(例如,寡肽,多肽抗体等)。
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