β-lactam
Transforming growth factor-β-activated kinase 1 (TAK1) / Mitogen-activated protein kinase kinase kinase 7 (MAP3K7). NG25 is a type II TAK1 inhibitor that binds to the ATP binding pocket of the target kinase. [3]

头孢洛林酯（TAK-599）是抗甲氧西林耐药金黄色葡萄球菌（MRSA）头孢菌素2a （T-91825）的新型n-膦前药，对青霉素结合蛋白（PBP） 2′(IC（50）具有高亲和力；0.90微克/毫升)，并显示出有效的体外抗MRSA活性(MIC抗MRSA N133；1.56微克/毫升)，与万古霉素（1.56微克/毫升）相当。［１］

---

单独使用 NG25 处理72小时后，通过CCK-8法检测，能以剂量依赖的方式降低五种乳腺癌细胞系的细胞活力。NG25在这些细胞系中的IC50值为：T-47D: 4.344 µM, MCF7: 2.827 µM, HCC1954: 4.498 µM, MDA-MB-231: 2.331 µM, BT-549: 14.12 µM。[3]
在CCK-8实验中，与单独使用阿霉素相比，NG25 (2 µM) 联合阿霉素处理48小时，能增强对上述乳腺癌细胞系增殖的细胞毒性效应，表现为联合用药组的细胞活力更低。[3]
在克隆形成实验中，与单独使用阿霉素相比，NG25 (2 µM) 与阿霉素联用处理72小时，随后在无药培养基中恢复培养两周，对所有五种乳腺癌细胞系的增殖显示出更强的抑制作用。[3]
在软琼脂实验中，与单独使用阿霉素相比，NG25 (2 µM) 与阿霉素联用培养三周，能显著减少四种乳腺癌细胞的集落形成。[3]
Western blot分析显示，在2、4、6小时的时间点，NG25 (2 µM) 能部分阻断阿霉素诱导的p38磷酸化和IκBα降解，表明其抑制了TAK1介导的NF-κB和MAPK通路激活。[3]
NG25 (2 µM) 单独处理24小时不能诱导PARP或Caspase-3/7的切割，但能显著增强阿霉素诱导的PARP和Caspase-3/7切割，表明其增强了细胞凋亡。时间梯度实验进一步证实了NG25增强阿霉素诱导的凋亡。[3]

ceftaroline fosamil (sc) 的 ED50 为 1.60–2.37 mg/kg，可保护小鼠免受金黄色葡萄球菌 N133 引起的实验性全身感染[1]。
在大鼠和猴子的血液中，ceftaroline fosamil (10 mg/kg； sc) 迅速消失并顺利转变为 T-91825[1]。

以枯草芽孢杆菌为试验菌，抗生素培养基2为扩散培养基，采用微生物法测定活性ceftaroline/头孢他林浓度 (低检出限，0.25 mg/升；日内及日内变动<10%)。［2］

细胞活力实验 (CCK-8): 将细胞接种于96孔板，24小时后，用不同浓度的NG25、阿霉素或其组合处理48或72小时。显微镜下观察细胞形态后，每孔加入CCK-8试剂与培养基的混合液，孵育1小时，用酶标仪在450 nm波长下测量吸光度。[3]
克隆形成实验: 将细胞接种于12孔板，用药物处理72小时后，更换为无药新鲜培养基继续培养两周。随后，用甲醇/结晶紫固定并染色集落，拍照记录。[3]
非锚定依赖性生长实验 (软琼脂): 在6孔板中制备含12% FBS的0.5%琼脂底层。将细胞与含药物的0.3%琼脂培养基混合，铺于底层之上，培养三周至肉眼可见集落形成。用结晶紫染色集落，拍照并使用软件计数。[3]
免疫印迹实验: 细胞用裂解液裂解，测定蛋白浓度。蛋白样品与上样缓冲液混合并煮沸，进行SDS-PAGE电泳并转膜至PVDF膜上。膜封闭后，与一抗在4°C孵育过夜，再与HRP标记的二抗孵育。使用ECL化学发光系统显影。[3]

Using the neutropenic lung infection model, 17 clinical S. aureus isolates (2 MSSA, 15 MRSA) are investigated. For a duration of 24 hours, groups of six mice are treated with Ceftaroline fosamil starting three hours after inoculation. Doses of ceftaroline fosamil are injected subcutaneously in increments of 0.2 mL. Normal saline is given to control animals in the same amounts, ways, and intervals as the treatment plans[1].

---

For ceftaroline, blood samples were taken from six healthy rabbits after administration of a ceftaroline acetate bolus of 10 and 30 mg/kg of body weight in order to determine the spontaneous drug kinetics. The simulation was intended to provide apparent values of pharmacokinetic parameters close to those observed in healthy volunteers after a 1-h infusion of a 600-mg dose (ca. 10 mg/kg) of ceftaroline acetate: mean half-life (t1/2), 1.57 to 2.63 h; peak concentration (Cmax), 18.96 to 21.02 mg/liter; and area under the curve (AUC), 56.08 mg·h/liter. A total dose of 58 mg/kg needed to be infused into the rabbit over a 12-h period in order to simulate the kinetics in human serum after the administration of a 10-mg/kg dose (i.e., 600 mg twice daily).
For each MRSA strain, the animals were randomly assigned to either no treatment (controls), ceftaroline regimen mimicking the human dose of 10 mg/kg every 12 h (q12h) (600 mg q12h), a linezolid regimen mimicking the human dose of 10 mg/kg q12h (600 mg q12h), and vancomycin administered by a constant intravenous infusion in order to reach a steady-state 20× MIC in serum.
Experimental endocarditis was induced with an inoculum of 108 CFU of S. aureus. Treatment was started 24 h after inoculation for a 4-day regimen. Aortic valve vegetations were excised, weighed, and then homogenized in 0.5 ml of saline buffer and used for quantitative cultures on agar for 24 h at 37°C. Dilutions at 10−1, 10−2, and 10−4 were prepared to eliminate potential carryover effects. To evaluate whether ceftaroline treatment could induce the selection of variants resistant in vivo, undiluted vegetation homogenates were spread on agar plates containing the active form of ceftaroline at a concentration corresponding to fourfold the MIC. Bacterial counts were determined after 48 h of incubation at 37°C.[2]

Absorption, Distribution and Excretion
primarily eliminated by the kidneys (6% in feces within 48 hours).
Median 20.3 L (18.3-21.6 L).

---

Metabolism / Metabolites
Ceftaroline fosamil is converted into bioactive ceftaroline in plasma by a phosphatase enzyme. Hydrolysis of the beta-lactam ring of ceftaroline occurs to form the microbiologically inactive, open-ring metabolite ceftaroline M-1.

---

Biological Half-Life
1.60 hours (600 mg dose).

---

TAK-599 has not only practical water solubility, but also good chemical stability in the solid state and solution.
Although cephalosporin 2a (T-91825) had insufficient water solubility (2.3 mg/mL) for parenteral administration, 1 (TAK-599) showed excellent water solubility (>100 mg/mL, pH 7) as well as good chemical stability in the solid state and solution. In pharmacokinetic studies, when 1 was administered intravenously to rats and monkeys, it was rapidly converted into 2a in the blood. These results show that 1 (TAK-599) is a highly promising parenteral cephalosporin targeted for MRSA infection.[1]

Protein Binding
approximately 20%.

---

The toxicity of NG25 was reported to be much lower in normal breast epithelial cell lines (HMEC and MCF-12A) compared to the breast cancer cell line MDA-MB-231. [3]

[1]. TAK-599, a novel N-phosphono type prodrug of anti-MRSA cephalosporin T-91825: synthesis, physicochemical and pharmacological properties. Bioorg Med Chem. 2003 May 29;11(11):2427-37.

[2]. In vivo efficacy of ceftaroline (PPI-0903), a new broad-spectrum cephalosporin, compared with linezolid and vancomycin against methicillin-resistant and vancomycin-intermediate Staphylococcus aureus in a rabbit endocarditis model. Antimicrob Agents Chemother. 2007 Sep;51(9):3397-400.

[3]. Ceftaroline fosamil, a cephalosporin derivative for the potential treatment of MRSA infection. Curr Opin Investig Drugs. 2008 Feb;9(2):201-9.

Pharmacodynamics
The time that unbound plasma concentration of ceftaroline exceeds the minimum inhibitory concentration (MIC) of the infecting organism has been shown to best correlate with efficacy in a neutropenic murine thigh infection model with S. aureus and S. pneumoniae. No significant effect on QTc (corrected QT interval) interval was detected at peak plasma concentration or at any other time.

---

NG25 is a synthesized type II TAK1 inhibitor, compared to the naturally derived inhibitor 5Z-7-oxozeaenol, offering potential economic benefits. [3]
The study proposes that NG25 enhances the efficacy of doxorubicin in breast cancer cells by inhibiting the TAK1-mediated activation of NF-κB and MAPK (p38) signaling pathways, which are pro-survival pathways induced by genotoxic stress from Dox. This inhibition shifts the balance towards apoptosis. [3]
The sensitizing effect of NG25 on Dox-mediated cytotoxicity was observed across different molecular subtypes of breast cancer cells (luminal A, HER2+, triple-negative/claudin-low). [3]
The study suggests that combining NG25 with Dox could be a strategy to allow dose reduction of Dox, thereby potentially minimizing its dose-dependent side effects (e.g., cardiotoxicity) while maintaining or enhancing anti-tumor efficacy. [3]

C22H21N8O8PS4

744.7

684.01

C, 38.71; H, 3.38; N, 15.05; O, 21.48; P, 4.16; S, 17.22

400827-46-5

Ceftaroline fosamil (hydrate)(acetate);400827-55-6;Ceftaroline fosamil (inner);229016-73-3;400827-46-5

56841980

White to light yellow solid powder

-2.84

346.85

5

19

11

47

1240

2

S1C([H])([H])C(=C(C(=O)[O-])N2C([C@]([H])([C@@]12[H])N([H])C(/C(/C1=NSC(N([H])P(=O)(O[H])O[H])=N1)=N/OC([H])([H])C([H])([H])[H])=O)=O)SC1=NC(C2C([H])=C([H])[N+](C([H])([H])[H])=C([H])C=2[H])=C([H])S1

UGHHNQFYEVOFIV-VRDMTWHKSA-N

InChI=1S/C22H21N8O8PS4.C2H4O2/c1-3-38-26-13(16-25-21(43-28-16)27-39(35,36)37)17(31)24-14-18(32)30-15(20(33)34)12(9-40-19(14)30)42-22-23-11(8-41-22)10-4-6-29(2)7-5-10;1-2(3)4/h4-8,14,19H,3,9H2,1-2H3,(H4-,24,25,27,28,31,33,34,35,36,37);1H3,(H,3,4)/b26-13-;/t14-,19-;/m1./s1

4-(2-(((6R,7R)-2-carboxy-7-((Z)-2-(ethoxyimino)-2-(5-(phosphonoamino)-1,2,4-thiadiazol-3-yl)acetamido)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)thio)thiazol-4-yl)-1-methylpyridin-1-ium acetate

T-91825; T 91825; T91825; Teflaro; Zinforo;TAK 599; TAK599; TAK-599; PPI 0903; PP 0903; PPI-0903;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中，避免吸湿/受潮。

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : 73~100 mg/mL ( 98.02~134.28 mM)

配方 1 中的溶解度: ≥ 2.08 mg/mL (2.79 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

---

配方 2 中的溶解度: ≥ 2.08 mg/mL (2.79 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

---

View More

配方 3 中的溶解度: ≥ 2.08 mg/mL (2.79 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

---

配方 4 中的溶解度: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.08 mg/mL (2.79 mM)

---

请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。