ML414 (NGI-1)   中文名称: ML414（NGI-1）

OST/oligosaccharyltransferase
Oligosaccharyltransferase (OST) complex, including catalytic subunits STT3A and STT3B [1]
Oligosaccharyltransferase (OST) complex [2]
Oligosaccharyltransferase (OST) complex [3]

体外活性：ML414（也称为 NGI-1）是一种新型的细胞渗透性寡糖转移酶 (OST) 抑制剂，OST 是一种异寡聚酶，存在于多种亚型中，可将寡糖转移至受体蛋白。 ML414 是通过基于细胞的高通量筛选和先导化合物优化活动鉴定出来的。在非小细胞肺癌细胞中，NGI-1 阻断表皮生长因子受体 (EGFR) 糖蛋白的细胞表面定位和信号传导，但仅选择性地阻止依赖 EGFR（或成纤维细胞生长因子）的细胞系的增殖，FGFR）以求生存。在这些细胞系中，OST 抑制会导致细胞周期停滞，并伴有 p21 的诱导、自发荧光和细胞形态变化，这些都是衰老的标志。这些结果表明 OST 抑制是治疗受体酪氨酸激酶依赖性肿瘤的潜在治疗方法，并为可逆调节哺乳动物细胞中的 N 连接糖基化提供了化学探针。激酶测定：之前已描述过在 D54-ERLucT 和 D54-LucT 细胞中使用生物发光 N 连接糖基化报告基因的 HTS 方法。简而言之，基于细胞的初级筛选使用具有三个 N 连接糖基化共有序列的修饰和 ER 翻译的荧光素酶蛋白来检测 N 连接聚糖位点占用。与对照相比，D54-ERLucT 中糖基化的抑制可恢复并增加荧光素酶活性，但不会增加非 ER 翻译的 D54-LucT 细胞系中的活性。初级 (D54-ERlucT)、二级假阳性 (D54-LucT) 和三级（荧光素酶抑制）筛选的方法以及使用 CellTitre Glo 进行的毒性测定均存放在 Pubchem (AID 588693) 中。使用具有 Smartfit 算法的 Genedata Screener 软件生成 AC40 值，用于类似物的比较分析。细胞检测：在非小细胞肺癌细胞中，NGI-1 阻断表皮生长因子受体 (EGFR) 糖蛋白的细胞表面定位和信号传导，但仅选择性地阻止依赖于 EGFR（或成纤维细胞生长因子（FGFR）以维持生存。在这些细胞系中，OST 抑制会导致细胞周期停滞，并伴有 p21 的诱导、自发荧光和细胞形态变化，这些都是衰老的标志。这些结果表明 OST 抑制是治疗受体酪氨酸激酶依赖性肿瘤的潜在治疗方法，并为可逆调节哺乳动物细胞中的 N 连接糖基化提供了化学探针。

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对拉沙病毒（LASV）及沙粒病毒的作用：有效降低重组沙粒病毒rLCMV/LASV GPC的感染性，且不影响细胞活力；导致LASV糖蛋白（GP）低糖基化，抑制病毒增殖。该作用对新旧世界沙粒病毒具有保守性，在HEK293T、A549、HeLa、Huh7、HEK293细胞中均表现出一致的抗病毒效果[1]
- 对NSCLC细胞RTK信号的抑制作用：阻断表皮生长因子受体（EGFR）的细胞表面定位和信号传导；选择性抑制依赖EGFR或成纤维细胞生长因子受体（FGFR）的非小细胞肺癌（NSCLC）细胞（PC9、H1581、H2444）增殖，诱导G1期细胞周期阻滞、p21表达、自荧光产生及衰老相关形态改变；对AR阴性Hela细胞或非RTK依赖的NSCLC细胞（A549）抑制作用微弱[2]
- 对胶质瘤细胞RTK活性及放射敏感性的调控作用：在ErbB家族激活水平较高的胶质瘤细胞系（D54、SKMG3、U251、T98G、42-MG）中，减少多种受体酪氨酸激酶（RTK，包括EGFR、ErbB2、ErbB3、MET、PDGFR、FGFR1）的糖基化、蛋白水平及激活；增强细胞对放射治疗的敏感性和化疗药物（替莫唑胺、依托泊苷）的细胞毒性，增加DNA损伤（γH2AX焦点增多）和G1期阻滞；在RTK激活水平低或PTEN缺失的胶质瘤细胞中无上述效果；糖基化非依赖型CD8-EGFR的表达可逆转这些作用，证实RTK抑制是其核心机制[3]

NGI-1在体内通过激活ErbB受体减少胶质母细胞瘤的肿瘤生长。[3]
为了评估ML414（NGI-1）对异种移植物肿瘤生长的影响，我们使用了一种克服该化合物低溶解度的ML414（NGI-1）纳米粒子制剂。首先，使用D54 ERLucT异种移植物测试NGI NP的效果，该异种移植物在抑制糖基化后增加了生物发光。我们发现，在24小时（1.7倍，p=.03；图5A）和48小时（1.7倍数，p=.003；图5B）的时间点，接受ML414（NGI-1）的小鼠明显诱导了生物发光。Tunicmaycin是另一种N-连接糖基化抑制剂，用作阳性对照并诱导生物发光（24小时时为4.2倍（p=.007））。这些结果证实了NGI-1 NP在体内抑制D54肿瘤糖基化的能力。[3]

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为了评估ML414（NGI-1）在体内的治疗潜力，我们测试了ML414（NGI-1）NP单独和与辐射联合对D54和SKMG3细胞系胶质瘤肿瘤生长的影响。在这些实验中，小鼠被随机分配到四组中的一组接受治疗：对照NP、对照NP+RT、NGI-1NP和NGI-1 NP+RT。每隔一天输送一次ML414（NGI-1）NP（20mg/kg），共3剂，RT以5剂2Gy的日剂量输送。在D54异种移植物中，单独放疗或放疗+NGI-NP治疗显著延迟了肿瘤生长。与仅用放射治疗的患者相比，在RT中添加NGI NP显著降低了肿瘤生长。在39天时，NGI-1 NP+RT组的中位肿瘤体积为566±200 mm3，而单独RT组为1383±305 mm3（p=.001；图5B）。在SKMG3异种移植物中观察到有利于NGI-1 NP和RT联合治疗的类似结果。在这种细胞系中，当作为单一疗法给药时，辐射和NGI NP都能减少肿瘤生长。NGI-1 NPs+RT的组合显著减少了肿瘤生长。放疗+NGI-1-NP组在第98天的平均肿瘤体积几乎无法检测到。相比之下，空白NP的肿瘤体积（379±38 mm3；p=.001）、辐射（139±27 mm3；p=.001）和NGI-1-NP（151±7 mm3；p>0.05）均显著更大（图5C）。对于两种体内异种移植物实验，没有证据表明NGI-NP治疗的动物体重明显减轻或其他毒性。综上所述，这些结果表明NGI-1+RT的组合可能是治疗胶质母细胞瘤的一种治疗方法。[3]

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抑制胶质瘤异种移植瘤生长：裸鼠皮下接种D54或SKMG3胶质瘤细胞后，给予ML414 (NGI-1)纳米颗粒制剂（20mg/kg，静脉注射，隔天一次，共3次）联合分次放疗（总剂量10Gy，每日2Gy）。每周测量两次肿瘤体积，结果显示联合治疗组肿瘤生长较单独放疗组或对照纳米颗粒组显著减慢；治疗期间动物未出现明显体重减轻或其他毒性反应[3]
- 体内糖基化抑制验证：接种D54-ERLucT异种移植瘤的小鼠，经ML414 (NGI-1)纳米颗粒（20mg/kg，静脉注射）处理后，24小时和48小时的生物发光信号显著增强（1.7倍），证实其在体内可有效抑制N-糖基化[3]

先前已描述过在 D54-ERLucT 和 D54-LucT 细胞中使用生物发光 N 连接糖基化报告基因的 HTS 方法。简而言之，基于细胞的初级筛选使用具有三个 N 连接糖基化共有序列的修饰和 ER 翻译的荧光素酶蛋白来检测 N 连接聚糖位点占用。与对照相比，D54-ERLucT 中糖基化的抑制可恢复并增加荧光素酶活性，但不会增加非 ER 翻译的 D54-LucT 细胞系中的活性。初级 (D54-ERlucT)、二级假阳性 (D54-LucT) 和三级（荧光素酶抑制）筛选的方法以及使用 CellTitre Glo 进行的毒性测定均存放在 Pubchem (AID 588693) 中。使用具有 Smartfit 算法的 Genedata Screener 软件生成 AC40 值，用于类似物的比较分析。

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细胞-free OST活性测定：在兔网织红细胞裂解物中加入犬胰腺粗微粒体，加入ML414 (NGI-1)或衣霉素，对Saposin-DDK-His6 mRNA进行60分钟翻译反应，通过³⁵S代谢标记检测翻译产物的糖基化水平，评估OST活性[2]
- 细胞热迁移实验（CETSA）：293T细胞用100μM ML414 (NGI-1)处理30分钟后进行热处理，通过Western blot检测OST亚基的热稳定性变化，验证药物与OST亚基的结合作用[2]

在非小细胞肺癌细胞中，NGI-1 阻断表皮生长因子受体 (EGFR) 糖蛋白的细胞表面定位和信号传导，但仅选择性地阻止依赖 EGFR（或成纤维细胞生长因子）的细胞系的增殖，FGFR）以求生存。在这些细胞系中，OST 抑制会导致细胞周期停滞，并伴有 p21 的诱导、自发荧光和细胞形态变化，这些都是衰老的标志。这些结果表明 OST 抑制是治疗受体酪氨酸激酶依赖性肿瘤的潜在治疗方法，并为可逆调节哺乳动物细胞中的 N 连接糖基化提供了化学探针。

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沙粒病毒感染及糖基化测定：HEK293T、A549、HeLa、Huh7、HEK293细胞以MOI=0.01感染rLCMV/LASV GPC病毒，病毒进入后加入不同浓度ML414 (NGI-1)（DMSO为对照），36小时后收集细胞和上清液；通过Western blot分析病毒GP的糖基化模式，采用免疫空斑法检测病毒滴度，qRT-PCR测定病毒RNA拷贝数[1]
- NSCLC细胞RTK信号及增殖测定：CHO-Lec15、CHO-Lec35、HeLa、HEK293及NSCLC细胞（PC9、A549、H1581、H2444）用1–10μM ML414 (NGI-1)处理24–72小时；Western blot检测EGFR的糖基化、磷酸化及下游信号分子表达；表面生物素化和共聚焦显微镜分析EGFR定位；MTT法检测细胞增殖；流式细胞术分析细胞周期分布；qRT-PCR定量cyclin D1 mRNA水平[2]
- 胶质瘤细胞RTK激活及放射敏感性测定：胶质瘤细胞（D54、SKMG3、U251、T98G、42-MG）用10μM ML414 (NGI-1)预处理48小时后，暴露于放射治疗（0–6Gy）或化疗药物（替莫唑胺10μM、依托泊苷0.1μM）；克隆形成实验评估放射敏感性；CellTiter 96实验检测细胞增殖；Western blot检测RTK的糖基化、磷酸化及DNA损伤标志物γH2AX；免疫荧光定量γH2AX焦点数量；流式细胞术分析细胞周期分布[3]

NGI-1 Therapeutic Studies in Glioma Xenografts:[3]
D54 and SKMG3 bilateral xenografts were established in nude mice by subcutaneous injection of 1×106 cells into hind limb. Four days after injection, mice were randomized to one of four treatment groups. They received either control or NGI-1 NPs i.v. (20mg/kg) every other day for a total of 3 doses and either sham irradiation or a total of 10 Gy administered in daily 2 Gy fractions using a Precision X-ray 250-kV orthovoltage unit. Tumor size was measured two times per week and calculated according to the formula π/6 × (large diameter) × (small diameter)2.

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All experimental procedures were approved in accordance with IACUC and Yale University institutional guidelines for animal care and ethics and guidelines for the welfare and use of animals in cancer research. NGI-1 delivery to glioma xenografts was evaluated using a bioluminescent imaging platform that detects inhibtion of NLG. Ten days after subcutaneous injection of 1 ×107 gliomas cells, mice bearing palpable tumors were treated with control or NGI-1 NPs (20 mg/kg), or tunicamycin 1mg/kg and imaged 5–30 minutes after delivery of i.p. luciferin (150 mg/kg). Signal intensity was quantified for a region of interest (ROI) encompassing each tumor and induction of bioluminscence was calculated by comparing peak bioluminescent activity from pre- and post-treatment imaging at 24 and 48 hours.[3]

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Glioma xenograft therapeutic assay: Nude mice were subcutaneously injected with 1×10^6 D54 or SKMG3 glioma cells into the hind limb. Four days later, mice were randomized into four groups: control nanoparticles, ML414 (NGI-1) nanoparticles (20 mg/kg i.v. every other day for 3 doses), sham irradiation, or radiation (10 Gy total, 2 Gy daily). Tumor size was measured twice weekly, and tumor volume was calculated using the formula π/6 × (large diameter) × (small diameter)² [3]
- In vivo glycosylation inhibition validation assay: Mice bearing D54-ERLucT xenografts (1×10^7 cells subcutaneously) were treated with control nanoparticles, ML414 (NGI-1) nanoparticles (20 mg/kg i.v.), or tunicamycin (1 mg/kg i.v.). At 5–30 minutes after intraperitoneal injection of luciferin (150 mg/kg), bioluminescent signal intensity was quantified at 24 and 48 hours to confirm glycosylation inhibition [3]

In vitro toxicity: At concentrations that inhibit viral infection, ML414 (NGI-1) had no effect on the viability of HEK293T, A549, HeLa, Huh7, and HEK293 cells [1]
- In vivo toxicity: Mice treated with ML414 (NGI-1) nanoparticles (20 mg/kg intravenously) did not show significant weight loss or other significant toxic side effects [3]

[1]. Comprehensive Interactome Analysis Reveals that STT3B is Required for the N-Glycosylation of Lassa Virus Glycoprotein. J Virol. 2019 Sep 11. pii: JVI.01443-19.

[2]. Oligosaccharyltransferase inhibition induces senescence in RTK-driven tumor cells. Nat Chem Biol. 2016 Dec;12(12):1023-1030.

[3]. Oligosaccharyltransferase Inhibition Reduces Receptor Tyrosine Kinase Activation and Enhances Glioma Radiosensitivity. Clin Cancer Res. 2019 Jan 15; 25(2): 784–795.

Lassa virus (LASV) is the pathogen of a deadly hemorrhagic fever in humans. LASV glycoproteins (GPs) mediate viral entry into host cells, and proper processing and modification of GPs by host factors are prerequisites for viral replication. This study used affinity purification-mass spectrometry (AP-MS) to identify 591 host proteins that interact with LASV GPs. Functional annotation of these proteins by gene ontology analysis revealed a high enrichment of the oligosaccharide transferase (OST) complex. Functional studies using CRISPR-Cas9-mediated gene knockout technology showed that two catalytically active isoforms of the OST complex, STT3A and STT3B, are crucial for the proliferation of the recombinant arenavirus rLCMV/LASV glycoprotein precursor, primarily through influencing viral infectivity. Knockout of STT3B (but not STT3A) resulted in insufficient LASV GP glycosylation, indicating that LASV preferentially depends on the STT3B-OST isoform. Furthermore, double knockout of two specific subunits of STT3B-OST—magnesium transporter 1 (MAGT1) and tumor suppressor candidate gene 3 (TUSC3)—also leads to insufficient LASV GP glycosylation and affects viral replication. Site-directed mutagenesis analysis showed that the CXXC oxidoreductase active site motif of MAGT1 or TUSC3 is crucial for LASV GP glycosylation. The small molecule OST inhibitor ML414 (NGI-1) effectively reduced viral infectivity without affecting cell viability. STT3B-dependent GP N-glycosylation is also conserved in other arenavirus genera, including Old World and New World arenaviruses. Our study systematically analyzed the interaction between Lassa virus (LASV) glycoprotein (GP) and the host and revealed the preferential dependence of STT3B on LASV GP N-glycosylation. Importance: Glycoproteins play a crucial role in the life cycle of arenaviruses, facilitating viral entry into host cells and participating in viral budding. N-glycosylation of glycoproteins is key to their normal function; however, little is known about virus-dependent host factors. This study comprehensively characterized the interaction genome of LASV GP and further found that arenavirus GP preferentially depends on STT3B-dependent N-glycosylation, and that this process is essential for viral infectivity. Two specific thioredoxin subunits, MAGT1 and TUSC3, of the STT3B-OST complex were found to be essential for viral GP N-glycosylation. In addition, the small molecule thioredoxin inhibitor ML414 (NGI-1) also showed significant inhibitory effects against arenavirus. Our study provides new insights into the interaction between Lassa virus glycoprotein (LASV GP) and the host and expands the potential targets for the development of novel therapies for Lassa fever. [1]

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Asparagine (N)-linked glycosylation is a protein modification that is essential for glycoprotein folding, stability and cellular localization. To identify novel small molecules capable of inhibiting this biosynthetic pathway, we initiated a cell-based high-throughput screening and lead compound optimization program, ultimately yielding a cell permeability inhibitor, ML414 (NGI-1). ML414 (NGI-1) targets oligosaccharide transferases (OSTs), heterooligomeric enzymes with multiple isoforms capable of transferring oligosaccharides to receptor proteins. In non-small cell lung cancer cells, ML414 (NGI-1) blocks the cell surface localization and signaling of the epidermal growth factor receptor (EGFR) glycoprotein, but selectively inhibits the proliferation of EGFR-dependent (or fibroblast growth factor, FGFR) cell lines. In these cell lines, OST inhibition leads to cell cycle arrest, accompanied by p21 induction, autofluorescence, and altered cell morphology—all hallmarks of aging. These results suggest that OST inhibition is a potential therapeutic approach for receptor tyrosine kinase-dependent tumors and provides a chemical probe for reversibly modulating N-linked glycosylation in mammalian cells. [2] Parallel signal transduction reduces the efficacy of receptor tyrosine kinase (RTK) therapy in gliomas. We hypothesized that inhibition of protein N-linked glycosylation (an endoplasmic reticulum co-translational and post-translational modification crucial for RTK maturation and activation) could provide a novel approach for radiosensitization in gliomas. Experimental Design: We investigated the effects of the oligosaccharide transferase small molecule inhibitor ML414 (NGI-1) on EGFR family receptors MET, PDGFR, and FGFR1. We determined the effects of glycosylation status on tumor cell radiosensitivity, chemotherapy-induced cytotoxicity, DNA damage, and cell cycle arrest, and correlated these effects with glioma cell receptor expression profiles. We tested the effect of ML414 (NGI-1) on xenograft tumor growth using a nanoparticle formulation validated by in vivo molecular imaging. The mechanistic role of the RTK signaling pathway was assessed by expressing a glycosylation-independent CD8-EGFR chimera. Results: ML414 (NGI-1) reduced the glycosylation, protein levels, and activation of most RTKs. ML414 (NGI-1) also enhanced the radiosensitivity and cytotoxicity of glioma cells with increased ErbB family activation, but had no effect on cells with low RTK activation. The radiosensitizing effect of ML414 (NGI-1) was associated with increased DNA damage and G1 phase cell cycle arrest. Compared with the control group, fractionated radiotherapy combined with ML414 (NGI-1) significantly inhibited tumor growth in glioma xenografts. The expression of CD8-EGFR eliminated the effect of ML414 (NGI-1) on G1 phase arrest, DNA damage and cell radiosensitivity, thus identifying RTK inhibition as the main mechanism of action of ML414 (NGI-1). [3] ML414 (NGI-1) is a cell-permeable small molecule oligosaccharide transferase (OST) inhibitor, which catalyzes N-linked glycosylation of proteins. It reversibly modulates N-linked glycosylation in mammalian cells without completely inhibiting OST activity [2]
ML414 (NGI-1) targets two catalytic subunits (STT3A and STT3B) of the OST complex, disrupting the maturation and function of glycoproteins (e.g., RTKs, viral glycoproteins) that rely on N-linked glycosylation for stability and localization [1][2][3]
ML414 (NGI-1) is a potential therapeutic for RTK-driven tumors (e.g., non-small cell lung cancer, glioma) and arenavirus infections (e.g., Lassa fever) by targeting common biosynthetic pathways essential for pathogen/virus survival and tumor progression [1][2][3]
In glioma cells,ML414 (NGI-1) primarily enhances radiosensitivity by inhibiting ErbB family RTKs. Signal transduction, such as the rescue effect of glycosylation-independent CD8-EGFR, has been demonstrated [3]. ML414 (NGI-1) exhibits selectivity for RTK-dependent cells and minimal impact on the viability of non-RTK-dependent cells or normal cells, indicating a favorable therapeutic window [2][3].

C17H22N4O3S2

394.51

394.113

C, 51.76; H, 5.62; N, 14.20; O, 12.17; S, 16.25

790702-57-7

2519269

White to off-white solid powder

1.4±0.1 g/cm3

1.634

2.75

119Ų

1

7

5

26

602

0

O=C(C1C(N2CCCC2)=CC=C(S(N(C)C)(=O)=O)C=1)NC1SC(C)=CN=1

QPKGRLIYJGBKJL-UHFFFAOYSA-N

InChI=1S/C17H22N4O3S2/c1-12-11-18-17(25-12)19-16(22)14-10-13(26(23,24)20(2)3)6-7-15(14)21-8-4-5-9-21/h6-7,10-11H,4-5,8-9H2,1-3H3,(H,18,19,22)

5-(dimethylsulfamoyl)-N-(5-methyl-1,3-thiazol-2-yl)-2-(pyrrolidin-1-yl)benzamide

NGI-1; NGI1; NGI 1; ML414; 5-(dimethylsulfamoyl)-N-(5-methyl-1,3-thiazol-2-yl)-2-(pyrrolidin-1-yl)benzamide; 5-(N,N-Dimethylsulfamoyl)-N-(5-methylthiazol-2-yl)-2-(pyrrolidin-1-yl)benzamide; MLS002248299; 5-(dimethylsulfamoyl)-N-(5-methyl-1,3-thiazol-2-yl)-2-pyrrolidin-1-ylbenzamide; SMR001315774; ML 414; ML-414;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

DMSO : 79~100 mg/mL ( 200.24~253.48 mM )

配方 1 中的溶解度: ≥ 2.5 mg/mL (6.34 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 25.0 mg/mL澄清DMSO储备液加入到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。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (6.34 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 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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配方 3 中的溶解度: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.5 mg/mL (6.34 mM);

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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。