TAS-103 dihydrochloride (BMS-247615 dihydrochloride)
(Synonyms: 6-[[2-(二甲基氨基)乙基]氨基]-3-羟基-7H-茚并[2,1-C]喹啉-7-酮二盐酸盐,BMS-247615 dihydrochloride) 目录号 : GC32822
A DNA topoisomerase I and II inhibitor
Cas No.:174634-09-4
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Cell experiment: | CCRF-CEM human acute lymphoblastic leukaemia cells are grown in RPMI-1640 supplemented with 3 mM l-glutamine, 10% foetal bovine serum, 50 U/mL of penicillin, and 40 μg/mL of streptomycin at 37°C in a humidified atmosphere containing 5% CO2. TAS-103, CPT and DACA are dissolved in DMSO. Exponentially growing cells (∼5 × 105) are exposed to either of the drugs for 2 hrs. Following drug exposure, cells are washed twice by centrifugation (400 × g, 3 min) in cold phosphate-buffered saline[1]. |
Animal experiment: | Lewislung carcinoma (LLC) cells are diluted with DMEM to obtain 5×106 cells/mL suspension, and 0.2 mL of the suspension is carefully injected subcutaneously into five-week-old C57BL/6 male mice. Liposomal TAS-103 (0.2 mL/mouse, 30 mg/kg as TAS-103), free TAS-103 or PBS is injected intravenously into a tail vein of the tumor-bearing mice on days 4, 8, and 12 after tumor implantation. Tumor volume of each mouse and the body weight change as an indicator of side effect are monitored daily thereafter. Tumor volume is calculated[2]. |
References: [1]. Padget K, et al. An investigation into the formation of N- [2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) and 6-[2-(dimethylamino)ethylamino]- 3-hydroxy-7H-indeno[2, 1-C]quinolin-7-one dihydrochloride (TAS-103) stabilised DNA topoisomerase I and II cleavable complexes in human leukaemia cells. Biochem Pharmacol. 2000 Sep 15;60(6):817-21. | |
TAS 103 is an inhibitor of DNA topoisomerase I and II (IC50s = 2 and 6.5 ?M, respectively).1 It stabilizes topoisomerase I-DNA and topoisomerase II-DNA cleavable complexes in KB cells when used at a concentration of 3 ?M. It is cytotoxic to P388 and KB cells (IC50s = 1.1 and 9.6 nM, respectively). TAS 103 (15, 26, and 45 mg/kg per day) reduces pulmonary metastasis in murine B16-BL6 melanoma and UV-2237M fibrosarcoma models of lung metastasis. It also reduces tumor growth in a variety of human cancer mouse xenograft models.
1.Utsugi, T., Aoyagi, K., Asao, T., et al.Antitumor activity of a novel quinoline derivative, TAS-103, with inhibitory effects on topoisomerases I and IIJpn. J. Cancer Res.88(10)992-1002(1997)
| Cas No. | 174634-09-4 | SDF | |
| 别名 | 6-[[2-(二甲基氨基)乙基]氨基]-3-羟基-7H-茚并[2,1-C]喹啉-7-酮二盐酸盐,BMS-247615 dihydrochloride | ||
| Canonical SMILES | O=C(C1=C2C3=CC=C(O)C=C3N=C1NCCN(C)C)C4=C2C=CC=C4.Cl.Cl | ||
| 分子式 | C20H21Cl2N3O2 | 分子量 | 406.31 |
| 溶解度 | Water : 15.3 mg/mL (37.66 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.4612 mL | 12.3059 mL | 24.6117 mL |
| 5 mM | 0.4922 mL | 2.4612 mL | 4.9223 mL |
| 10 mM | 0.2461 mL | 1.2306 mL | 2.4612 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
A new mechanism of 6-((2-(dimethylamino)ethyl)amino)-3-hydroxy-7H-indeno(2,1-c)quinolin-7-one dihydrochloride (TAS-103) action discovered by target screening with drug-immobilized affinity beads
Mol Pharmacol 2008 Mar;73(3):987-94.PMID:18089836DOI:10.1124/mol.107.043307.
6-((2-(Dimethylamino)ethyl)amino)-3-hydroxy-7H-indeno(2,1-c)-quinolin-7-one dihydrochloride (TAS-103) is a quinoline derivative that displays antitumor activity in murine and human tumor models. TAS-103 has been reported to be a potent topoisomerase II poison. However, other studies have indicated that cellular susceptibility to TAS-103 is not correlated with topoisomerase II expression. Because the direct target of TAS-103 remained unclear, we searched for a TAS-103 binding protein using high-performance affinity latex beads. We obtained a component of the signal recognition particle (SRP) as a TAS-103 binding protein. This component is a 54-kDa subunit (SRP54) of SRP, which mediates the proper delivery of secretory proteins in cells. We fractioned 293T cell lysates using gel-filtration chromatography and performed a coimmunoprecipitation assay using 293T cells expressing FLAG-tagged SRP54. The results revealed that TAS-103 disrupts SRP complex formation and reduces the amount of SRP14 and SRP19. TAS-103 treatment and RNAi-mediated knockdown of SRP54 or SRP14 promoted accumulation of the exogenously expressed chimeric protein interleukin-6-FLAG inside cells. In conclusion, we identified signal recognition particle as a target of TAS-103 by using affinity latex beads. This provides new insights into the mechanism underlying the effects of chemotherapies comprising TAS-103 and demonstrates the usefulness of the affinity beads.
Establishment and characterization of 6-[[2-(Dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one dihydrochloride (TAS-103)-resistant cell lines
Jpn J Cancer Res 2000 May;91(5):543-50.PMID:10835500DOI:10.1111/j.1349-7006.2000.tb00979.x.
6-2-(Dimethylamino)ethylămino-3-hydroxy-7H-indeno2, 1-cquinolin-7-one dihydrochloride (TAS-103) is a novel anticancer agent that was developed to target both topoisomerase (Topo) I and Topo II. To elucidate its mechanism of action, we have established and characterized TAS-103-resistant cells, derived from mouse leukemia (P388), human colon cancer (DLD-1), and human lung adenocarcinoma (A549) cell lines, by exposure to stepwisely increasing concentrations of TAS-103 in the culture medium. P388 / TAS cells showed only cross-resistance to VP-16 and adriamycin (ADR). The Topo II activity in these cells was decreased to below one-fourth of that in the parental cells, while the Topo I activity remained unchanged. DLD / TAS cells appeared to be cross-resistant to VP-16, ADR, camptothecin (CPT), SN-38 and vincristine (VCR). The enzymatic activities of both Topo I and Topo II in these cells were decreased to one-fourth of that observed in the parental cells. Furthermore, the decreased activities were accompanied by lower expression at the mRNA and protein levels. A549 / TAS cells acquired cross-resistance to VP-16, ADR and VCR, though the Topo activities were virtually unchanged. In this cell line, the intracellular accumulation of TAS-103 was significantly decreased and the expression of multidrug resistance associated protein (MRP) was elevated when compared with the parental cells. The results indicate that the affected activities of Topo I and / or Topo II, and in some instances decreased accumulation of TAS-103, are associated with the development of resistance to TAS-103, although the main mechanism of resistance to TAS-103 varied among cell lines.
Cancer chemotherapy by liposomal 6-[12-(dimethylamino)ethyl]aminol-3-hydroxy-7H-indeno[2,1-clquinolin-7-one dihydrochloride (TAS-103), a novel anti-cancer agent
Biol Pharm Bull 2002 Oct;25(10):1385-7.PMID:12392102DOI:10.1248/bpb.25.1385.
A novel anti-tumor agent, 6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one dihydrochloride (TAS-103), effectively inhibits both topoisomerase I and II activities. To enhance anti-tumor efficacy and to reduce the side effects of the agent, liposomalization of TAS-103 was performed. TAS-103 was effectively entrapped in liposomes by a remote-loading method, and was stable at 4 degrees C and in the presence of 50% serum. To evaluate the anti-tumor efficacy of liposomal TAS-103, the growth inhibition against Lewis lung carcinoma cells in vitro and the therapeutic efficacy against solid tumor-bearing mice in vivo were examined. Liposomal TAS-103 showed strong cytotoxic effect against Lewis lung carcinoma cells in a dose dependent manner and effectively suppressed solid tumor growth accompanying longer survival time of tumor-bearing mice in comparison with the mice treated with free TAS-103. These results suggest that liposomal TAS-103 is useful for cancer therapy.
Self-association and unique DNA binding properties of the anti-cancer agent TAS-103, a dual inhibitor of topoisomerases I and II
Biochim Biophys Acta 2002 Jul 18;1587(2-3):155-63.PMID:12084457DOI:10.1016/s0925-4439(02)00078-9.
The objective of our study was to investigate the self-association and DNA-binding properties of the DNA topoisomerases I (Topo I) and II (Topo II) dual inhibitor: 6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinoline-7-one dihydrochloride (TAS-103), by means of 1H-NMR and 31P-NMR spectroscopy, structure computation techniques, thermal melting study, and UV-Visible spectroscopy. In aqueous solution, all chemical shifts of TAS-103 underwent upfield shifts depending with an increase in concentration. The two-dimensional (2D)-NMR spectra and structure computations indicated that TAS-103 self-associated through pi-pi stacking and hydrophobic interactions of the aromatic chromophores. Thermal melting indicated that the binding of TAS-103 to DNA with a potency equal to that of ethidium bromide (EtBr). The UV-Visible spectra of TAS-103 titrated by several DNA exhibited hypochromic and hypsochromic effects. The 31P-NMR spectrum of the 6:1 TAS-103/d(CGCGAATTCGCG)(2) complex showed two broadening signals. 2D-NMR spectra of the 1:1 TAS-103/d(CGCGAATTCGCG)(2) complex indicated that the chemical shift differences of the DNA are very small. However, those of the terminal region are relatively large. The chemical shift differences of TAS-103 showed that the proton resonances except H2 underwent downfield shifts. From these observations, we conclude that TAS-103 binds to DNA by two modes. The major binding mode is on the surface (outside binding) and the minor binding mode by intercalation.
An investigation into the formation of N- [2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) and 6-[2-(dimethylamino)ethylamino]- 3-hydroxy-7H-indeno[2, 1-C]quinolin-7-one dihydrochloride (TAS-103) stabilised DNA topoisomerase I and II cleavable complexes in human leukaemia cells
Biochem Pharmacol 2000 Sep 15;60(6):817-21.PMID:10930536DOI:10.1016/s0006-2952(00)00402-0.
The antitumour agents DACA (XR5000; N-[2-(dimethylamino)ethyl]acridine-4-carboxamide) and TAS-103 (6-[2-(dimethylamino)ethylamino]-3-hydroxy-7H-indeno[2, 1-c]quinolin-7-one dihydrochloride) have been shown to inhibit two essential nuclear enzymes in vitro, DNA topoisomerase I and DNA topoisomerase (topo) II. To examine whether DACA or TAS-103 stabilise topo I, topo IIalpha, and topo IIbeta cleavable complexes in human leukaemia CCRF-CEM cells, the TARDIS assay (trapped in agarose DNA immunostaining) was used. This assay can reveal drug-stabilised topo-DNA complexes formed in situ in individual cells. The results showed that both DACA and TAS-103 can stabilise topo IIalpha cleavable complexes in these cells. Topo IIbeta cleavable complexes were also formed, but only at high concentrations of DACA and TAS-103. The effect on topo I was less clear, with TAS-103 showing only low levels of cleavable complex formation and DACA having no detectable effect under these assay conditions. This is in contrast to the purified enzyme cleavable complex assay, where both DACA and TAS-103 poisoned topo I. Although both DACA and TAS-103 show a preference for topo IIalpha in whole cells using the TARDIS assay, the formation of low levels of topo I or topo IIbeta cleavable complexes may still play a role in cell death.