Gimatecan
(Synonyms: ST1481) 目录号 : GC60873
Gimatecan(ST1481)是一种有效的拓扑异构酶I(topoisomeraseI)抑制剂。Gimatecan是一种具有口服活性的喜树碱类似物。具有抗肿瘤活性。
Cas No.:292618-32-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Gimatecan (ST1481) is a potent topoisomerase I inhibitor. Gimatecan is an orally bioavailable camptothecin analogue with antitumor activity[1].
Gimatecan (3 to 300 ng/mL) significantly inhibits the growth of human bladder cancer models (HT1376 and MCR), thus reflecting antiproliferative potency[1].Gimatecan causes a persistent S-phase arrest At 0.003 µg/mL and the number of S-phase cells increased after treatment with a higher concentration (0.03 µg/mL)[1]. Cell Proliferation Assay[1] Cell Line: HT1376 cells harbor a p53 mutation; MCR cells harbor two p53 mutations: one in exon 4 (CGC→CCC) and one in exon 9 (CAG→TAG)
Gimatecan (2 mg/kg; treatment per os, every fourth day for four times) is effective for inhibiting tumor growth[1]. Animal Model: Athymic Swiss nude mice bearing HT1376 model[1]
[1]. Paola Ulivi, et al. Cellular Basis of Antiproliferative and Antitumor Activity of the Novel Camptothecin Derivative, Gimatecan, in Bladder Carcinoma Models. Neoplasia. 2005 Feb;7(2):152-61.
| Cas No. | 292618-32-7 | SDF | |
| 别名 | ST1481 | ||
| Canonical SMILES | CC(C)(C)O/N=C/C1=C2C(C(N3C2)=CC([C@@]4(O)CC)=C(COC4=O)C3=O)=NC5=CC=CC=C15 | ||
| 分子式 | C25H25N3O5 | 分子量 | 447.48 |
| 溶解度 | 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 | 2.2347 mL | 11.1737 mL | 22.3474 mL |
| 5 mM | 0.4469 mL | 2.2347 mL | 4.4695 mL |
| 10 mM | 0.2235 mL | 1.1174 mL | 2.2347 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。
Gimatecan, a novel camptothecin with a promising preclinical profile
Anticancer Drugs 2004 Jul;15(6):545-52.PMID:15205595DOI:10.1097/01.cad.0000131687.08175.14.
The realization that position 7 of camptothecin allows several options in chemical manipulation of the drug has stimulated a systematic investigation of a variety of substituents in this position. These efforts resulted in the identification of a novel series of 7-oxyiminomethyl derivatives. Among compounds of this series we have selected a promising lipophilic derivative, Gimatecan, for further development. The relevant features of Gimatecan are: (i) marked cytotoxic potency, likely related to multiple factors, including a potent inhibition of topoisomerase I, a persistent stabilization of the cleavable complex, an increased intracellular accumulation and a peculiar subcellular localization; (ii) lack of recognition by known resistance-related transport systems; (iii) increased lactone stability and favorable pharmacokinetics; (iv) good oral bioavailability; and (v) an impressive antitumor efficacy in a large panel of human tumor xenografts, with various treatment schedules. Phase I clinical studies with oral administration support the preclinical results of the novel camptothecin. Using different schedules and dosing durations, Gimatecan exhibited an acceptable toxicity profile, with myelotoxicity being the dose-limiting toxic effect. An appreciable number of tumor responses was achieved and favorable pharmacokinetics with a very long terminal half-life was observed. The clinical development of Gimatecan is currently ongoing, with phase II studies in diverse tumor types (colon, lung, breast carcinoma and pediatric tumors).
High Efficacy of Intravenous Gimatecan on Human Tumor Xenografts
Anticancer Res 2018 Oct;38(10):5783-5790.PMID:30275200DOI:10.21873/anticanres.12917.
Background/aim: The lipophilic, orally bioavailable camptothecin analogue Gimatecan is characterized by improved efficacy over conventional camptothecins on human tumor xenografts. Gimatecan produced excellent outcomes orally with prolonged, low-dose, daily treatments. The aim of this study was to assess the antitumor efficacy of i.v. administered Gimatecan. Materials and methods: The antitumor activity of Gimatecan delivered i.v. q4dx4 was evaluated in nude mice bearing human tumors and compared to clinically available anticancer drugs. Results: Intravenous administration of Gimatecan showed superior efficacy with remarkable achievements at well tolerated doses. Moreover, prolonged treatments with i.v. administered Gimatecan showed efficacy in models of cancer refractory to current therapeutic approaches, like an orthotopic brain tumor. Conclusion: Although the oral route is practical for Gimatecan administration, the results support the interest in developing a suitable i.v. formulation in an attempt to further exploit the therapeutic potential of the compound.
Gimatecan exerts potent antitumor activity against gastric cancer in vitro and in vivo via AKT and MAPK signaling pathways
J Transl Med 2017 Dec 13;15(1):253.PMID:29237470DOI:10.1186/s12967-017-1360-z.
Background: We investigated antitumor activity and underlying mechanisms of DNA topoisomerase I (TopI) inhibitor Gimatecan and irinotecan in gastric cancer (GC) in vitro cell lines and in vivo patient-derived xenograft (PDX) models. Methods: GC cell lines SNU-1, HGC27, MGC803 and NCI-N87 were used to evaluate cell viability and apoptosis after Gimatecan or irinotecan treatment, using a cell proliferation assay and flow cytometry, respectively. DNA TopI expression and critical molecules of PI3K/AKT, MAPK and apoptosis signaling pathways were analyzed with western blot. For in vivo studies, five PDXs models were treated with Gimatecan or irinotecan to assess its antitumor activity. Immunohistochemistry staining of Ki-67 was performed after mice were sacrificed. Results: Gimatecan inhibited the proliferation of GC cells in vitro in a dose- and time-dependent manner by inducing apoptosis, and Gimatecan had greater inhibitory effects than irinotecan. In addition, both Gimatecan and irinotecan demonstrated significant tumor growth inhibition in in vivo PDX models. Gimatecan treatment significantly inhibited the expression of DNA TopI, phosphorylated AKT (pAKT), phosphorylated MEK (pMEK) and phosphorylated ERK (pERK). Meanwhile, Gimatecan could also activate the JNK2 and p38 MAPK pathway as indicated by upregulation of phosphorylated p38 MAPK (p-p38) and phosphorylated JNK2 (pJNK2). Conclusions: For the first time, we have shown that the antitumor activity of Gimatecan in GC via suppressing AKT and ERK pathway and activating JNK2 and p38 MAPK pathway, which indicated that Gimatecan might be an alternative to irinotecan in the treatment of GC.
Gimatecan and other camptothecin derivatives poison Leishmania DNA-topoisomerase IB leading to a strong leishmanicidal effect
Biochem Pharmacol 2013 May 15;85(10):1433-40.PMID:23466420DOI:10.1016/j.bcp.2013.02.024.
The aim of this work is the in vitro and ex vivo assessment of the leishmanicidal activity of camptothecin and three analogues used in cancer therapy: topotecan (Hycantim®), Gimatecan (ST1481) and the pro-drug irinotecan (Camptosar®) as well as its active metabolite SN-38 against Leishmania infantum. The activity of camptothecin and its derivatives was studied on extracellular L. infantum infrared-emitting promastigotes and on an ex vivo murine model of infected splenocytes with L. infantum fluorescent amastigotes. In situ formation of SDS/KCl precipitable DNA-protein complexes in Leishmania promastigotes indicated that these drugs are DNA topoisomerase IB poisons. The inhibitory potency of camptothecin derivatives on recombinant L. infantum topoisomerase IB was assessed in vitro showing that Gimatecan is the most active compound preventing the relaxation of supercoiled DNA at submicromolar concentrations. Cleavage equilibrium assays in Leishmania topoisomerase IB show that Gimatecan changes the equilibrium towards cleavage at much lower concentrations than the other camptothecin derivatives and that this effect persists over time. Gimatecan and camptothecin were the most powerful compounds preventing cell growth of free-living L. infantum promastigotes within the same concentration range. All these compounds killed L. infantum splenocyte-infecting amastigotes within the nanomolar range. The amastigote form showed higher sensitivity to topoisomerase IB poisons (with high therapeutic selectivity indexes) than free-living promastigotes. All the compounds assayed poisoned L. infantum DNA topoisomerase IB leading to a strong leishmanicidal effect. Camptothecin derivatives are suitable for reducing the parasitic burden of ex vivo infected splenocytes. The selectivity index of Gimatecan makes it a promising drug against this neglected disease.
Gimatecan (sigma-tau industrie farmaceutiche riunite/novartis)
IDrugs 2005 Jul;8(7):578-88.PMID:15973567doi
Sigma-Tau Industrie Farmaceutiche Riunite SpA and Novartis AG are developing oral Gimatecan, a camptothecin derivative, for the potential treatment of tumors, including glioblastoma.