Amphethinile (Amphetinile)
(Synonyms: Amphetinile; CRC 82-07) 目录号 : GC33370
Amphetinile (Amphetinile) 是一种抗微管蛋白剂。 Amphetinile (Amphetinile) 与微管蛋白结合的亲和常数 (Ka) 为 1.3 μM。
Cas No.:91531-98-5
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Cell experiment: | The volume of methanol in the final incubation mixture is <1%, which does not modify the uptake of any of the drugs used in either drug sensitive or resistant lines. In addition, the same level of methanol is used in the control cultures. Drug incubations (1O μM, 2h, 37°C) are performed in RPMI medium in the presence or absence of horse serum (10%). Cell suspensions (100 mL) are centrifuged (800 g, 10 min, 4°C), washed in PBS, lysed in distilled water by sonication, and the drug extracted into CHC13. The amphethinile concentration is determined spectrophotometrically (λ=304 nm) relative to a standard curve[2]. |
Animal experiment: | Mouse: Initial toxicity studies on this agent are performed under contract in MFI-strain male mice following an acute i.v. and i.p. administration as well as a 4-weekly 5 day sub acute study. Preclinical toxicology is undertaken using the clinically formulated drug. The formulation consisted of 10 g amphethinile and 100 g Solutol HS15 diluted to 200 mL with70% ethanolic citrate buffer at pH 6.0. The resulting drug concentration is 50mg mL[2]. |
References: [1]. McGown AT, et al. Interaction of the novel agent amphethinile with tubulin. Br J Cancer. 1989 Jun;59(6):865-8. | |
Amphethinile is an anti-tubulin agent. The affinity constant for the association (Ka) of Amphethinile with tubulin is 1.3 μM.
Amphethinile shows a remarkable similarity to colchicine in terms of its binding to tubulin and inhibition of microtubular assembly. Amphethinile binds strongly to microtubule protein (Ka=1.3 μM). This interaction has been shown to be capable of inhibiting tubulin assembly, but shows no rapid stimulation of disassembly when added to assembled tubulin. The concentration of amphethinile required to inhibit assembly by 50% (12 μM) is very similar to that for colchicine (11 μM). Amphethinile has been shown to be capable of competing for colchicine binding sites but not for those of the vinca alkaloids. Amphethinile can also be shown to stimulate the GTPase activity of tubulin in a manner similar to that observed for combretastatin A4 and 2-methoxy-5-(2',3',4'-trimethoxyphenyl) tropolone (MTPT)[1]. Amphethinile has been shown to cause a G2/M phase block in the cell cycle. In addition, this agent has been shown to be equally toxic toward parental and daunorubicin-resistant P388 cells. Whereas resistance in this cell line is associated with decreased drug accumulation in the case of daunorubicin, vincristine and vinblastine, this effect is much less pronounced for amphethinile[2].
Pharmacokinetic studies in male mice are undertaken. Area under the curve values (AUC), show that levels of 313 μg/L per hour are attained at doses equivalent to the LD10. The alpha half life is 8 min after a bolus intravenous injection. The beta half life is 100 min and relatively independent of dose level[2].
[1]. McGown AT, et al. Interaction of the novel agent amphethinile with tubulin. Br J Cancer. 1989 Jun;59(6):865-8. [2]. McGown AT, et al. Pre-clinical studies of a novel anti-mitotic agent, amphethinile. Br J Cancer. 1988 Feb;57(2):157-9.
| Cas No. | 91531-98-5 | SDF | |
| 别名 | Amphetinile; CRC 82-07 | ||
| Canonical SMILES | N#CC1=C(N)NC2=C1C=C(SC3=CC=CC=C3)C=C2 | ||
| 分子式 | C15H11N3S | 分子量 | 265.33 |
| 溶解度 | Soluble in DMSO | 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 | 3.7689 mL | 18.8445 mL | 37.6889 mL |
| 5 mM | 0.7538 mL | 3.7689 mL | 7.5378 mL |
| 10 mM | 0.3769 mL | 1.8844 mL | 3.7689 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。
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A phase I and pharmacokinetic study of Amphethinile
Br J Cancer 1988 Jun;57(6):623-7.PMID:3408647DOI:10.1038/bjc.1988.142.
Amphethinile is a new spindle poison with a novel structure that has shown activity in the L1210, ADJ/PC6 and Walker carcinoma rodent tumours. In addition the agent appeared to have an improved therapeutic ratio compared to existing spindle poisons and is well absorbed when administered orally. The starting dose for the phase I study was 40 mg m-2 (1/10th mouse LD10) and further patients were studied at 200, 400, 800 and 1200 mg m-2, dose escalation being based on pharmacological monitoring. Significant toxic effects were seen only at 800 and 1200 mg m-2. At these doses patients experienced nausea and vomiting, light headedness during the infusion and varying degrees of lethargy following therapy. Two of six patients at 800 mg m-2 developed severe pain in the tumour bearing area 1-2 h after treatment and one experienced colicky abdominal pain. At 1200 mg m-2 two patients died within 48 h of treatment from what appeared to be vascular causes. Following these episodes the trial was discontinued. Neutropenia and alopecia occurred in two patients, one at 800 and one at 1200 mg m-2. These patients achieved the highest drug exposure in terms of area under the concentration x time curve. It was not possible to achieve an AUC consistently high enough to produce cytotoxic effects due to the occurrence of dose limiting toxicities thus Amphethinile cannot at present be recommended for phase II testing by the i.v. route. The dose escalation scheme based on pharmacological monitoring resulted in a considerable saving in the duration of the trial. Further evaluation of this methodology is recommended.
The impact of pharmacokinetically guided dose escalation strategies in phase I clinical trials: critical evaluation and recommendations for future studies
Ann Oncol 1992 May;3(5):339-47.PMID:1616887DOI:10.1093/oxfordjournals.annonc.a058203.
Phase I studies requiring multiple dose escalation steps have led to the development of pharmacokinetically guided dose escalation (PGDE) strategies to expedite the conduct of early clinical trials. This article critically reviews PGDE strategies for a number of new anticancer agents including Amphethinile, brequinar sodium, iodo-doxorubicin, the anthrapyrazoles (DuP 941, DuP 942 and DuP 937), rhizoxin, and aphidicolin glycinate. The benefits and problems associated with PGDE are examined. Recommendations are made for the optimal deployment of pharmacological information in future phase I studies.
Structural and biochemical comparison of the anti-mitotic agents colchicine, combretastatin A4 and Amphethinile
Anticancer Drug Des 1989 Mar;3(4):249-54.PMID:2930627doi
The novel agents Amphethinile and combretastatin A4 are shown to be very similar to colchicine in their interactions with purified tubulin. All three agents can inhibit tubulin assembly at similar treatment levels and have comparable affinity constants for tubulin. Amphethinile and combretastatin A4 are capable of displacing colchicine but not vinblastine from tubulin. A comparison of the structures of these agents shows that whereas colchicine and combretastatin A4 contain a trimethoxybenzene group (a moiety also found in other colchicine-like agents such as podophyllotoxins and steganacin) no obvious similarity is seen for Amphethinile. The three-dimensional structures of these agents, determined from either crystallographic data or by energy minimization procedures, show, however, that all three agents consist of two planar, or almost planar, ring systems which are tilted with respect to each other. Using computer graphic techniques it can be shown that their ring systems are superimposable and that the planar sections of each molecule are at an angle of 50-60 degrees to each other. It is proposed that the angular bicyclic structure of these agents is one determining factor for their efficient binding to tubulin.
Interaction of the novel agent Amphethinile with tubulin
Br J Cancer 1989 Jun;59(6):865-8.PMID:2736224DOI:10.1038/bjc.1989.183.
The novel agent Amphethinile is shown to inhibit tubulin assembly in vitro. This agent is capable of displacing colchicine but not vinblastine from tubulin and causes a stimulation in GTPase activity in vitro. The affinity constant for the association of this drug with tubulin has been determined (Ka = 1.3 x 10(6) M-1). It is concluded that Amphethinile belongs to the class of agents which share a common binding site with colchicine on the tubulin molecule.
Pre-clinical studies of a novel anti-mitotic agent, Amphethinile
Br J Cancer 1988 Feb;57(2):157-9.PMID:3358906DOI:10.1038/bjc.1988.32.
A new antitumour agent is described, which has been shown to induce a G2/M block in murine leukaemia cells in vitro. In addition this agent has been shown to be equally toxic toward parental and daunorubicin-resistant P388 cells in vitro. These resistant cells are highly cross-resistant to the established anti-mitotic agents vincristine and vinblastine. Drug accumulation studies in cells have shown that whereas resistance in this cell line is associated with decreased drug accumulation in the case of daunorubicin, vincristine and vinblastine, this effect is much less pronounced for Amphethinile. It is proposed that Amphethinile is a poor substrate for the drug efflux process associated with the pleiotropic resistance mechanism operating in these cells. The data suggest that cell sensitivity towards Amphethinile differs qualitatively from that of the vinca alkaloids and anthracycline. Pharmacokinetic studies in male mice were undertaken. Area under the curve values (AUC), show that levels of approximately 313 micrograms l-1 h-1 were attained at doses equivalent to the LD10. The alpha half life is approximately 8 min after a bolus intravenous injection. The beta half life was approximately 100 min and relatively independent of dose level.