Acivicin
(Synonyms: 异恶唑醋酸) 目录号 : GC42707A glutamine antagonist with anti-tumorigenic activity
Cas No.:42228-92-2
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
Acivicin is a glutamine analog that irreversibly inhibits glutamine-dependent amidotransferases involved in nucleotide and amino acid biosynthesis (Kis = 10 and 560 μM for anthranilate synthase and glutamate synthase, respectively). It also reversibly inhibits γ-glutamyl transpeptidase. Acividin has been used to elucidate aspects of glutathione metabolism and has known anti-tumorigenic activity.
| Cas No. | 42228-92-2 | SDF | |
| 别名 | 异恶唑醋酸 | ||
| Canonical SMILES | ClC1=NO[C@@]([C@H](N)C(O)=O)([H])C1 | ||
| 分子式 | C5H7ClN2O3 | 分子量 | 178.6 |
| 溶解度 | PBS (pH 7.2): 1.4 mg/ml | 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 | 5.5991 mL | 27.9955 mL | 55.991 mL |
| 5 mM | 1.1198 mL | 5.5991 mL | 11.1982 mL |
| 10 mM | 0.5599 mL | 2.7996 mL | 5.5991 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。
Acivicin in 1985
Adv Enzyme Regul 1985;24:179-205.PMID:3915184DOI:10.1016/0065-2571(85)90076-7.
This review, as its title indicates, views Acivicin at a particular point in the ongoing process of its development. There is a large body of biochemical information which permits the formulation of a number of hypotheses regarding the drug's optimal regimen, mechanism of CNS toxicity, and potential role in combination chemotherapy. We have attempted to survey those data and to project some avenues of future research which may circumvent the drug's limitations. Current deficits exist in our information, particularly in the area of the clinical activity spectrum of Acivicin. Yet the final definition of the set of human tumors in which Acivicin may find clinical utility will probably not occur until we have defined the optimal regimen for the drug, both as a single agent and in combination, and have identified and addressed the toxic effects which limit its use. A coordinated effort between the preclinical pharmacologists and clinicians will be necessary in the next few years, if Acivicin is to play an important role in the treatment of human malignancies.
Decreased glutamate transport in Acivicin resistant Leishmania tarentolae
PLoS Negl Trop Dis 2021 Dec 16;15(12):e0010046.PMID:34914690DOI:10.1371/journal.pntd.0010046.
Studies of drug resistance in the protozoan parasites of the genus Leishmania have been helpful in revealing biochemical pathways as potential drug targets. The chlorinated glutamine analogue Acivicin has shown good activity against Leishmania cells and was shown to target several enzymes containing amidotransferase domains. We selected a Leishmania tarentolae clone for Acivicin resistance. The genome of this resistant strain was sequenced and the gene coding for the amidotransferase domain-containing GMP synthase was found to be amplified. Episomal expression of this gene in wild-type L. tarentolae revealed a modest role in Acivicin resistance. The most prominent defect observed in the resistant mutant was reduced uptake of glutamate, and through competition experiments we determined that glutamate and Acivicin, but not glutamine, share the same transporter. Several amino acid transporters (AATs) were either deleted or mutated in the resistant cells. Some contributed to the Acivicin resistance phenotype although none corresponded to the main glutamate transporter. Through sequence analysis one AAT on chromosome 22 corresponded to the main glutamate transporter. Episomal expression of the gene coding for this transporter in the resistant mutant restored glutamate transport and Acivicin susceptibility. Its genetic knockout led to reduced glutamate transport and Acivicin resistance. We propose that Acivicin binds covalently to this transporter and as such leads to decreased transport of glutamate and Acivicin thus leading to Acivicin resistance.
Acivicin. An antitumor antibiotic
Cancer Clin Trials 1981 Fall;4(3):327-30.PMID:7026076doi
Acivicin [(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid; AT-125; NSC-163501] is a fermentation product of Streptomyces sviceus which is active in a variety of mouse tumor models including the L1210 and P388 leukemias, the M5076 ovarian carcinoma, and the MX-1 human breast tumor xenograft. Antitumor activity is probably mediated through the inhibition of enzymes catalyzing amido transfer from L-glutamine, especially CTP synthetase and XMP aminase. In mice, Acivicin is absorbed systemically via the p.o., I.P., and S.C. routes and is predominantly excreted in the urine in unchanged form. Although a wide variety of toxicities, including myelosuppression, were noted in dogs and monkeys, vomiting, diarrhea, and pathologic lesions of the GI tract predominated in both species. A marked cumulative toxicity was noted in dogs with 16 mg/m2/day being the lethal dose on the daily x 5 schedule compared to 1000 mg/m2 on the single-dose schedule. An interesting phenomenon was noted in mice wherein older male mice were more resistant to the toxic effects of the drug than female or younger male mice. This sex and age difference in susceptibility to Acivicin toxicity was shown to be correlated with differences in pharmacokinetics; older male mice cleared Acivicin at approximately twice the rate of females or younger males. No sex differences in toxicity were noted in dogs or monkeys. Because of its activity in mouse tumor systems and acceptable preclinical toxicology patterns, the drug is being introduced into clinical phase I studies under the sponsorship of the National Cancer Institute.
Carrier-mediated transport of the antitumor agent Acivicin across the blood-brain barrier
Biochem Pharmacol 1995 Mar 30;49(7):941-5.PMID:7741766DOI:10.1016/0006-2952(95)00005-k.
The cytotoxic agent Acivicin has been shown to be effective against several types of tumors. However, the clinical utilization of Acivicin has been prohibited because of its dose-limiting neurotoxicity. Acivicin is believed to be transported into the brain by the large neutral amino acid (LNAA) carrier, which is expressed at the blood-brain barrier (BBB). In this study, we used an in situ rat brain perfusion technique to determine the kinetics of the LNAA carrier-mediated transport of Acivicin across the BBB. We found that the Vmax of Acivicin (1.05 nmol/sec/g) obtained in this study was comparable to the Vmax of L-leucine (1.07 nmol/sec/g) and other LNAAs as determined by other investigators. The Km was high compared with other LNAAs, but this could be explained by the low lipophilicity of Acivicin. Acivicin transport across the BBB was inhibited by other LNAAs but not by Acivicin derivatives with structural modifications at the amino or carboxyl group. The ASC (alanine, serine, cysteine) carrier system did not influence the transport of Acivicin across the BBB. These results suggest that the CNS toxicity of Acivicin might be reduced by coadministration of other LNAAs. Acivicin derivatives with structural modifications at the amino or carboxyl group of Acivicin lack affinity for the LNAA carrier at the BBB and, therefore, will exhibit less CNS toxicity than Acivicin.
Acivicin-induced alterations in renal and hepatic glutathione concentrations and in gamma-glutamyltransferase activities
Biochem Pharmacol 2004 Apr 1;67(7):1421-6.PMID:15013858DOI:10.1016/j.bcp.2003.10.014.
gamma-Glutamyltransferase (gamma-GT) catalyzes the hydrolysis of glutathione, glutathione S-conjugates, and gamma-substituted l-glutamate derivatives. Acivicin is an irreversible inhibitor of gamma-GT that has been used to study the role of gamma-GT in glutathione homeostasis and glutathione-dependent bioactivation reactions. The present studies were undertaken because of reported conflicting effects of Acivicin on the nephrotoxicity of some haloalkenes that undergo glutathione-dependent bioactivation. The objective of this study was to test the hypothesis that Acivicin may alter renal glutathione concentrations; acivicin-induced changes in renal glutathione concentrations may alter the susceptibility of the kidney to the nephrotoxic effects of haloalkenes. Hence, diurnal and acivicin-induced changes in renal and hepatic glutathione concentrations along with renal and hepatic gamma-GT activities were investigated. The previously observed diurnal variations in hepatic glutathione concentrations in fed rats were confirmed, but no diurnal variations were observed in renal glutathione concentrations or in renal or hepatic gamma-GT activities. Renal and hepatic glutathione concentrations and gamma-GT activities were measured in tissue homogenates from rats given 0, 0.1, or 0.2 mmol Acivicin/kg (i.p.) and killed 0, 2, 4, 8, 12, or 24 hr later. Renal glutathione concentrations were increased above control values in acivicin-treated rats, whereas Acivicin had no effect on hepatic glutathione concentrations. Renal gamma-GT activities decreased within 2 hr after giving Acivicin and remained decreased for 24 hr. Acivicin had no effect on hepatic gamma-GT activities, except at 24 hr after treatment when values in acivicin-treated rats were elevated compared with controls. Although the present studies do not afford an explanation of the mechanism whereby Acivicin increases the nephrotoxicity of some haloalkenes, they do indicate that Acivicin is not a reliable probe to investigate the role of gamma-GT in haloalkene-induced nephrotoxicity.