Nitracrine
(Synonyms: 二胺硝吖啶) 目录号 : GC33400
Nitracrine是一种已在临床上使用数年的抗肿瘤药物。
Cas No.:4533-39-5
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: | Six-week-old male rats are injected with 3-methylcholanthrene (4 mg/animal) for 3 days before decapitation. Livers are removed, homogenized in a homogenizer, and centrifuged for 30 min at 10000g.The activation of ledakrin with the microsomal fraction of rat liver is carried out in 0.16 M Trizma base buffer (pH 7.4). The incubation mixture consists of 125 mM nicotinamide, 100 mM glucose 6-phosphate, 10 mM NADPH, glucose-6-phosphate dehydrogenase (40 units), rat liver microsomes (5 mg/mL), andledakrin (1 mmol)[1]. |
References: [1]. Gorlewska K, et al. Products of metabolic activation of the antitumor drug ledakrin (nitracrine) in vitro. | |
Nitracrine is an antitumor drug that has been used clinically for several years.
It is demonstrated during the reduction of ledakrin that a key metabolite, a compound with anadditional five-membered ring attaching to positions 1 and 9 of the acridine core and with the retained 9-aminoalkyl side chain, is formed in all the systems that are studied. It is determined that the reactive nitrogen atoms of this additional ring undergo further transformations resulting in the formation of a six-membered ring produced by the addition of a carbon atom to the dihydropyrazoloacridine ring. Furthermore, it is observed that positions 2 and 4 of ledakrin's acridine ring are susceptible to nucleophilic substitution as revealing by the studies with dithiothreitol. Additionally, although most products from the reduction of ledakrin are extremely unstable, 1-aminoacridinone, producing enzymatically and with dithiothreitol, exhibiting persistent stability under the studied conditions[1].
[1]. Gorlewska K, et al. Products of metabolic activation of the antitumor drug ledakrin (nitracrine) in vitro.
| Cas No. | 4533-39-5 | SDF | |
| 别名 | 二胺硝吖啶 | ||
| Canonical SMILES | O=[N+](C1=CC=CC2=NC3=CC=CC=C3C(NCCCN(C)C)=C21)[O-] | ||
| 分子式 | C18H20N4O2 | 分子量 | 324.38 |
| 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 | 3.0828 mL | 15.414 mL | 30.828 mL |
| 5 mM | 0.6166 mL | 3.0828 mL | 6.1656 mL |
| 10 mM | 0.3083 mL | 1.5414 mL | 3.0828 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。
Nitracrine and its congeners--an overview
Gen Pharmacol 1995 May;26(3):473-81.PMID:7789719DOI:10.1016/0306-3623(94)00143-b.
1. An anticancer drug, Nitracrine 1-nitro-9(3'3'-dimethylaminopropylamino)acridine (Ledakrin, C-283) exhibits potent cytostatic effects which can be ascribed to interactions of the drug with DNA. 2. The reduction of the nitro group of Nitracrine is one of the activation steps leading to the drug covalent binding to DNA and proteins both in subcellular systems and in the cell. 3. DNA-drug non-covalent interactions and covalent complexes are examined in several model systems and compared with the properties of a number of derivatives with programmed structural changes. 4. DNA-protein crosslinks and interstrand crosslinks are detected in the cells following exposition to the drug. 5. The drug exhibits selective toxicity and radiosensitization effects to hypoxic mammalian cells.
Are lethal effects of Nitracrine on L5178Y cell sublines associated with DNA-protein crosslinks?
Biochem Pharmacol 1993 Aug 17;46(4):615-20.PMID:8363635DOI:10.1016/0006-2952(93)90546-9.
Nitracrine (Ledakrin, 1-nitro-9-(3,3-N,N-dimethylaminopropylamino)-acridine) is of interest as a DNA intercalator and alkylator with very high cytotoxic potency, especially against hypoxic cells. DNA-DNA crosslinks [Konopa et al., Chem Biol Interact 43: 175-197, 1983; Pawlak et al., Cancer Res 44: 4289-4296, 1984] or DNA-protein crosslinks (DPCs) [Woynarowski et al., Biochem Pharmacol 38: 4095-4101, 1989; Szmigiero and Studzian, Biochim Biophys Acta 1008: 339-345, 1989] are related to the toxicity of the drug. The cytotoxic effect of and DNA damage induced by Nitracrine were measured in two sublines of mouse lymphoma L5178Y, LY-R (resistant to ionizing radiation) and LY-S (sensitive to ionizing radiation). LY-R cells were more sensitive to Nitracrine (D10 = 0.11 microM) than LY-S (D10 = 0.35 microM) when treated for 1 hr at 37 degrees. To a DNA-DNA crosslinking agent, mitomycin C, the comparative sensitivity was opposite. LY-R cells were more resistant to this drug than LY-S cells (D10 = 7.1 vs 2.3 microM). DNA damage induced by Nitracrine was measured by the alkaline elution method and by nitrocellulose filter binding assay. Nitracrine treatment with biologically relevant concentrations (0.1-3.0 microM, 1 hr, 37 degrees) induced only DPCs. Interstrand crosslinks and DNA breaks were not detected. Nitracrine produced about two times more DPCs in LY-R cells than in LY-S cells. Both sublines removed 50% of initial lesions during 2 hr post-treatment incubation. The greater sensitivity of LY-R cells to Nitracrine is thus not related to the efficiency of DNA repair, but may be a consequence of enhanced initial damage in the form of DPCs. This finding is consistent with the latter lesion being responsible for the cytotoxicity of Nitracrine.
Anaerobic incubation and mutagenicity of Nitracrine analogues in Salmonella typhimurium
Mutagenesis 1987 Jul;2(4):253-7.PMID:3325754DOI:10.1093/mutage/2.4.253.
Nitracrine [1-nitro-9-(dimethylaminopropylamino)-acridine] is a clinical antitumour agent with hypoxia-selective cytotoxicity and radiosensitizing activity. Developments in tumour therapy using either Nitracrine itself or some of its analogues under development are likely to be targeted at anaerobic regions of tumours. We have investigated the effects of anaerobiosis on mutagenic activity of Nitracrine and a small series of analogues in three derivatives of Salmonella typhimurium frameshift strain hisC3076. Nitracrine-induced mutagenicity was apparently enhanced by a period of anaerobic incubation followed by an aerobic period, with maximal mutagenic effectiveness (as revertants/nmol) being seen at 24 h anaerobiosis. However, the maximal number of nitracrine-induced revertants was not increased by anaerobic incubation, and the relationship between mutagenicity and toxicity remained similar. Comparisons of the effects of anaerobiosis on mutagenicity of bacterial strains with different DNA repair capacities suggested that anaerobiosis was not simply depressing 'SOS' repair. Comparisons of Nitracrine with four of its analogues showed that this effect was not a universal characteristic of either acridine derivatives or of Nitracrine analogues. Rather, the dose displacements obtained paralleled hypoxic cell selective cytotoxicity in mammalian cells. If this result extends to other compounds, experiments of this nature using the bacterial strains could provide a novel and useful screening system to identify hypoxia-selective cytotoxic anticancer drugs of potential clinical value.
Selective toxicity of Nitracrine to hypoxic mammalian cells
Br J Cancer 1984 Feb;49(2):215-23.PMID:6696822DOI:10.1038/bjc.1984.34.
Hypoxic cells in solid tumours are resistant to ionizing radiation and may be refractory to treatment by many chemotherapeutic agents. For these reasons the identification of drugs with selective toxicity towards hypoxic cells is an important objective in cancer chemotherapy. Nitroimidazoles such as misonidazole demonstrate such hypoxia-selective toxicity but have very low dose potency. The 1-nitroacridine derivative 1-nitro-9-(dimethylaminopropylamino)acridine (Nitracrine) binds reversibly to DNA but also forms covalent adducts with DNA in vivo. We have found Nitracrine to be selectively toxic to the Chinese hamster ovary cell line AA8 under hypoxic conditions in culture, with a potency approximately 100,000 times higher than that of misonidazole. The effect of oxygen is not a simple dose-modifying one in this system, probably in part because of rapid metabolic inactivation of Nitracrine under hypoxic conditions. Viscometric studies with the mini col E1 plasmid PML-21 confirmed that Nitracrine binds to DNA by intercalation, and provided an unwinding angle of 16 degrees (relative to 26 degrees for ethidium). It is proposed that the cytotoxicity of Nitracrine under hypoxia is due to reductive metabolism to form an alkylating species, but that intercalation of the chromophore may enhance reactivity towards DNA and hence contribute to the marked enhancement of potency with respect to simple nitroheteroaromatic drugs.
Effect of intercalating and groove-binding ligands on formation of covalent complexes between Nitracrine (Ledakrin, C-283) or 8-methoxypsoralen and DNA
Biochim Biophys Acta 1984 Jul 18;782(3):285-94.PMID:6733111DOI:10.1016/0167-4781(84)90064-2.
The effect of ethidium bromide, actinomycin D, distamycin A and netropsin on covalent binding of Nitracrine (1-nitro-9-(3,3-N,N-dimethylaminopropylamino)acridine, Ledakrin, C-283) and 8-methoxypsoralen to DNA was examined. The competition was assayed either directly with [3H]- and [14C]Nitracrine or indirectly by estimation of transcriptional template activity of nitracrine-DNA and 8-methoxypsoralen-DNA complexes formed in the presence of the ligands. A higher protective effect of ethidium bromide and distamycin on the photo-binding of 8-methoxypsoralen than on the dithiothreitol-dependent attachement of Nitracrine to DNA assayed at 0.15 M KCl or NaCl was observed. The non-intercalating antibiotics showed lower competitive effect on 8-methoxypsoralen binding than ethidium bromide. Actinomycin D showed relatively low competition for both drugs with DNA. In contrast to the reaction of 8-methoxypsoralen, the decrease of Nitracrine binding in the presence of competing ligands considerably depends on ionic strength. Particularly high inhibition of the adduct formation in the presence of ethidium at 1 M KCl was shown, while the amount of Nitracrine bound in the presence of distamycin increases at elevated ionic strength. The results may indicate steric demands of the reaction between Nitracrine and DNA.