86639-62-5
10-Nitrocamptothecin
CAS: 86639-62-5
Molecular Formula: C20H15N3O6
86639-62-5 - Names and Identifiers
| Name | 10-Nitrocamptothecin |
| Synonyms | RUBETICAN 9-NITRO-CPT 10-Nitrocamptothecin 9-Nitro-20(S)-camptothecine CAMPTOTHECIN, 9-NITRO-20(S)- |
| CAS | 86639-62-5 |
86639-62-5 - Physico-chemical Properties
| Molecular Formula | C20H15N3O6 |
| Molar Mass | 393.35 |
| Density | 1.63±0.1 g/cm3(Predicted) |
| Boling Point | 827.4±65.0 °C(Predicted) |
| pKa | 11.17±0.20(Predicted) |
86639-62-5 - References
| background and overview | Camptothecaacuminate Decne is a plant of the genus Acanthaceae in the family Davidia involucrata. In 1985, Hsing et al. discovered that camptothecin and its derivatives are DN A topoisomerase I(Topo I) as the target and inhibit the synthesis of DN A in the organism to exert anti-tumor effects, the research and development of new anti-tumor drugs with high efficiency and low toxicity of camptothecin has become a hot topic for pharmaceutical workers. Camptothecin (Camptothecin,CPT) is an active substance extracted from the fruit of Chinese Davidia involucrata plant (Camptothecacuminata) by American chemist Wall and others, and its structure is determined to be an alkaloid, which is an effective ingredient of traditional Chinese medicine with anti-tumor effect. This type of alkaloid exists in two forms: lactone type and carboxylate type. The lactone type with a lactone ring structure is saponified in an alkaline aqueous solution to form a carboxylate type dissolved in water, and it is repeated under acidic conditions. Synthesis of lactone type. However, due to its adverse reactions to the digestive system and urinary system, related studies have been greatly reduced in the following 10 years. Until 1985, Hisang et al. revealed a new mechanism of camptothecin inhibiting topoisomerase I(TopoI), which once again attracted great attention from the medical circles at home and abroad. In order to find low toxicity and high efficiency camptothecin analogs, researchers have made various structural modifications to camptothecin, and a large number of derivatives have emerged. Some have been used in clinical anticancer therapy, such as topotecan (ropotee n) and irinotecan (irinoteean). 9-nitrocamptothecin (rubitecan,9-NC) is a new type of semi-synthetic camptothecin derivative, also known as RFS200 0, and the trade name is Lubitecan (rubiteean). It is a semi-synthetic camptothecin derivative developed by Super Gene Company in the United States. It has a five-ring structure and contains a pyrrole [3,4-b] quinoline ring (A,B,C),A conjugated pyridone ring (D) and a six-membered α-hydroxylactone ring (E), there is a nitro group at the 9th position of the ring. A necessary condition for complete α-hydroxy lactone ring activity, and only 20(S) configurations are active. Preclinical pharmacological studies have shown that this drug is a very ideal anti-tumor drug. It not only has a highly effective inhibitory effect on common tumors, but also has a good synergistic effect with currently commonly used anti-tumor drugs such as 5-Fu. It can also inhibit sublethal damage recovery and can be used as a sensitizer for tumor radiotherapy. The drug can also inhibit the replication of HIV virus and is also expected to be used in the treatment of acquired immunodeficiency syndrome AIDS in the future. | |
| mechanism of action | camptothecin and its derivatives are topoisomerase I as the target to inhibit the synthesis of DN A. Topoisomerase I is a kind of essential enzyme widely existing in organisms, which participates in all key processes such as DNA replication, transcription, recombination and repair. Topo I is a monomeric enzyme with a molecular weight of 91 ku and a total of 765 amino acids, located on chromosome 20. Topo I is mainly concentrated in the active transcription region of DNA, which can break and reconnect DNA strands. In the normal enzyme-catalyzed cycle, Topo I binds to DNA, and one strand of DNA breaks to form a cleavable complex, thereby changing the number of sequences and superhelices of DNA. 9-Nitrocamptothecin takes Topo I as the target, its lactone ring opens, the acyl group interacts with the nucleophilic part of Topo I, and reversibly binds to the Topo I-DN A break complex to form the drug-Topo I- DNA ternary complex, thereby stabilizing the cleavable complex, so that the replication fork cannot proceed, thereby causing cell death. Due to the high Topo I content of cancerous cells, cancerous cells are more susceptible to Topo I inhibition than normal cells. whether cells can divide depends on entering s phase and m phase. studies have found that 9-NC can induce apoptosis. after administration, both s phase and G2M phase of cell growth are delayed. 9-NC is inhibited throughout the cell cycle and it is found that this inhibitory effect is dose-and time-dependent. | |
| pharmacological action | in vitro experiment 1) anti-tumor effect: different concentrations of 9-NC(20, 40, 80nmol/L) can inhibit the growth of human malignant melanoma cells (MEL cells and BRO cells) in vitro. For MEL cells, 9-NC causes their cell cycle to stagnate at the junction of S phase and G2 phase, causing no or only a few cell apoptosis. For BRO cells, 9-NC stops the cell cycle in the S phase and can trigger apoptosis. This apoptosis is difficult to undo and can continue even if the drug is stopped. experiments with human ovarian cancer SKOV-3 cells found that 9-NC can accelerate the apoptosis of some SKOV-3 cells, suggesting that the sensitivity of cells to 9-NC is different. Experiments with DU145 prostate cancer cells showed that 9-NC can trigger the occurrence of apoptosis, and the triggering process is mediated by CD95 system. 9-NC can increase the expression of CD95 and CD95L, and make DU145 cells change from non-apoptotic state to pre-apoptotic state, thus triggering the occurrence of apoptosis. 2) Radiation enhancement: 9-NC was added to a culture dish to culture human H460 lung cancer cells, and then combined with radiotherapy. The results showed that H460 cells were cultured with l0 nmol/L 9-NC for 4-24h at different times, and the radiation enhancement was observed in all experimental groups, and there was no significant difference between the groups. In addition, the experimenters used 5, 10, 15nmol/L 9-NC to culture H460 cells for 24 hours. The radiation dose enhancement rates (ER) of the three groups were 1.22, 1.54 and 2.0 respectively. 3) antiviral effect: U937 monocytes infected with human immunodeficiency virus type I (HIV-I) were used for experiments. the results showed that 9-NC could inhibit virus replication and HIV-I release from infected cells, and the response was dose-dependent. Other experiments have also confirmed the antiviral activity of 9-NC. For example, 9-NC can inhibit the activation of tumor necrosis factor-mediated HIV-I and accelerate the apoptosis of potentially infected T cells. Using peripheral blood lymphocytes from infected HIV-I into experiments, the results also showed that 9-NC can inhibit the replication of HIV-I in host cells and induce apoptosis. in vivo experiment 1) anti-tumor effect: in the two models of lung metastasis of cancer cells, 9-NC showed good anti-tumor activity. Mice inoculated with B16 melanoma cells were treated with 9-NC liposome aerosol for 1h per week, divided into 5d. After 3 weeks of treatment, the lung weight of mice was reduced and the number of tumor lesions decreased significantly. Comparing this result with the untreated group, the macroscopic tumor nodules were significantly reduced and reduced. Mice inoculated with human osteosarcoma were treated with the same administration regimen. After 8 or 10 weeks, the number of mice with lesions observed by microscope and naked eye decreased significantly, the volume of individual tumor nodules decreased significantly, and the total number of tumor lesions in the lung also decreased significantly. Intramuscular injection of 9-NC suspension 4 mg/kg to mice inoculated with human lung cancer, twice a week, can significantly inhibit tumor growth, and can cause significant changes in the cell cycle of tumor cells, so that cells apoptosis and eventually be normal tissue clear out of the body. Mice inoculated with human breast cancer were injected intramuscularly with 9-NC suspension 4mg/kg twice a week, and the tumor did not continue to develop. It can be seen that 9-NC can inhibit the growth of breast cancer tumor. Mice inoculated with human ovarian cancer were injected intramuscularly with 9-NC suspension 4 mg/kg twice a week, and 50% of the smaller tumors were inhibited after 5 days. After 52d, the tumor was generally reduced or completely removed. Another group of experiments also showed that the smaller tumors were completely inhibited during the administration period, and there was still no regrowth within 45 days after stopping the drug. Mice inoculated with U-937 leukemia were injected intramuscularly with 9-NC suspension 4 mg/kg twice a week. The results showed that 9-NC could delay tumor growth to a large extent. The experimenter transplanted U-937 cells to 7 mice, and 9-NC treatment was given 1 day later, and the time required for the tumor to grow to measurable h was recorded. Among them, 5 only need 26d, L needs 40 d,1 tumor is not generated, while the tumor growth time of the control group without treatment only needs 5-7d. Mice inoculated with different types of tumors (breast cancer, colon cancer, lung cancer) were treated with 9-NC liposome aerosol, at a dose of 200 μg/kg/d, 5 times per week. after treatment, the growth rate of tumors was greatly reduced, and some were completely undetectable after several weeks of treatment. Experiments have shown that when 9-NC is used in the form of aerosols for treatment, its effective dose is smaller than when treated with traditional dosing. If the above dose is given to mice orally, there is no substantial effect; intramuscular injection of the same dose is only partial and very limited. 2) radiation enhancement: mice inoculated with H460 cells were divided into 3 groups, 9-NC group (l mg/kg), radiotherapy group and 9-NC combined with radiotherapy group. The results show that 9-NC can enhance the effect of radiotherapy, and its enhancement factor (EF) is 1.64. | |
| synthetic route | 20(S)-9-nitrocamptothecin was synthesized by mixed nitrification agent. With camptothecin as raw material, concentrated sulfuric acid as the reaction medium, mixed nitrate as nitrification agent for nitrification reaction, and then by chromatography purification to obtain the target product 9-NC. The yield of 9-NC increased from 31% to about 40%. The optimum technological conditions were as follows: camptothecin 0.5g, concentrated sulfuric acid 30ml; Nitrate 0.007mol, molar ratio of ammonium nitrate to calcium nitrate 1:1; The reaction temperature was 20 ℃, and the reaction time was 1 day. This method has the advantages of high yield, easy separation and purification, and the specific reaction process is as follows: | |
| Pharmacokinetics | It is known that 9-NC is converted into 9-aminocamptothecin (9-AC) in vivo. The pharmacokinetic parameters of 9-NC to 9-AC were determined by experiments on mice, dogs and humans. 1) mice were taken as experimental subjects. after a single dose of 9-NC 4.1 mg/kg, Tmax was 0.1h,Cmax was 732ng/mL,t1/2 was 10.0 h,AUC was 441ng/h/mL. When 9-NC is converted into 9-AC, the Tmax of 9-AC is 0.6h,Cmax is 26ng/mL,t1/2 is 1.2 h, and AUC is 63ng/h/mL. 2) after taking dogs as experimental subjects and taking 9-NC 1.0 mg/kg orally, Tmax was 0.7 h,Cmax was 19.1ng/mL,t1/264h,AUC was 186ng/h/mL. When 9-NC is converted into 9-AC, the Tmax of 9-AC is 2.9 h,Cmax is 9.2ng/mL,t1/2 is 21.lh,AUC is 310 ng/h/mL. 3) in human test, single dose of 9-NC 0.1 mg/kg,Tmax 3.4 h,Cmax 483 ng/mL,AUC 2600 ng/h/mL ,t1/2 2.5h. When 9-NC is converted into 9-AC, the Tmax of 9-AC is 10.3 h,Cmax is 14.0 ng/mL,AUC is 3l1 ng/h/mL,t1/2 is 7.l h. A single oral dose of 9-NC 1.0 mg/kg,Tmax 5.3h, Cmax ng/mL,AUC 17194 ng/h/mL,t1/2 4.9 h. When 9-NC is converted into 9-AC, the Tmax of 9-AC is 17.2 h,Cmax is 208 ng/mL,AUC is 9121 ng/h/mL, and t1/2 is 13.l h. | |
| Drug interaction | The test confirmed that 9-nitrocamptothecin and 5-fluorouracil (5-FU) have a synergistic effect in the treatment of tumors. HCT-8 colon cancer cells were used for experiments. 9-NC was combined with 5-FU, and the drug activity was enhanced. In addition, 9-NC and then 5-FU must be given in the experiment to show the synergistic effect of the two, suggesting that the order of administration is very important. Experiments were conducted with mice inoculated with leukemia P-388 cells, and 9-NC was combined with phenylalanine nitrogen mustard (melphalan). The results showed that after the combination of the two drugs, the anti-cancer activity was enhanced, indicating that 9-NC and melphalan have a synergistic effect in the treatment of tumors. | |
| dosage form study | liposome 9-NC was made into liposome, its pharmaceutical properties were investigated, and the effects of free drugs and liposomes on proliferation and apoptosis of HepG2, Bel-7402, Hep3B and L02 cells in vitro, as well as anti-HCC liver cancer effects in vivo were compared. The results showed that the average particle size of liposomes was 190nm, the potential was about -1.1mV, and the liposomes were stably and continuously released in vitro. The liposomes could improve the solubility and stability of 9-NC, with less side effects and more promising in the anti-tumor effect of 9-NC. nanoparticles the average particle size of 9-NC loaded into nanoparticles by nano sedimentation method is 207±26nm, the drug encapsulation efficiency is 33.5%, and the drug can be continuously released in PBS for 160h. after intravenous administration, it is found that 9-NC nanoparticles can effectively improve the content and total amount of lactone type in plasma compared with 9-NC free drugs, the AUC of lactone type and area under the total time concentration curve is 3.63 and 5.40 times that of free drugs. inclusion compound using hydroxypropyl-β-cyclodextrin as inclusion material, 9-NC inclusion compound is prepared by freeze-drying method, which increases the solubility of almost insoluble 9-NC in water to 0.52 mg/mL, the AUC of inclusion compound after intramuscular injection is 632.79ng/h/ml, while the free drug is 439.39 ng/h/ml, the AUC of the inclusion compound after intravenous injection was 538.0553ng/h/ml, while the free drug was 385.39 ng/h/ml. Not only that, the proportion of lactone type has also increased. This result suggests that 9-NC hydroxypropyl-β-cyclodextrin inclusion complex is very promising for cancer treatment. self-microemulsion self-microemulsion is a new and promising drug delivery system. it is a mixture of oil phase surfactant co-surfactant and drug. the main principle is that O/W type microemulsion can be formed spontaneously under mild agitation through the addition of water phase, while the peristalsis of human gastrointestinal tract provides the conditions for spontaneous formation of microemulsion. Self-microemulsion can increase the bioavailability of 9-NC oral absorption and anti-tumor effect. There are two prescriptions prepared from microemulsions: one is based on ethyl oleate as the oil phase, Tween-80 as the surfactant, and PEG400 as the co-surfactant; the other is based on polyoxyethylene castor oil Replace Tween-80 as a surfactant. In vitro anti-tumor experiments found that 9-NC self-microemulsion can significantly reduce the human ovarian tumors planted on nude mice compared with free drugs. micelles 9-NC is loaded into the polymeric micelles coupled with folic acid, and its prescription process is evaluated by detecting its critical micelle concentration, particle size, potential, encapsulation efficiency, etc. The materials used for the formed micelles are DSPE-PEG to avoid phagocytosis of macrophages in the body, achieve the effect of long circulation, and help the drug reach the target site of the tumor to exert its efficacy. | |
| main reference | [1] yin qi et al., a new anti-tumor drug under study, 9-nitrocamptothecin. Chinese journal of new drugs. 2005,14(2):226-230. [2] Hu rongrong et al.. research progress of 9-nitrocamptothecin. journal of Nanjing university of traditional chinese medicine. 2012,28(5):498-500. [3] Zheng Yan et al. Research Progress of 9-Nitrocamptothecin. Chemistry and Bioengineering. 200 6,23 (6):11-13. [4] Li Qingyong et al. Synthesis and in vitro antitumor activity of 9-nitrocamptothecin derivatives. Chinese Pharmaceutical Journal. 2007,42(10):786-789. [5] Li Jian et al. Synthesis of 20(S)-9-nitrocamptothecin. Journal of Medical Research. 2008,37(3):105-106. [6] Yan Jing et al.. pharmacokinetic study of 9-nitrocamptothecin dogs. Chinese clinical pharmacology and therapeutics. 2005 ,10 (11):1220-1223. |
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