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J Zhejiang Univ (Med Sci)  2017, Vol. 46 Issue (2): 160-166    DOI: 10.3785/j.issn.1008-9292.2017.04.07
Synthesis, characterization and antitumor activity of 5-fluorouracil-nicotinamide cocrystal
WU Min(),LIU Xingang,XUE Yu,CHEN Qi,HU Xiurong,ZHOU Jun,TANG Guping*()
Department of Chemistry, Zhejiang University, Hangzhou 310027, China
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Objective: To synthesize 5-fluorouracil-nicotinamide (5-FU-NCT) cocrystal and to investigate its physicochemical and biological properties. Methods: The cocrystal of 5-Fu-NCT was prepared through the cooling technology. PXRD, NMR, FTIR and DSC were used to characterize the structure of 5-FU-NCT cocrystal. Solubility was measured by HPLC method. Drug resistant human liver cancer BEL-7402/5-FU cells were treated with 5-FU-NCT cocrystal, the inhibition effect was tested by MTT and HE staining, and cancer cell migration was determined by scratch test. Results: According to PXRD, NMR, FTIR and DSC results, the cocrystal of 5-Fu-NCT had been synthesized successfully. The characteristic diffraction peaks (2θ/°) of the cocrystal were 16.4, 20.4, 22.3, 27.9 and 30.1. The solubility of 5-FU-NCT was 13.5 g/L as measured by HPLC. The antitumor activity tests showed that 5-FU-NCT cocrystal enhanced anticancer effect of 5-FU, and the IC50 of 5-FU and 5-FU-NCT was 129.6 μg/mL and 42.6 μg/mL, respectively. Conclusion: 5-Fu-NCT cocrystal have been synthesized successfully through the cooling technology and it shows an enhanced anticancer effect in comparison to 5-FU on BEL-7402/5-FU cells.

Key wordsTechnology, pharmaceutical      Lens, crystalline      Pharmaceutical preparations/chemistry      Niacinamide/pharmacology      Fluorouracil/pharmacology      Solubility      Antibiotics, anti antibiotics, Antineoplastic neoplastic/pharmacology     
Received: 02 November 2016      Published: 31 October 2017
Corresponding Authors: TANG Guping     E-mail:;
Cite this article:

WU Min,LIU Xingang,XUE Yu,CHEN Qi,HU Xiurong,ZHOU Jun,TANG Guping. Synthesis, characterization and antitumor activity of 5-fluorouracil-nicotinamide cocrystal. J Zhejiang Univ (Med Sci), 2017, 46(2): 160-166.

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目的:以烟酰胺(NCT)为共晶形成物制备5-氟尿嘧啶—烟酰胺共晶(5-Fu-NCT),对其理化特性和生物学性质进行研究。方法:采用冷却结晶法制备5-Fu-NCT共晶,用X射线粉末衍射法、核磁共振、红外光谱、差示扫描量热法等方法对其结构进行表征,用高效液相色谱法测定其溶解度,用MTT法、HE染色和细胞划痕实验测定其对肿瘤细胞活性的影响。结果:成功制备了5-FU-NCT,其特征衍射峰(2θ/°)为16.4、20.4、22.3、27.9、30.1。共晶溶解度为13.5 g/L。体外细胞试验结果表明,5-Fu和5-Fu-NCT作用于BEL-7402/5-Fu细胞的半数致死浓度值(IC50值)分别是129.6 μg/mL、42.6 μg/mL;细胞划痕试验、HE染色结果表明,5-Fu-NCT对耐5-Fu的BEL-7402/5-Fu细胞的毒性更强。结论:采用冷却结晶法成功制备了5-Fu-NCT。相比5-Fu,5-Fu-NCT对BEL-7402/5-Fu细胞有更强的抗肿瘤活性。

关键词: 工艺学,制药,  晶体,  药用制剂/化学,  烟酰胺/药理学,  5-氟尿嘧啶/药理学,  溶解度,  抗生素类,抗肿瘤/药理学 
Fig 1 Synthesis of 5-Fu-NCT cocrystals
Fig 2 X-ray powder diffraction pattern of 5-Fu-NCT, 5-Fu/NCT, NCT and 5-Fu
Fig 3 1H NMR spectra of 5-Fu-NCT in D2O
Fig 4 DSC/TG spectra of 5-Fu-NCT、5-Fu/NCT、NCT and 5-Fu
Fig 5 FTIR spectra of 5-Fu-NCT、5-Fu/NCT、NCT、5-Fu
Fig 6 HPLC spectra of 5-Fu-NCT、5-Fu/NCT、NCT and 5-Fu
Fig 7 Solubility curves of 5-Fu-NCT、5-Fu/NCT、NCT and 5-Fu
Fig 8 Surival rates of BEL-7402/5-Fu (n=4)
Fig 9 The HE staining in BEL-7402/5-Fu treated with each group for 24 h
Fig 10 The wound healing assay of each group in BEL-7402/5-Fu
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