Synthesis, characterization and antitumor activity of 5-fluorouracil-nicotinamide cocrystal

doi:10.3785/j.issn.1008-9292.2017.04.07

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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Abstract

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 words： Technology, 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: wumin_chem@zju.edu.cn;tangguping@zju.edu.cn

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	WU Min
	LIU Xingang
	XUE Yu
	CHEN Qi
	HU Xiurong
	ZHOU Jun
	TANG Guping

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.

URL:

http://www.zjujournals.com/xueshu/med/10.3785/j.issn.1008-9292.2017.04.07 OR http://www.zjujournals.com/xueshu/med/Y2017/V46/I2/160

5-氟尿嘧啶—烟酰胺共晶的制备及其抗肿瘤活性研究

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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