七元瓜环对阿糖胞苷稳定性的影响

doi:10.7503/cjcu20130966

高等学校化学学报 ›› 2014, Vol. 35 ›› Issue (6): 1224.doi: 10.7503/cjcu20130966

七元瓜环对阿糖胞苷稳定性的影响

黄英^1,², 宋桂先², 唐青¹, 王娟², 陶朱¹, 薛赛凤²(), 张建新³()

1. 贵州大学西南药用生物资源教育部工程研究中心, 2. 贵州省大环化学与超分子化学重点实验室,3. 贵州省中国科学院天然产物化学重点实验室, 贵阳 550025

收稿日期:2013-09-30 出版日期:2014-06-10 发布日期:2013-12-05
作者简介:联系人简介: 薛赛凤, 女, 教授, 博士生导师, 主要从事超分子化学研究. E-mail:sfxue@gzu.edu.cn;张建新, 男, 教授, 从事核磁共振波谱研究. E-mail:zjxnmr@126.com
基金资助:
国家自然科学基金(批准号: 21202026)、国家重大科学仪器设备开发专项项目(批准号: 2011YQ120035)、贵州省科技厅国际合作项目(批准号: 黔科合外G字[2012]7003号)、教育部春晖计划(批准号: Z2011034)和贵州省英才培育项目(批准号: 2012154)资助

Encapsulation of Cytarabine in Cucurbit[7]uril and Its Effects on Stability of the Drug^†

HUANG Ying^1,², SONG Guixian², TANG Qing¹, WANG Juan², TAO Zhu¹, XUE Saifeng^2,^*(), ZHANG Jianxin^3,^*()

1. The Engineering and Research Center for Southwest Bio-Pharmaceutical Resources, Ministry of Education,2. Key Laboratory of Macrocyclic and Supramolecular Chemistry of Guizhou Province,3. The Key Laboratory of Chemistry for Nature Products of Gui Zhou Province and Chinese Academy of Science,Guizhou University, Guiyang 550025, China

Received:2013-09-30 Online:2014-06-10 Published:2013-12-05
Contact: XUE Saifeng,ZHANG Jianxin E-mail:sfxue@gzu.edu.cn;zjxnmr@126.com
Supported by:
† Supported by the the National Natural Science Foundation of China(No.21202026), the National Major Scienpngic Instruments Development Project, China(No.2011YQ120035), the International Cooperation Projects of Science and Technology Agency of Guizhou Province, China(No.20127003), the “Chun-Hui” Fund of Ministry of Education, China(No.Z2011034) and the Young Talent Development Project of Guizhou Province, China(No.2012154)

摘要/Abstract

摘要：

研究了七元瓜环(Q[7])与抗癌药物阿糖胞苷(Ara-C)的不同质子化存在形式之间的超分子相互作用, 探讨了超分子包合作用对药物电离平衡常数及药物稳定性的影响. 结果表明, Q[7]使得Ara-C的pK_a降低了约0.3个单位, Q[7]与Ara-C的2种存在形式(Ara-C⁺及Ara-C)均可形成1∶1的主客体包结配合物, Ara-C以其嘧啶环进入Q[7]空腔, 而核糖环位于瓜环端口发生相互作用; Q[7]与Ara-C作用后对药物起到保护性载体的作用, 从而提高了药物的稳定性.

关键词: 阿糖胞苷, 七元瓜环, 主客体配合物, 稳定性

Abstract:

The interaction of cucurbit[7]uril(Q[7]) with cytarabine(Ara-C) in different proton forms were studied by ultraviolet absorption spectroscopy and ¹H NMR technique in details. Complexation by Q[7] has also been investigated to cause pK_a shifts and stability of drug. The results showed that Q[7] encapsulated the Ara-C and shifted its pK_a value by down to 0.3 units. Ara-C in different proton forms with Q[7] informed 1∶1 inclusion complexes, and the formation constants were (9.48±0.29)×10³ L/mol and (6.30±0.04)×10³ L/mol for the Q[7]-Ara-C⁺ system and Q[7]-Ara-C system, respectively. Moreover, The formation of inclusion complexes between Q[7] with Ara-C was confirmed by ¹H NMR, the pyrimidine moiety of Ara-C were entrapped in the cavity of the host and the D-ribose ring was likely located at the outside cucurbituril cavity. In addition, stability studies were investigated by initial uniform rate experiment. The results revealed that complexation of Ara-C with Q[7] offers a major improvement in drug stability.

Key words: Cytarabine, Cucurbit[7]uril, Inclusion complex, Stability

TrendMD:

黄英, 宋桂先, 唐青, 王娟, 陶朱, 薛赛凤, 张建新. 七元瓜环对阿糖胞苷稳定性的影响. 高等学校化学学报, 2014, 35(6): 1224.

HUANG Ying, SONG Guixian, TANG Qing, WANG Juan, TAO Zhu, XUE Saifeng, ZHANG Jianxin. Encapsulation of Cytarabine in Cucurbit[7]uril and Its Effects on Stability of the Drug^†. Chem. J. Chinese Universities, 2014, 35(6): 1224.

图/表 6

Fig.1 Structures of Q[7](A) and Ara-C(B)

Fig.2 Absorption spectra of Ara-C at different pH values(A) and the variation in absorbance with pH at 280 nm(B) (A) pH, a—i: 0.32, 1.06, 1.98, 2.93, 4.04, 5.01, 6.02, 7.00, 7.90.

Fig.3 Four-state thermodynamic model

Fig.4 Absorption spectra of Ara-C(4×10-5 mol/L) in the presence of 4×10-5 mol/L Q[7] at different pH values(A) and the variation in absorbance with pH at 280 nm(B)(A) pH, a—i: 0.30, 1.11, 2.05, 2.94, 3.90, 5.02, 6.00, 6.96, 7.99; (B) ■ without Q[7]; ○ in 4×10-5 mol/L Q[7].

Fig.5 Electronic absorption spectra of Ara-C in aqueous solution at pH=2(A) and pH=7(C) with different concentrations of Q[7](A, C) and corresponding job’s plot for the Q[7]-Ara-C complex(B, D)

Table 1 Storage period(day) at room temperature for the Ara-C and Q[7]-Ara-C system(n=6)

Number	1	2	3	4	5	6
Ara-C	7.5	6.8	10.0	8.1	7.3	7.6
Q[7]-Ara-C	57.5	58.6	56.9	59.2	57.3	58.6

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七元瓜环对阿糖胞苷稳定性的影响

Encapsulation of Cytarabine in Cucurbit[7]uril and Its Effects on Stability of the Drug^†

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七元瓜环对阿糖胞苷稳定性的影响

Encapsulation of Cytarabine in Cucurbit[7]uril and Its Effects on Stability of the Drug†

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Encapsulation of Cytarabine in Cucurbit[7]uril and Its Effects on Stability of the Drug^†