Syntheses and Property Evaluation of N-Salicylaldehyde Hydrazone Modified 11-Azaartemisinins and Their Derivatives

doi:10.6023/cjoc201902024

Chinese Journal of Organic Chemistry ›› 2019, Vol. 39 ›› Issue (10): 2860-2866.DOI: 10.6023/cjoc201902024 Previous Articles Next Articles

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N-水杨醛腙修饰11-氮杂青蒿素衍生物的合成及性质研究

李四聪^a, 季绍聪^b, 赵亮^a, 廖晓雨^b, 刘传峰^a, 汤浩东^a, 舒正宁^a, 杨鹏^a^*(), 裴月湖^b^*()

a 沈阳药科大学无涯学院沈阳 110016
b 沈阳药科大学中药学院沈阳 110016

收稿日期:2019-02-22 修回日期:2019-04-29 发布日期:2019-06-06
通讯作者: 杨鹏,裴月湖 E-mail:yangpeng@syphu.edu.cn;peiyueh@vip.163.com
基金资助:
辽宁省自然科学基金(20180550874)

Syntheses and Property Evaluation of N-Salicylaldehyde Hydrazone Modified 11-Azaartemisinins and Their Derivatives

Li, Sicong^a, Ji, Shaocong^b, Zhao, Liang^a, Liao, Xiaoyu^b, Liu, Chuanfeng^a, Tang, Haodong^a, Shu, Zhengning^a, Yang, Peng^a^*(), Pei, Yuehu^b^*()

a Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016
b School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016

Received:2019-02-22 Revised:2019-04-29 Published:2019-06-06
Contact: Yang, Peng,Pei, Yuehu E-mail:yangpeng@syphu.edu.cn;peiyueh@vip.163.com
Supported by:
Project supported by the Natural Science Foundation of Liaoning Province(20180550874)

N-Salicylaldehyde hydrazone modified 11-azaartemisinins and their deoxy analogues were designed and synthesized. By using various techniques including UV-vis, fluorescence, NMR as well as molecular modeling, the conformations of (3R,5aS,6R,8aS,9R,12S,12aR)-11-(((E)-2-hydroxy-5-(4-hydroxy-3-((E)-(((3R,5aS,6R,8aS,9R,12R,12aR)-3,6,9-trimethyl-10- oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)imino)methyl)benzyl)benzylidene)amino)-3,6,9-trimethyldecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-10(3H)-one (3) was analyzed, the binding behavior between 3 and hemin was measured, and the solubility-enhancing property of 3 by calix[4]carbazole was evaluated. The results show that the intramolecular hydrogen binding between the N atom of Schiff base in N-salicylaldehyde hydrazone bond and the OH favors the formation of tweezer-like conformation of 3, which enables it to interact with hemin in 1∶1 ratio. Moreover, the poor solubility of 3 in water could be enhanced due to its interaction with calix[4]carbazole, which pave the way for the further evaluation of the bioactivities of 3 in the future.

Key words: macrocycle, molecular recognition, carbazole, artemisinin

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Li, Sicong, Ji, Shaocong, Zhao, Liang, Liao, Xiaoyu, Liu, Chuanfeng, Tang, Haodong, Shu, Zhengning, Yang, Peng, Pei, Yuehu. Syntheses and Property Evaluation of N-Salicylaldehyde Hydrazone Modified 11-Azaartemisinins and Their Derivatives[J]. Chinese Journal of Organic Chemistry, 2019, 39(10): 2860-2866.

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Fig. & Tab. 12

Scheme 1. Synthetic routes of the target compounds 1~4

Figure 1. Possible configuration of 3

Figure 2. Partial 1H NMR (a) and partial NOESY (b) of 3

Figure 3. Optimized conformation of 3 with the lowest energy

Figure 4. Molecular structure of hemin

Figure 5. UV-vis spectra (a) and the fitted curve (b) of hemin (10 μmol/L) upon addition of 3

Figure 6. UV-vis spectra of hemin upon addition of 1

Figure 7. Optimized binding pattern of hemin with 3 (a) Front view, (b) side view

Figure 8. Structure of calix[4]carbazole

Figure 9. UV-vis spectra of calix[4]carbazole upon addition of 3 (a) [3]/[calixcarbazole]<1.0, (b) [3]/[calixcarbazole]>1.0

Figure 10. Fluorescence spectra of calix[4]carbazole upon addition of 3 (a) and the fitted curve (b)

Figure 11. Enhanced solubility of 3 by calix[4]carbazole (left: calix[4]carbazole/3 complexes; right: 3 alone)

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N-水杨醛腙修饰11-氮杂青蒿素衍生物的合成及性质研究

Syntheses and Property Evaluation of N-Salicylaldehyde Hydrazone Modified 11-Azaartemisinins and Their Derivatives

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