新型杯[3]咔唑衍生物的合成及其对羟喜树碱识别与检测研究

doi:10.6023/cjoc202407038

摘要/Abstract

羟喜树碱(HCPT)是一种广谱的抗肿瘤药物, 对其具有识别作用的荧光分子不但可以用于检测, 还可因药物递送性能的提高而获得更高的活性. 因此, 寻找高选择性识别HCPT的荧光主体分子具有研究价值, 但具有一定挑战性. 合成了两亲性杯咔唑大环(3), 利用荧光光谱、核磁共振、扫描电镜和透射电镜等方法研究了其与HCPT的主客体间相互作用. 结果表明, 化合物3可经荧光共振能量转移效应实现比率型荧光选择性识别HCPT, 化学计量比为2∶1, 结合常数为1.26×10¹⁴ (mol/L)^－2. 检测限(Limit of detection, LOD)为11.7 nmol•L^－1. 此外, 化合物3的存在显著增强了HCPT体外抑制人乳腺癌细胞(MCF-7)细胞增殖活性, IC₅₀值降低了两个数量级, 表明化合物3兼具分子荧光探针和药物分子载体的双重功能, 为后续深入研究提供科学依据.

关键词: 主客体, 荧光探针, 杯咔唑

The fluorescent molecule capable of recognizing 10-hydroxycamptothecin (HCPT), a broad-spectrum anti-tumor drug, is not only able to detect it, but also able to enhance its activity due to the improvement of the delivery. Therefore, the construction of highly selective fluorescent hosts of HCPT is valuable, but remains challenging. In this work, an amphiphilic carbazole macrocyclic molecule (3) was synthesized and the host-guest interaction between 3 and HCPT was studied by fluorescence spectroscopy, NMR, scanning electron microscopy and transmission electron microscopy. The results showed that 3 could recognize HCPT with a stoichiometric ratio of 2∶1 via the mechanism of fluorescence resonance energy transfer (FRET) and a binding constant of 1.26×10¹⁴ (mol/L)^－2. The detection of limit (LOD) is 11.7 nmol•L^－1. In addition, the complexation enhanced the activity of HCPT to inhibit the proliferation of MCF-7 (Michigan Cancer Foundation-7) cells in vitro, and the IC₅₀ value decreased by two orders of magnitude, indicating that 3 possessed the dual function of both fluorescence probe and molecular carrier, thus providing scientific basis for further research.

Key words: host-guest, fluorescent probe, calix[n]carbazole

引用此文

张文博, 苏思铭, 杨鹏. 新型杯[3]咔唑衍生物的合成及其对羟喜树碱识别与检测研究[J]. 有机化学, 2025, 45(4): 1395-1401.

Wenbo Zhang, Siming Su, Peng Yang. Synthesis of A Novel Calix[3]carbazole Derivative and Its Recognition and Detection of 10-Hydroxycamptothecin[J]. Chinese Journal of Organic Chemistry, 2025, 45(4): 1395-1401.

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图/表 12

图1. (a) HCPT和(b)杯[3]咔唑的结构式

Figure 1. Structural formula of (a) HCPT and (b) of calix[3]- carbazole

图2. 3的合成路线

Figure 2. Synthesis route of 3 Reaction conditions: (a) 2-bromo-propanoicaciethylester, NaH, DMF; (b) (CH2O)n, FeCl3, DCE; (c) 1,2-benzenedimethanol, DDQ, DCM, 0 ℃; (d) Monoethanolamine, DMF, 80 ℃

Entry	Catalyst	Yield/%
1	ZnCl₂	0
2	FeCl₃	39.6
3	AlCl₃	5.3
4	BF₃•OEt₂	15.2

表1. 催化剂对环合反应收率的影响

Table 1. Effects of catalysts on the yield of cyclozation

Entry	Solvent	Yield/%
1	DCM	39.8
2	DCE	46.7
3	TCM	23.3
4	CCl₄	19.2

表2. 溶剂对环合反应收率的影响

Table 2. Effects of solvents on yiled of cyclozation

图3. (a) 3与HCPT的紫外吸收光谱、(b) 3与HCPT的荧光光谱、(c) 3的荧光光谱与HCPT的紫外光谱

Figure 3. (a) UV-Vis of 3 and HCPT, (b) fluorescence of 3 and HCPT, and (c) fluorescence of 3 and UV-Vis of HCPT

图4. (a) 3与HCPT的正向荧光滴定光谱和(b) 3与HCPT的反向荧光滴定光谱

Figure 4. (a) Forward fluorescence titration spectra of 3 and HCPT, and (b) reverse fluorescence titration spectra of 3 and HCPT

图5. (a) 3与HCPT的Job’s Plot曲线, 以及(b) 3与HCPT的非线性校正曲线拟合曲线

Figure 5. (a) Job’s Plot curve of 3 and HCPT, and (b) nonlinear fitting curve of 3 and HCPT

图6. (A) F549 nm/F364 nm与HCPT浓度之间的荧光滴定光谱校正曲线, 以及(B) 3与客体分子的F549 nm/F364 nm对比图

Figure 6. (A) Fluorescence titration spectrum calibration curve between F549 nm/F364 nm and the concentration of HCPT, and (B) comparison of F549 nm/F364 nm between guests and 3 (a) o-Phenanthroline, (b) 2,2'-bipyridine, (c) 4,4'-bipyridine, (d) (R)-naproxen, (e) (S)-naproxen, (f) acenaphthenequinone, (g) anthraquinone, (h) Ca2＋, (i) Co2＋, (j) Mg2＋, (k) Pb2＋, (l) Fe3＋, (m) podophyllotoxin, (n) matrine, (o) quinoline, (p) artemisinin, (q) santonin, (r) dihydroqinghaosu, (s) ursolicacid, (t) corydaline, (u) etoposide, (v) paclitaxel, (w) 10-hydroxycamptothecin.

图7. 3的NOESY图谱[D2O/DMSO-d6 (V∶V=4∶6)]

Figure 7. NOESY of 3 [D2O/DMSO-d6 (V∶V=4∶6)]

图8. (a) 3、(b) HCPT、(c) 3与HCPT复合物的扫描电子显微镜图

Figure 8. Scanning electron microscope (SEM) images of (a) 3, (b) HCPT, (c) 3 and HCPT complexes

图9. (a) 3, (b) HCPT, (c) 3与HCPT复合物的透射电子显微镜图

Figure 9. Transmission electron mcroscope (TEM) images of (a) 3, (b) HCPT, (c) 3 and HCPT complexes

Sample	IC₅₀/(μmol•L^－1)
3	>50
HCPT	0.21±0.03
3-HCPT	0.0026±0.0005

表3. 样品的IC50值a

Table 3. IC50 values of samples

参考文献 10

[1]	Zhang, Y.; Jiang, K.; Qing, D.; Huang, B.; Jiang, J.; Wang, S.; Yan, C. RSC Adv. 2017, 7, 12185.
[2]	Xu, Y.; Villalona-calero, M. A. Ann. Oncol. 2002, 13, 1841. doi: 10.1093/annonc/mdf337 pmid: 12453851
[3]	Chen, Y.; Wang, Z.; Wang, X.; Su, M.; Xu, F.; Yang, L.; Jia, L.; Zhang, Z. Int. J. Nanomed. 2022, 17, 4227.
[4]	Yang, P.; Jian, Y.; Zhou, X.; Li, G.; Deng, T.; Shen, H.; Yang, Z.; Tian, Z. J. Org. Chem. 2016, 81, 2974.
[5]	Li, G.; Song, X. Y.; Yu, H.; Hu, C.; Liu, M.; Cai, J.; Zhao, L.; Chen, Y.; Yang, P. Sens. Actuators, B 2018, 259, 177.
[6]	Yang, Z. Z.; Chen, Y.; Li, G.; Tian, Z.; Zhao, L.; Wu, X.; Ma, Q.; Liu, M.; Yang, P. Chem.-Eur. J. 2018, 24, 6087.
[7]	Zhang, F.; Du, X. S.; Zhang, D. W.; Wang, Y. F.; Lu, H. Y.; Chen, C. F. Angew. Chem., Int. Ed. 2021, 60, 15291.
[8]	Li, G.; Zhao, L.; Yang, P.; Yang, Z.; Tian, Z.; Chen, Y.; Shen, H.; Hu, C. Anal. Chem. 2016, 88, 10751.
[9]	Zhao, L.; Kang, L.; Chen, Y.; Li, G.; Wang, L.; Hu, C.; Yang, P. Spectrochim. Acta A 2018, 193, 276.
[10]	Chen, D. L.; Xiao, T. X.; Monflier, E.; Wang, L.Y. Commun. Chem. 2024, 7, 88.

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