Design and Synthesis of Novel Nature-Inspired Stilbene Analogues as Potential Topoisomerase 1 Inhibitors

doi:10.6023/cjoc202102031

Abstract

In order to find novel antitumor drug leads, twenty-three nature-inspired stilbene analogues containing thiazole moiety were designed and synthesized, and their structures were confirmed by NMR and ESI-HRMS. These compounds were screened for their topoisomerase I (Top1) inhibitory activity using Top1-mediated relaxation assay, and (E)-5-bromo-2- (2-chlorostyryl)-4-(4-fluorophenyl)thiazole (6k) possessed promising Top1 inhibitory activity. Molecular docking was also established to study the structure-activity relationship and a good correlation was observed between Top1 inhibitory activity and molecular docking study. Furthermore, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay against human breast cancer (MCF-7) and human colon cancer (HCT116) cell lines indicated that (E)-5-bromo-4-(4-fluorophenyl)- 2-(4-(trifluoromethyl)styryl)thiazole (6e), (E)-5-bromo-2-(2-chlorostyryl)-4-(4-fluorophenyl)thiazole (6k), and (E)-5-bromo- 2-(4-chlorostyryl)-4-(4-fluorophenyl)thiazole (6l) showed high cytotoxicity at low micromolar concentrations.

Key words: natural stilbene, thiazole, topoisomerase 1 inhibitor, synthesis, cytotoxicity

Cite this article

Qi Lu, Feixia Ye, Xiaotong Sun, Jianquan Weng, Qian Yu, Dexuan Hu. Design and Synthesis of Novel Nature-Inspired Stilbene Analogues as Potential Topoisomerase 1 Inhibitors[J]. Chinese Journal of Organic Chemistry, 2021, 41(8): 3321-3329.

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References 34

[1]	Champoux, J. J. Annu. Rev. Biochem. 2001, 70, 369. pmid: 11395412
[2]	Stewart, L.; Redinbo, M. R.; Qui, X.; Hol, W. G. J.; Champoux, J. J. Science 1998, 279, 1534. pmid: 9488652
[3]	Berger, J. M.; Gamblin, S. J.; Harrison, S. C.; Wang, J. C. Nature 1996, 379, 225. doi: 10.1038/379225a0
[4]	Lian, Q.; Xu, J.; Yan, S.; Huang, M.; Ding, H.; Sun, X.; Bi, A.; Ding, J.; Sun, B.; Geng, M. Cell Res. 2017, 27, 784. doi: 10.1038/cr.2017.54
[5]	Pommier, Y. Nat. Rev. Cancer 2006, 6, 789. pmid: 16990856
[6]	Thomas, A.; Pommier, Y. Clin. Cancer Res. 2019, 25, 6581. doi: 10.1158/1078-0432.CCR-19-1089 pmid: 31227499
[7]	Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2020, 83, 770. doi: 10.1021/acs.jnatprod.9b01285 pmid: 32162523
[8]	Loiseleur, O. Chimia 2017, 71, 810. doi: 10.2533/chimia.2017.810 pmid: 29289242
[9]	Lin, Z. Q.; Xia, W. L.; Liu, R. Y.; Jiang, S. H.; Ma, Z. Q. Chin. J. Org. Chem. 2020, 40, 2980. (in Chinese) doi: 10.6023/cjoc202005006
	(林芷晴, 夏婉铃, 刘仁义, 姜少华, 马志强, 有机化学, 2020, 40, 2980.) doi: 10.6023/cjoc202005006
[10]	Rimando, A. M.; Cuendet, M.; Desmarchelier, C.; Mehta, R. G.; Pezzuto, J. M.; Duke, S. O. J. Agric. Food Chem. 2002, 50, 3453. doi: 10.1021/jf0116855
[11]	Kimura, Y.; Okuda, H.; Arichi, S. Biochim. Biophys. Acta 1985, 834, 275. pmid: 3922423
[12]	Stivala, L. A.; Savio, M.; Carafoli, F.; Perucca, P.; Bianchi, L.; Maga, G.; Forti, L.; Pagnoni, U. M.; Albini, A.; Prosperi, E.; Vannini, V. J. Biol. Chem. 2001, 276, 22586. pmid: 11316812
[13]	Mahady, G. B.; Pendland, S. L.; Chadwick, L. R. Am. J. Gastroenterol. 2003, 98, 1440.
[14]	Shi, D.; An, R.; Zhang, W. B.; Zhang, G. L.; Yu, Z. G. J. Agric. Food Chem. 2017, 65, 60. doi: 10.1021/acs.jafc.6b04303
[15]	Kronenwerth, M.; Dauth, C.; Kaiser, M.; Pemberton, I.; Bode, H. B. Eur. J. Org. Chem. 2014, 36, 8026.
[16]	Mizuno, C. S.; Schrader, K. K.; Rimando, A. M. J. Agric. Food Chem. 2008, 56, 9140. doi: 10.1021/jf801988p
[17]	Weng, J. Q.; Ali, A.; Estep, A.; Becnel, J.; Meyer, S. L. F.; Wedge, D. E.; Jacob, M.; Rimando, A. M. Chem. Biodiversity 2016, 13, 1165. doi: 10.1002/cbdv.v13.9
[18]	Lu, Q.; Yu, Q.; Zhu, Y. B.; Weng, J. Q.; Yuan, J.; Hu, D. X.; Chen, J.; Liu, X. H.; Tan, C. X. J. Mol. Struct. 2019, 1180, 780. doi: 10.1016/j.molstruc.2018.12.068
[19]	Mabkhot, Y. N.; Alharbi, M. M.; Al-Showiman, S. S.; Ghabbour, H. A.; Kheder, N. A.; Soliman, S. M.; Frey, W. Chem. Cent. J. 2018, 12, 56. doi: 10.1186/s13065-018-0420-7 pmid: 29748782
[20]	Kouatly, O.; Geronikaki, A.; Kamoutsis, C.; Hadjipavlou-Litina, D.; Eleftheriou, P. Eur. J. Med. Chem. 2009, 44, 1198. doi: 10.1016/j.ejmech.2008.05.029 pmid: 18603333
[21]	Pember, S. O.; Mejia, G. L.; Price, T. J.; Pasteris, R. J. Bioorg. Med. Chem. Lett. 2016, 26, 2965.
[22]	Koti, R. S.; Kolavi, G. D.; Hegde, V. S.; Khazi, I. M. Indian J. Chem. B 2006, 45, 1900.
[23]	Weng, J. Q.; Tan, C. X.; Liu, X. H. J. Pestic. Sci. 2012, 37, 164.
[24]	Yu, H. B.; Qin, Z. F.; Dai, H.; Zhang, X.; Qin, X.; Wang, T. T.; Fang, J. X. J. Agric. Food Chem. 2018, 56, 11356. doi: 10.1021/jf802802g
[25]	Weng, J. Q.; Liu, X. H.; Huang, H.; Tan, C. X.; Chen, J. Molecules 2012, 17, 989. doi: 10.3390/molecules17010989
[26]	Zhang, J. H.; Zhu, Y. B.; Weng, J. Q.; Yu, Q.; Yuan, J.; Chen, J. Chin. J. Org. Chem. 2020, 40, 1055. (in Chinese) doi: 10.6023/cjoc201910023
	(章俊辉, 朱亚波, 翁建全, 余茜, 袁静, 陈杰, 有机化学, 2020, 40, 1055.) doi: 10.6023/cjoc201910023
[27]	Kong, Y. L.; Xu, W. X.; Liu, X. H.; Weng, J. Q. Chin. Chem. Lett. 2020, 31, 3245. doi: 10.1016/j.cclet.2020.05.022
[28]	Xu, W. X.; Ye, F. X.; Liu, X. H.; Weng, J. Q. Tetrahedron Lett. 2020, 61, 151807. doi: 10.1016/j.tetlet.2020.151807
[29]	Dou, D. F.; He, G. J.; Li, Y.; Lai, Z.; Wei, L. Q.; Alliston, K. R.; Lushington, G. H.; Eichhorn, D. M.; Groutas, W. C. Bioorg. Med. Chem. 2010, 18, 1093. doi: 10.1016/j.bmc.2009.12.057
[30]	Kocabas, E.; Sariguney, A. B.; Coskun, A. Heterocycles 2010, 81, 2849. doi: 10.3987/COM-10-12067
[31]	Zhu, D. J.; Chen, J. X.; Wu, D. Z.; Liu, M. C.; Ding, J. C.; Wu, H. Y. J. Chem. Res. 2009, (2), 84.
[32]	Wetherill, J. P., Hann, R. M. J. Am. Chem. Soc. 1934, 56, 970. doi: 10.1021/ja01319a068
[33]	Pommier, Y.; Covey, J. M.; Kerngan, D.; Markovits, J.; Pham, R. Nucleic Acids Res. 1987, 15, 6713. pmid: 2819825
[34]	Staker, B. L.; Hjerrild, K.; Feese, M. D.; Behnke, C. A.; Burgin, A. B.; Jr.; Stewart, L. P. Natl. Acad. Sci. U. S. A. 2002, 99, 15387. doi: 10.1073/pnas.242259599

Compd.	X	R	Relaxation assay^a	Compd.	X	R	Relaxation assay^a
6a	F	H	+	6m	F	2,4-Cl₂	++
6b	F	2-Me	+	6n	F	2-Br	++
6c	F	3-Me	+	6o	F	3-Br	+
6d	F	4-Me	+	6p	Cl	4-CF₃	++
6e	F	4-CF₃	++	6q	Cl	4-tert-Bu	+
6f	F	4-tert-Bu	+	6r	Cl	3-OMe	+
6g	F	2-OMe	+	6s	Cl	3,4,5-(OMe)₃	+
6h	F	3-OMe	+	6t	Cl	2-F	+
6i	F	4-OMe	+	6u	Cl	3-Br	+
6j	F	4-F	++	6v	Br	2-F	++
6k	F	2-Cl	+++	6w	Br	4-F	++
6l	F	4-Cl	++

Compd.	X	R	Relaxation assay^a	Compd.	X	R	Relaxation assay^a
6a	F	H	+	6m	F	2,4-Cl₂	++
6b	F	2-Me	+	6n	F	2-Br	++
6c	F	3-Me	+	6o	F	3-Br	+
6d	F	4-Me	+	6p	Cl	4-CF₃	++
6e	F	4-CF₃	++	6q	Cl	4-tert-Bu	+
6f	F	4-tert-Bu	+	6r	Cl	3-OMe	+
6g	F	2-OMe	+	6s	Cl	3,4,5-(OMe)₃	+
6h	F	3-OMe	+	6t	Cl	2-F	+
6i	F	4-OMe	+	6u	Cl	3-Br	+
6j	F	4-F	++	6v	Br	2-F	++
6k	F	2-Cl	+++	6w	Br	4-F	++
6l	F	4-Cl	++

Compd.	IC₅₀/(µmol•L^–1)		Compd.	IC₅₀/(µmol•L^–1)
Compd.	MCF-7	HCT116	Compd.	MCF-7	HCT116
6a	22.16±5.01	15.78±1.89	6n	20.95±1.41	58.38±3.49
6b	>100	>100	6o	>100	>100
6c	>100	>100	6p	>100	>100
6d	95.52±3.11	31.87±4.29	6q	>100	>100
6e	6.31±0.51	0.72±0.09	6r	61.92±8.05	5.26±0.35
6f	59.42±4.21	6.47±0.62	6s	>100	>100
6g	49.53±9.08	17.8±1.16	6t	>100	>100
6h	29.85±5.47	4.99±0.80	6u	>100	62.91±2.34
6i	57.20±1.79	17.32±1.05	6v	64.57±1.45	37.18±6.65
6j	49.64±3.58	8.06±0.92	6w	>100	63.25±6.17
6k	2.29±1.08	7.37±1.15	vp-16^a	24.68±3.12	18.95±1.35
6l	13.45±2.46	3.07±0.53	CPT^a	0.34	0.012
6m	72.43±2.15	4.79±0.73

Compd.	IC₅₀/(µmol•L^–1)		Compd.	IC₅₀/(µmol•L^–1)
Compd.	MCF-7	HCT116	Compd.	MCF-7	HCT116
6a	22.16±5.01	15.78±1.89	6n	20.95±1.41	58.38±3.49
6b	>100	>100	6o	>100	>100
6c	>100	>100	6p	>100	>100
6d	95.52±3.11	31.87±4.29	6q	>100	>100
6e	6.31±0.51	0.72±0.09	6r	61.92±8.05	5.26±0.35
6f	59.42±4.21	6.47±0.62	6s	>100	>100
6g	49.53±9.08	17.8±1.16	6t	>100	>100
6h	29.85±5.47	4.99±0.80	6u	>100	62.91±2.34
6i	57.20±1.79	17.32±1.05	6v	64.57±1.45	37.18±6.65
6j	49.64±3.58	8.06±0.92	6w	>100	63.25±6.17
6k	2.29±1.08	7.37±1.15	vp-16^a	24.68±3.12	18.95±1.35
6l	13.45±2.46	3.07±0.53	CPT^a	0.34	0.012
6m	72.43±2.15	4.79±0.73

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