Design, Synthesis, Anti-cancer Activities and Computational Analysis of Novel Diamides Conformationally Restricted by Cyclopropane

doi:10.6023/cjoc202106053

Abstract

A series of diamides conformationally restricted by cyclopropane were designed and synthesized. Most of the racemates containing cis-cyclopropane possessed promising inhibitory activity against four cancer cell lines (MCF-7, BGC-823, HepG2 and NCI-H460). In particular, racemate cis-N¹-(2-methyl-4-(perfluoropropan-2-yl)phenyl)-N²-(4-phenoxy- benzyl)cyclopropane-1,2-dicarboxamide (1-19) showed the potential for further optimization as an anti-cancer lead with the IC₅₀ value of (8.38±0.67) mg•L^–1 on MCF-7. Moreover, steryl-sulfatase (STS) was predicated as the potential target protein and molecular docking was performed to explore the binding mode.

Key words: diamides, cyclopropane, anti-cancer activities, target prediction, docking

Cite this article

Ruijia Chen, Cong Zhou, Xiwen Pang, Jiajun Liu, Yucheng Gu, Jianwen Liu, Zhong Li. Design, Synthesis, Anti-cancer Activities and Computational Analysis of Novel Diamides Conformationally Restricted by Cyclopropane[J]. Chinese Journal of Organic Chemistry, 2022, 42(1): 277-292.

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References 49

[1]	Torre, L. A.; Bray, F.; Siegel, R. L.; Ferlay, J.; Lortet-Tieulent, J.; Jemal, A. CA-Cancer J. Clin. 2015, 65, 87. doi: 10.3322/caac.21262
[2]	Sung, H.; Ferlay, J.; Siegel, R. L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. CA-Cancer J. Clin. 2021, 71, 209. doi: 10.3322/caac.v71.3
[3]	Dickens, E.; Ahmed, S. Surgery (Oxford) 2018, 36, 134. doi: 10.1016/j.mpsur.2017.12.002
[4]	Jagoe, K. N. R. T.; Abalo, R. Front. Pharmacol. 2018, 9, 245. doi: 10.3389/fphar.2018.00245
[5]	Janganati, V.; Ponder, J.; Thakkar, S.; Thakkar, S.; Jordan, C. T.; Crooks, P. A. Bioorg. Med. Chem. 2017, 25, 3694.
[6]	Pattabiraman, V. R.; Bode, J. W. Nature 2011, 480, 471. doi: 10.1038/nature10702
[7]	Kumari, S.; Carmona, A. V.; Tiwari, A. K.; Trippier, P. C. J. Med. Chem. 2020, 63, 12290 doi: 10.1021/acs.jmedchem.0c00530
[8]	Vlaar, C. P.; Castillo-Pichardo, L.; Medina, J. I.; Marrero-Serra, C. M.; Vélez, E; Ramos, Z.; Hernández, E. Bioorg. Med. Chem. 2018, 26, 884. doi: 10.1016/j.bmc.2018.01.003
[9]	Rai, U. S.; Isloor, A. M.; Shetty, P.; Pai, K. S. R.; Fun, H. K. Arabian J. Chem. 2015, 8, 317. doi: 10.1016/j.arabjc.2014.01.018
[10]	Shao, P. P.; Ok, D.; Fisher, M. H.; Garcia, M. L.; Kaczorowski, G. J.; Li, C.; Lyons, K. A.; Martin, W. J.; Meinke, P. T.; Priest, B. T.; Smith, M. M.; Wyvratt, M. J.; Ye, F.; Parsons, W. H. Bioorg. Med. Chem. Lett. 2005, 15, 1901. doi: 10.1016/j.bmcl.2005.02.002
[11]	Tarzia, G.; Shiatti, P.; Selva, D.; Favara, D.; Ceriani, S. Eur. J. Med. Chem. 1976, 11, 263.
[12]	Hickey, S. M.; Ashton, T. D.; Khosa, S. K.; Robson, R. N.; White, J. M.; Li, J.; Nation, R. L.; Yu, H. Y.; Elliott, A. G.; Butler, M. S.; Huang, J. X.; Cooper, M. A.; Pfeffer, F. M Org. Biomol. Chem. 2015, 22, 6255.
[13]	Saudi, M.; Zmurko, J.; Kaptein, S.; Rpzenski, J.; Gadakh, B.; Chaltin, P.; Marchand, A.; Neyts, J.; Aerschot, A. V. Eur. J. Med. Chem. 2016, 12, 158.
[14]	Tohnishi, M.; Nakao, H.; Furuya, T.; Seo, A.; Kodama, H.; Tsubata, K.; Fujioka, S.; Kodama, H.; Hirooka, T.; Nishimatsu, T. J. Pestic. Sci. 2005, 30, 354. doi: 10.1584/jpestics.30.354
[15]	Galano, A.; Alvarez-Idaboy, J. R.; Vivier-Bunge, A. Theor. Chem. Acc. 2007, 118, 597. doi: 10.1007/s00214-007-0353-z
[16]	Talele, T. T. J. Med. Chem. 2016, 59, 8712. doi: 10.1021/acs.jmedchem.6b00472
[17]	Julius, D. A. Am. J. Psychiatry 1979, 136, 782. doi: 10.1176/ajp.136.6.782
[18]	Yakes, F. M.; Chen, J.; Tan, J.; Yamaguchi, K.; Shi, Y.; Yu, P.; Qian, F.; Chu, F.; Bentzien, F.; Cancilla, B.; Orf, J.; You, A.; Laird, A. D.; Engst, S.; Lee, L.; Lesch, J.; Chou, Y.-C.; Joly, A. H. J. Clin. Oncol. 2017, 35, 591. doi: 10.1200/JCO.2016.70.7398
[19]	Chopra, N.; Nathan, P. D. Expert Rev. Anticancer Ther. 2015, 15, 749. doi: 10.1586/14737140.2015.1060127
[20]	Scheciiter, M. S.; Sullivan, W. N.; Schoof, H. F.; Maddock, D. R.; Amyx, C. M.; Porter, J. E. J. Med. Entomol. 1974, 11, 231. pmid: 4851258
[21]	Matsui, K.; Kido, Y.; Watari, R.; Kashima, Y.; Yoshida, Y.; Shuto, S. Chem. Eur. J. 2017, 23, 3034. doi: 10.1002/chem.201604946
[22]	Lavedan, C.; Forsberg, M.; Gentile, A. J. Neuropharmacology 2015, 91, 142. doi: 10.1016/j.neuropharm.2014.12.004
[23]	Yamaguchi, K.; Kazuta, Y.; Hirano, K.; Yamada, S.; Matsuda, A.; Shuto, S. Bioorg. Med. Chem. 2008, 16, 8875. doi: 10.1016/j.bmc.2008.08.061
[24]	Martin, S. F.; Dorsey, G. O.; Gane, T.; Hillier, M. C.; Kessler, H.; Baur, M.; Mathä, B.; Erickson, J. W.; Bhat, T. N.; Munshi, S.; Gulnik, S. V.; Topol, I. A. J. Med. Chem. 1998, 41, 1581. pmid: 9572884
[25]	Chen, Y.; Le, V.; Xu, X.; Shao, X.; Liu, J.; Li, Z. Bioorg. Med. Chem. Lett. 2014, 24, 3948. doi: 10.1016/j.bmcl.2014.06.041
[26]	Ozoe, Y.; Kita, T.; Ozoe, F.; Nakao, T.; Sato, K.; Hirase, K. Pestic. Biochem. Physiol. 2013, 107, 285. doi: 10.1016/j.pestbp.2013.09.005
[27]	Shang, J.; Liu, Q.; Wang, B.; Li, Z. Chin. J. Org. Chem. 2019, 39, 1489. (in Chinese) doi: 10.6023/cjoc201810025
	(尚俊峰, 刘巧霞, 王宝雷, 李正名, 有机化学, 2019, 39, 1489.) doi: 10.6023/cjoc201810025
[28]	Chen, K.; Liu, Q.; Ni, J.; Zhu, H.; Li, Y.; Wang, Q. Pest Manage. Sci. 2014, 71, 1503. doi: 10.1002/ps.3954
[29]	Duan, J. J.-W.; Lu, Z.; Jiang, B.; Stachura, S.; Weigelt, C. A.; Sack, J. S.; Khan, J.; Ruzanov, M.; Galella, M. A.; Wu, D.-R.; Yarde, M.; Shen, D.-R.; Shuster, D. J.; Borowski, V.; Xie, J. H.; Zhang, L.; Vanteru, S.; Gupta, A. K.; Mathur, A.; Zhao, Q.; Foster, W.; Salter-Cid, L. M.; Carter, P. H.; Dhar, T. G. M. ACS Med. Chem. Lett. 2019, 10, 367. doi: 10.1021/acsmedchemlett.9b00010
[30]	Li, Z.; Xu, X.; Chen, Y.; Liu, J.; Li, W. CN 103435562, 2013. (in Chinese)
[31]	Li, Z.; Chen, Y.; Liu, A.; Li, Y.; Wang, B.; Pan, L.; Wan, Y.; Liu, J.; Chen, W. CN 104402785, 2015. (in Chinese)
[32]	Lepri, S.; Goracci, L.; Valeri, A.; Cruciani, G. Eur. J. Med. Chem. 2016, 121, 658. doi: 10.1016/j.ejmech.2016.06.006
[33]	Simpkins, L. M.; Bolton, S.; Pi, Z.; Sutton, J. C.; Kwon, C.; Zhao, G.; Magnin, D. R.; Augeri, D. J.; Gungor, T.; Rotella, D. P.; Sun, Z.; Liu, Y.; Slusarchyk, W. S.; Marcinkeviciene, J.; Robertson, J. G.; Wang, A.; Robl, J. A.; Atwal, K. S.; Zahler, R. L.; Parker, R. A.; Kirby, M. S.; Hamann, L. G. Bioorg. Med. Chem. Lett. 2007, 17, 6476. pmid: 17937986
[34]	Wang, F.; Xu, X. Wang, F; Peng, L.; Zhang, Y.; Wang, L.; Wang, L. Lett. Org. Chem. 2015, 12, 741. doi: 10.2174/1570178612666150907204813
[35]	Milewska, M. J.; Gdaniec, M.; Poloński, T. Tetrahedron: Asymmetry 1996, 7, 3169. doi: 10.1016/0957-4166(96)00419-3
[36]	Beutner, G. L.; Young, I. S.; Davies, M. L.; Hickey, M. R.; Park, H.; Stevens, J. M.; Ye, Q. Org. Lett. 2018, 20, 4218. doi: 10.1021/acs.orglett.8b01591
[37]	Liu, X.; Ouyang, S.; Yu, B.; Liu, Y.; Huang, K.; Gong, J.; Zheng, S.; Li, Z.; Li, H.; Jiang, H. Nucleic Acids Res. 2010, 38, 609.
[38]	Wang, X.; Pan, C.; Gong, J.; Liu, X.; Li, H. J. Chem. Inf. Model. 2016, 56, 1175. doi: 10.1021/acs.jcim.5b00690 pmid: 27187084
[39]	Wang, X.; Shen, Y.; Wang, S.; Li, S.; Zhang, W.; Liu, X.; Lai, L.; Pei, J.; Li, H. Nucleic Acids Res. 2017, 45, 356. doi: 10.1093/nar/gkx374 pmid: 28472422
[40]	Ferrante, P.; Messali, S.; Meroni, G.; Ballabio, A. Eur. J. Hum. Genet. 2002, 10, 813. doi: 10.1038/sj.ejhg.5200887 pmid: 12461688
[41]	Hernandez-Guzman, F. G.; Higashiyama, T.; Pangborn, W.; Osawa, Y.; Ghosh, D. J. Biol. Chem. 2003, 278, 22989. pmid: 12657638
[42]	Geisler, J.; Sasano, H.; Chen, S.; Purohit, A. J. Steroid Biochem. Mol. Biol. 2011, 125, 39. doi: 10.1016/j.jsbmb.2011.02.002
[43]	Purohit, A.; Foster, P. A. J. Endocrinol. 2012, 212, 99. doi: 10.1530/JOE-11-0266 pmid: 21859802
[44]	Leese, M. P.; Hejaz, H. A. M.; Mahon, M. F.; Newman, S. P.; Purohit, A.; Reed, M. J.; Potter, B. V. L. J. Med. Chem. 2005, 48, 5243. doi: 10.1021/jm050066a
[45]	A. Purohit, Woo, L. W. L.; Potter, B. V. L. Cancer Res. 2000, 60, 3394. pmid: 10910045
[46]	Kertesz, N.; Krasnoperov, V.; Reddy, R.; Leshanski, L.; Kumar, S. R.; Zozulya, S.; Gill, P. S. Blood 2006, 107, 2330. doi: 10.1182/blood-2005-04-1655
[47]	Pasquale, E. B. Nat. Rev. Cancer 2010, 10, 165. doi: 10.1038/nrc2806 pmid: 20179713
[48]	Dohle, W.; Jourdan, F. L.; Menchon, G.; Prota, A. E.; Foster, P. A.; Mannion, P.; Hamel, E.; Thomas, M. P.; Kasprzyk, P. G.; Ferrandis, E.; Steinmetz, M. O.; Leese, M. P.; Potter, B. V. L. J. Med. Chem. 2018, 61, 1031. doi: 10.1021/acs.jmedchem.7b01474
[49]	Maltais, R.; Djiemeny, A. N.; Roy, J.; Barbeau, X.; Lambert, J.-P.; Poirier, D. Bioorg. Med. Chem. 2020, 28, 115368. doi: 10.1016/j.bmc.2020.115368

Compd.	Structure (Relative stereochemistry)	Growth-inhibition (200 μg•mL^–1)
Compd.	Structure (Relative stereochemistry)	MCF-7	BGC-823	HepG2	NCI-H460
1-2		83.46±3.64	54.78±1.16	48.13±1.69	97.31±0.18
1-31		19.42±1.19	–28.92±2.03	38.24±5.37	14.20±6.58

Compd.	Structure (Relative stereochemistry)	Growth-inhibition (200 μg•mL^–1)
Compd.	Structure (Relative stereochemistry)	MCF-7	BGC-823	HepG2	NCI-H460
1-2		83.46±3.64	54.78±1.16	48.13±1.69	97.31±0.18
1-31		19.42±1.19	–28.92±2.03	38.24±5.37	14.20±6.58

Compd.	R¹	Growth-inhibition (200 μg•mL^–1)
Compd.	R¹	MCF-7	BGC-823	HepG2	NCI-H460
1-1	Methyl	37.23±3.34	32.39±1.17	23.47±4.79	47.37±0.50
1-2	Ethyl	83.46±3.64	54.78±1.16	48.13±1.69	97.31±0.18
1-3	tert-Butyl	85.73±2.92	4.17±0.52	57.57±1.57	94.34±2.25
1-4	Benzyl	96.83±0.69	97.75±0.08	99.14±0.28	98.42±0.16
1-30	Phenethyl	90.96±0.28	91.19±0.99	93.00±8.44	97.46±0.16

Compd.	R¹	Growth-inhibition (200 μg•mL^–1)
Compd.	R¹	MCF-7	BGC-823	HepG2	NCI-H460
1-1	Methyl	37.23±3.34	32.39±1.17	23.47±4.79	47.37±0.50
1-2	Ethyl	83.46±3.64	54.78±1.16	48.13±1.69	97.31±0.18
1-3	tert-Butyl	85.73±2.92	4.17±0.52	57.57±1.57	94.34±2.25
1-4	Benzyl	96.83±0.69	97.75±0.08	99.14±0.28	98.42±0.16
1-30	Phenethyl	90.96±0.28	91.19±0.99	93.00±8.44	97.46±0.16

Compd.	R¹	IC₅₀/(μg•mL^–1)
Compd.	R¹	MCF-7	BGC-823	HepG2	NCI-H460
1-1	Methyl	>200	>200	>200	>200
1-2	Ethyl	33.81±2.06	>200	>200	29.80±2.91
1-3	tert-Butyl	29.27±5.83	>200	>200	38.38±1.40
1-4	Benzyl	40.79±2.18	50.90±0.99	26.09±2.97	26.78±2.78
1-5	4-Methylbenzyl	32.29±1.7	21.25±3.03	10.44±1.60	20.38±1.21
1-6	3-Methylbenzyl	40.35±5.19	35.50±3.97	35.01±1.54	30.59±1.18
1-7	2-Methylbenzyl	33.80±1.72	25.42±2.29	23.20±1.07	21.60±1.60
1-8	4-Chlorobenzyl	36.89±2.29	19.47±5.37	17.65±1.24	10.06±1.82
1-9	3-Chlorobenzyl	36.80±4.39	30.58±2.65	28.62±0.81	22.48±0.71
1-10	2-Chlorobenzyl	80.47±6.93	31.75±4.74	22.75±0.84	21.61±1.30
1-11	4-Fluorobenzyl	67.45±2.43	29.55±2.70	27.07±1.05	25.27±2.85
1-12	4-Bromobenzyl	17.65±0.99	28.29±2.54	21.17±0.81	21.01±1.25
1-13	4-Iodobenzyl	27.57±6.26	26.24±2.70	26.29±1.43	26.15±1.36
1-14	4-Methoxybenzyl	20.78±1.38	24.51±2.57	24.14±1.23	25.17±1.84
1-15	4-Difluoromethoxybenzyl	75.61±14.80	50.03±2.97	39.52±6.27	56.80±10.58
1-16	4-tert-Butylbenzyl	>200	92.61±16.39	>200	95.35±17.62
1-17	4-Cyanobenzyl	47.75±9.06	42.49±4.12	37.92±2.94	30.26±3.15
1-18	4-Trifluoromethylbenzyl	25.66±1.11	21.39±1.11	21.23±1.99	15.12±1.43
1-19	(4-Phenoxyphenyl)methyl	8.38±0.67	22.67±0.80	19.30±1.10	20.49±1.32
1-20	4-Phenylbenzyl	25.88±2.95	24.97±1.27	27.06±3.07	22.94±1.15
1-21	2,4-Difluorobenzyl	40.84±1.24	51.29±1.09	23.52±2.50	28.35±2.28
1-22	2,6-Dichlorobenzyl	>200	>200	19.74±0.79	39.89±9.27
1-23	3,4,5-Trimethoxybenzyl	19.16±3.01	34.39±3.52	27.22±2.61	20.39±1.41
1-24	(Tetrahydrofuran-3-yl)methyl	153.9±20.2	50.30±6.65	46.88±5.39	56.51±11.21
1-25	(6-Chloropyridine-3-yl)methyl	27.12±0.92	32.39±3.46	34.15±0.94	29.36±1.79
1-26	(2-Chlorothiazole-5-yl)methyl	>200	>200	>200	>200
1-27	Furan-2-ylmethyl	25.8±1.32	32.39±4.40	15.42±4.40	27.03±2.49
1-28	Thiophene-3-ylmethyl	83.43±4.37	>200	>200	>200
1-29	Naphthalene-1-ylmethyl	32.53±2.82	22.91±1.20	23.55±1.97	20.52±0.98
1-30	Phenethyl	59.05±3.60	53.12±1.16	26.76±1.18	30.37±2.36
5-Fu	—	8.23±1.33	10.31±1.40	7.09±1.61	2.26±0.80

以环丙烷限制构象的新型双酰胺的设计、合成、抗癌活性及计算分析