Citation: Feng Kechang, Liang Yuru, Zhou Pengfei, Liu Mingming, Wang Yang. Structural Modification and Inhibitory Activity on Tumor Cell Proliferation of Novel Diaryl-β-lactam Compounds as Tubulin Aggregation Inhibitors[J]. Chinese Journal of Organic Chemistry, ;2017, 37(3): 683-690. doi: 10.6023/cjoc201610023 shu

Structural Modification and Inhibitory Activity on Tumor Cell Proliferation of Novel Diaryl-β-lactam Compounds as Tubulin Aggregation Inhibitors

School of Pharmacy, Fudan University, Shanghai 201203

Corresponding author: Liu Mingming, lmm@fudan.edu.cn Wang Yang, wangyang@shmu.edu.cn
Received Date: 13 October 2016
Revised Date: 25 November 2016

Fund Project: the National Natural Science Foundation of China 81302257the National Natural Science Foundation of China 21472025

Figures(2)

Our previous studies have found that diaryl-β-lactam derivative (S)-4-(3-hydroxy-4-methoxyphenyl)-3-methylene-1-(3, 4, 5-trimethoxyphenyl) azetidin-2-one (3a) possesses potent antitumor activity and its mechanism of action was confirmed as a tubulin aggregation inhibitor. In this paper, 22 novel analogs were synthesized through modifications of the phenolic hydroxyl group in B ring of compound 3a. The structures of all target compounds were characterized by ¹H NMR, ¹³C NMR and HRMS data. The inhibition against proliferation of A2780, MDA-MB-231, SKOV-3 and Hela cells were tested by thiazolyl blue tetrazolium bromide (MTT) assay, and the bioassay results demonstrated that most of these derivatives showed good anti-proliferative activities. Among them, (S)-1-(3, 4, 5-trimethoxyphenyl)-4-(3-(4-nitrobenzoyloxyl)-4-methoxyphenyl)-3-meth-ylene-azetidin-2-one (5n) exhibited most potent activities against the above four cancer cells with the corresponding IC₅₀ values of 0.055, 0.105, 0.084 and 0.102 μmol/L, respectively, indicating that these type of compounds merit further investigation.
- diaryl-β-lactam,
- tubulin aggregation inhibitor,
- antitumor
1. [1]
  Jordan, A.; Hadfield, J. A.; Lawrence, N. J.; McGown, A. T. Med. Res. Rev. 1998, 18, 259. doi: 10.1002/(ISSN)1098-1128
2. [2]
  Pettit, G. R.; Singh, S. B.; Boyd, M. R.; Hamel, E.; Pettit, R. K.; Schmidt, J. M.; Hogan, F. J. Med. Chem. 1995, 38, 1666. doi: 10.1021/jm00010a011
3. [3]
  Mikstacka, R.; Stefanski, T.; Rozanski, J. Cell. Mol. Biol. Lett. 2013, 18, 368-397.
4. [4]
  Monk, B. J.; Minion, L. E.; Coleman, R. L. Ann. Oncol. 2016, 27, i33. doi: 10.1093/annonc/mdw093
5. [5]
  Carr, M.; Greene, L. M.; Knox, A. J.; Lloyd, D. G.; Zisterer, D. M.; Meegan, M. J. Eur. J. Med. Chem. 2010, 45, 5752. doi: 10.1016/j.ejmech.2010.09.033
6. [6]
  Lu, Y.; Chen, J.; Xiao, M.; Li, W.; Miller, D. D. Pharm. Res. 2012, 29, 2943. doi: 10.1007/s11095-012-0828-z
7. [7]
  Kaur, R.; Kaur, G.; Gill, R. K.; Soni, R.; Bariwal, J. Eur. J. Med. Chem. 2014, 87, 89. doi: 10.1016/j.ejmech.2014.09.051
8. [8]
  Zheng, S.; Zhong, Q.; Mottamal, M.; Zhang, Q.; Zhang, C.; Lemelle, E.; McFerrin, H.; Wang, G. J. Med. Chem. 2014, 57, 3369. doi: 10.1021/jm500002k
9. [9]
  Chaudhary, V.; Venghateri, J. B.; Dhaked, H. P.; Bhoyar, A. S.; Guchhait, S. K.; Panda, D. J. Med. Chem. 2016, 59, 3439. doi: 10.1021/acs.jmedchem.6b00101
10. [10]
  O'Boyle, N. M.; Carr, M.; Greene, L. M.; Bergin, O.; Nathwani, S. M.; McCabe, T.; Lloyd, D. G.; Zisterer, D. M.; Meegan, M. J. J. Med. Chem. 2010, 53, 8569. doi: 10.1021/jm101115u
11. [11]
  Tripodi, F.; Pagliarin, R.; Fumagalli, G.; Bigi, A.; Fusi, P.; Orsini, F.; Frattini, M.; Coccetti, P. J. Med. Chem. 2012, 55, 2112. doi: 10.1021/jm201344a
12. [12]
  Greene, T. F.; Wang, S.; Greene, L. M.; Nathwani, S. M.; Pollock, J. K.; Malebari, A. M.; McCabe, T.; Twamley, B.; O'Boyle, N. M.; Zisterer, D. M.; Meegan, M. J. J. Med. Chem. 2016, 59, 90. doi: 10.1021/acs.jmedchem.5b01086
13. [13]
  Perez-Perez, M. J.; Priego, E. M.; Bueno, O.; Martins, M. S.; Canela, M. D.; Liekens, S. J. Med. Chem. 2016, 59, 8685. doi: 10.1021/acs.jmedchem.6b00463
14. [14]
  Wang, X.; Meng, F.; Wang, Y.; Han, Z.; Chen, Y. J.; Liu, L.; Wang, Z.; Ding, K. Angew. Chem., Int. Ed. 2012, 51 (37), 9276. doi: 10.1002/anie.201204925
15. [15]
  Wang, X.; Guo, P.; Han, Z.; Wang, X.; Wang, Z.; Ding, K. J. Am. Chem. Soc. 2014, 136 (1), 405. doi: 10.1021/ja410707q
16. [16]
  Zhou, P.; Liu, Y.; Zhou, L.; Zhu, K.; Feng, K.; Zhang, H.; Liang, Y.; Jiang, H.; Luo, C.; Liu, M.; Wang, Y. J. Med. Chem. 2016, 59, 10329. doi: 10.1021/acs.jmedchem.6b01268
17. [17]
  Franklin, T. J.; Jacobs, V.; Jones, G.; Plé, P.; Bruneau, P. Cancer Res. 1996, 56, 984.
18. [18]
  Pettit, G. R.; Toki, B.; Herald, D. L.; Verdier-Pinard, P.; Boyd, M. R.; Hamel, E.; Pettit, R. K. J. Med. Chem. 1998, 41, 1688. doi: 10.1021/jm970644q
19. [19]
  Coggiola, B.; Pagliai, F.; Allegrone, G.; Genazzani, A. A.; Tron, G. C. Bioorg. Med. Chem. Lett. 2005, 15, 3551. doi: 10.1016/j.bmcl.2005.05.052
20. [20]
  Orsini, F.; Pelizzoni, F.; Bellini, B.; Miglierini, G. Carbohydr. Res. 1997, 301, 95. doi: 10.1016/S0008-6215(97)00087-6
1. [1]
  Fa Wang , Yu Chen , Hui Chao . Ruthenium(II) Complexes as Photoactivated Chemo-Prodrugs for Hypoxic Tumor Therapy. University Chemistry, 2025, 40(7): 200-212. doi: 10.12461/PKU.DXHX202410024
2. [2]
  Ping Song , Nan Zhang , Jie Wang , Rui Yan , Zhiqiang Wang , Yingxue Jin . Experimental Teaching Design on Synthesis and Antitumor Activity Study of Cu-Pyropheophorbide-a Methyl Ester. University Chemistry, 2024, 39(6): 278-286. doi: 10.3866/PKU.DXHX202310087
3. [3]
  Jiahao Zeng , Hui Chao . 诱导程序性细胞死亡的金属抗肿瘤药物研究. University Chemistry, 2025, 40(6): 145-159. doi: 10.12461/PKU.DXHX202406019
4. [4]
  Jing WU , Puzhen HUI , Huilin ZHENG , Pingchuan YUAN , Chunfei WANG , Hui WANG , Xiaoxia GU . Synthesis, crystal structures, and antitumor activities of transition metal complexes incorporating a naphthol-aldehyde Schiff base ligand. Chinese Journal of Inorganic Chemistry, 2024, 40(12): 2422-2428. doi: 10.11862/CJIC.20240278
5. [5]
  Lili Jiang , Shaoyu Zheng , Xuejiao Liu , Xiaomin Xie . Copper-Catalyzed Oxidative Coupling Reactions for the Synthesis of Aryl Sulfones: A Fundamental and Exploratory Experiment for Undergraduate Teaching. University Chemistry, 2025, 40(7): 267-276. doi: 10.12461/PKU.DXHX202408004
6. [6]
  Nan Xiao , Fang Sun . 二芳基硫醚化合物的构建及应用. University Chemistry, 2025, 40(6): 360-363. doi: 10.12461/PKU.DXHX202407099
7. [7]
  Jian Li , Yu Zhang , Rongrong Yan , Kaiyuan Sun , Xiaoqing Liu , Zishang Liang , Yinan Jiao , Hui Bu , Xin Chen , Jinjin Zhao , Jianlin Shi . 高效靶向示踪钙钛矿纳米系统光电增效抗肿瘤. Acta Physico-Chimica Sinica, 2025, 41(5): 100042-. doi: 10.1016/j.actphy.2024.100042
8. [8]
  Geyang Song , Dong Xue , Gang Li . Recent Advances in Transition Metal-Catalyzed Synthesis of Anilines from Aryl Halides. University Chemistry, 2024, 39(2): 321-329. doi: 10.3866/PKU.DXHX202308030
9. [9]
  Aidang Lu , Yunting Liu , Yanjun Jiang . Comprehensive Organic Chemistry Experiment: Synthesis and Characterization of Triazolopyrimidine Compounds. University Chemistry, 2024, 39(8): 241-246. doi: 10.3866/PKU.DXHX202401029
10. [10]
  Yanhui Zhong , Ran Wang , Zian Lin . Analysis of Halogenated Quinone Compounds in Environmental Water by Dispersive Solid-Phase Extraction with Liquid Chromatography-Triple Quadrupole Mass Spectrometry. University Chemistry, 2024, 39(11): 296-303. doi: 10.12461/PKU.DXHX202402017
11. [11]
  Feng Han , Fuxian Wan , Ying Li , Congcong Zhang , Yuanhong Zhang , Chengxia Miao . Comprehensive Organic Chemistry Experiment: Phosphotungstic Acid-Catalyzed Direct Conversion of Triphenylmethanol for the Synthesis of Oxime Ethers. University Chemistry, 2025, 40(3): 342-348. doi: 10.12461/PKU.DXHX202405181
12. [12]
  Hao Wu , Zhen Liu , Dachang Bai . ¹H NMR Spectrum of Amide Compounds. University Chemistry, 2024, 39(3): 231-238. doi: 10.3866/PKU.DXHX202309020
13. [13]
  Yihui Song , Shangshang Qin , Kai Wu , Chengyun Jin , Bin Yu . 生物化学在高水平创新型药学人才培养中的交叉融合应用——以去甲基化酶LSD1抑制剂的活性评价为例. University Chemistry, 2025, 40(6): 341-352. doi: 10.12461/PKU.DXHX202406018
14. [14]
  Chi Li , Jichao Wan , Qiyu Long , Hui Lv , Ying Xiong . N-Heterocyclic Carbene (NHC)-Catalyzed Amidation of Aldehydes with Nitroso Compounds. University Chemistry, 2024, 39(5): 388-395. doi: 10.3866/PKU.DXHX202312016
15. [15]
  Hong Zheng , Xin Peng , Chunwang Yi . The Tale of Caprolactam Cyclic Oligomers: The Ever-changing Life of “Princess Cyclo”. University Chemistry, 2024, 39(9): 40-47. doi: 10.12461/PKU.DXHX202403058
16. [16]
  Zhuoming Liang , Ming Chen , Zhiwen Zheng , Kai Chen . Multidimensional Studies on Ketone-Enol Tautomerism of 1,3-Diketones By ¹H NMR. University Chemistry, 2024, 39(7): 361-367. doi: 10.3866/PKU.DXHX202311029
17. [17]
  Yanan Liu , Yufei He , Dianqing Li . Preparation of Highly Dispersed LDHs-based Catalysts and Testing of Nitro Compound Reduction Performance: A Comprehensive Chemical Experiment for Research Transformation. University Chemistry, 2024, 39(8): 306-313. doi: 10.3866/PKU.DXHX202401081
18. [18]
  Qianlang Wang , Jijun Sun , Qian Chen , Quanqin Zhao , Baojuan Xi . The Appeal of Organophosphorus Compounds: Clearing Their Name. University Chemistry, 2025, 40(4): 299-306. doi: 10.12461/PKU.DXHX202405205
19. [19]
  Xinyu ZENG , Guhua TANG , Jianming OUYANG . Inhibitory effect of Desmodium styracifolium polysaccharides with different content of carboxyl groups on the growth, aggregation and cell adhesion of calcium oxalate crystals. Chinese Journal of Inorganic Chemistry, 2024, 40(8): 1563-1576. doi: 10.11862/CJIC.20230374
20. [20]
  Yihao Zhao , Jitian Rao , Jie Han . Synthesis and Photochromic Properties of 3,3-Diphenyl-3H-Naphthopyran: Design and Teaching Practice of a Comprehensive Organic Experiment. University Chemistry, 2024, 39(10): 149-155. doi: 10.3866/PKU.DXHX202402050

Get Citation

PDF

XML

Metrics

PDF Downloads(3)
Abstract views(1238)
HTML views(141)

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142