Design, Synthesis and Biological Evaluation of Novel (Quinolinyl-3-pyridinyl)benzenesulfonamide-Based Hydroxamic Acids as PI3K and HDAC Dual Targeting Inhibitors

doi:10.6023/cjoc201908021

Chinese Journal of Organic Chemistry ›› 2020, Vol. 40 ›› Issue (1): 95-107.DOI: 10.6023/cjoc201908021 Previous Articles Next Articles

新型吡啶苯磺酰胺联喹啉基异羟肟酸类PI3K/HDAC双靶点抑制剂的设计、合成和生物活性研究

顾依钰^a, 吕晓庆^b, 马晓东^c, 张浩健^a, 嵇媛媛^a, 丁婉婧^a, 沈立^a

a 浙江大学海洋学院浙江舟山 316021;
b 嘉兴学院医学院浙江嘉兴 314001;
c 安徽中医药大学药学院合肥 230012

收稿日期:2019-08-13 修回日期:2019-09-05 发布日期:2019-09-18
通讯作者: 沈立 E-mail:shenli@zju.edu.cn
基金资助:
国家自然科学基金青年基金（No.81402845）和舟山市科技计划（No.2018C81035）资助项目.

Design, Synthesis and Biological Evaluation of Novel (Quinolinyl-3-pyridinyl)benzenesulfonamide-Based Hydroxamic Acids as PI3K and HDAC Dual Targeting Inhibitors

Gu Yiyu^a, Lü Xiaoqing^b, Ma Xiaodong^c, Zhang Haojian^a, Ji Yuanyuan^a, Ding Wanjing^a, Shen Li^a

a Ocean College, Zhejiang University, Zhoushan, Zhejiang 316021;
b College of Medicine, Jiaxing University, Jiaxing, Zhejiang 314001;
c School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012

Received:2019-08-13 Revised:2019-09-05 Published:2019-09-18
Supported by:
Project supported by the National Natural Science Foundation for Young Scientists of China (No. 81402845) and the Foundation for the Science and Technology Project of Zhoushan City (No. 2018C81035).

1. 200095S.pdf.pdf(5066KB)

Abstract

Polypharmacology has emerged as a promising approach to drug discovery, especially antitumor drug. This study reports the design, synthesis, and biological evaluation of novel phosphatidylinositol 3-kinases (PI3Ks) and histone deacetylases (HDACs) dual inhibitors on the basis of GSK2126458 under clinical evaluation and vorinostat approved. Among these hybrid molecules, GYB-4 and GYB-5 possessed potent inhibition against both PI3Kα (1.0 and 1.3 nmol/L, respectively) and HDAC1 (4.2 and 4.8 nmol/L, respectively). Antiproliferative assays with HCT116, PC3 and A2780 cell lines subsequently were performed. The structure-activity relationship study will guide to optimization of dual PI3K and HDAC inhibitors.

Key words: phosphatidylinositol 3-kinases (PI3K), histone deacetylases (HDAC), dual targeting inhibitor, bioactivity

Cite this article

Gu Yiyu, Lü Xiaoqing, Ma Xiaodong, Zhang Haojian, Ji Yuanyuan, Ding Wanjing, Shen Li. Design, Synthesis and Biological Evaluation of Novel (Quinolinyl-3-pyridinyl)benzenesulfonamide-Based Hydroxamic Acids as PI3K and HDAC Dual Targeting Inhibitors[J]. Chinese Journal of Organic Chemistry, 2020, 40(1): 95-107.

Export EndNote|Reference Manager|ProCite|BibTeX|RefWorks

share this article

References

[1] Porta, C.; Paglino, C.; Mosca, A. Front Oncol. 2014, 4, 64.
[2] Pons-Tostivint, E.; Thibault, B.; Guillermet-Guibert, J. Trends Cancer 2017, 3, 454.
[3] Nelson, C. M.; Chen, C. S. FEBS Lett. 2002, 514, 238.
[4] Okkenhaug, K.; Vanhaesebroeck, B. Nat. Rev. Immunol. 2003, 3, 317.
[5] Cantley, L. C. Science 2002, 296, 1655.
[6] Ikenoue, T.; Kanai, F.; Hikiba, Y.; Obata, T.; Tanaka, Y.; Imamura, J.; Ohta, M.; Jazag, A.; Guleng, B.; Tateishi, K.; Asaoka, Y.; Matsumura, M.; Kawabe, T.; Omata, M. Cancer Res. 2005, 65, 4562.
[7] Fruman, D. A.; Rommel, C. Nat. Rev. Drug Discovery 2014, 13, 140.
[8] West, A. C.; Johnstone, R. W. J. Clin. Invest. 2014, 124, 30.
[9] Polo, S. E.; Almouzni, G. Cancer Lett. 2005, 220, 1.
[10] Vidanes, G. M.; Bonilla, C. Y.; Toczyski, D. P. Cell 2005, 121, 973.
[11] Friedrich, M.; Gerbeth, L.; Gerling, M.; Rosenthal, R.; Steiger, K.; Weidinger, C.; Keye, J.; Wu, H.; Schmidt, F.; Weichert, W.; Siegmund, B.; Glauben, R. Mucosal Immunol. 2019, 12, 656.
[12] Yang, J.; Jin, X.; Yan, Y.-Q.; Shao, Y.-J.; Pan, Y.-Q.; Roberts, L. R.; Zhang, J.; Huang, H.-J.; Jiang, J.-T. Sci. Rep. 2017, 7, 43864.
[13] Zhou, W.-Q.; Feng, X.-Y.; Han, H.; Guo, S.-C.; Wang, G.-D. Sci. Rep. 2016, 6, 28004.
[14] Marks, P. A.; Breslow, R. Nat. Biotechnol. 2007, 25, 84.
[15] McKinsey, T. A. Annu. Rev. Pharmacol. Toxicol. 2012, 52, 303.
[16] Xing, S.-F.; Nie, F.; Xu, Q.; Deng, Y.-X.; Li, W.; Yang, Z.-W.; Zhao, X.-Y.; Zhu, P.; Wang, X.-R.; Gao, Y.; He, Z.-Y. Lab. Invest. 2015, 95, 1105.
[17] Grant, S.; Easley, C.; Kirkpatrick, P. Nat. Rev. Drug Discovery 2007, 6, 21.
[18] Bertino, E. M.; Otterson, G. A. Expert Opin. Investig. Drugs 2011, 20, 1151.
[19] Poole, R. M. Drugs 2014, 74, 1543.
[20] Garnock-Jones, K. P. Drugs 2015, 75, 695.
[21] Ning, Z.-Q.; Li, Z.-B.; Newman, M. J.; Shan, S.; Wang, X.-H.; Pan, D.-S.; Zhang, J.; Dong, M.; Du, X.; Lu, X.-P. Cancer Chemother. Pharmacol. 2012, 69, 901.
[22] Nervi, C.; De Marinis, E.; Codacci-Pisanelli, G. Clin. Epigenet. 2015, 7, 127.
[23] Ozaki, K.; Kosugi, M.; Baba, N.; Fujio, K.; Sakamoto, T.; Kimura, S.; Tanimura, S.; Kohno, M. Biochem. Biophys. Res. Commun. 2010, 391, 1610.
[24] Yoshioka, T.; Yogosawa, S.; Yamada, T.; Kitawaki, J.; Sakai, T. Gynecol. Oncol. 2013, 129, 425.
[25] Ellis, L.; Ku, S. Y.; Ramakrishnan, S.; Lasorsa, E.; Azabdaftari, G.; Godoy, A.; Pili, R. Oncotarget 2013, 4, 2225.
[26] Rahmani, M.; Aust, M. M.; Benson, E. C.; Wallace, L.; Friedberg, J.; Grant, S. Clin. Cancer Res. 2014, 20, 4849.
[27] Anighoro, A.; Bajorath, J.; Rastelli, G. J. Med. Chem. 2014, 57, 7874.
[28] Peters, J. U. J. Med. Chem. 2013, 56, 8955.
[29] Gupta, A. K.; Arshad, S.; Poulter, N. R. Hypertension 2010, 55, 399.
[30] Knight, S. D.; Adams, N. D.; Burgess, J. L.; Chaudhari, A. M.; Darcy, M. G.; Donatelli, C. A.; Luengo, J. I.; Newlander, K. A.; Parrish, C. A.; Ridgers, L. H.; Sarpong, M. A.; Schmidt, S. J.; Van Aller, G. S.; Carson, J. D.; Diamond, M. A.; Elkins, P. A.; Gardiner, C. M.; Garver, E.; Gilbert, S. A.; Gontarek, R. R.; Jackson, J. R.; Kershner, K. L.; Luo, L.; Raha, K.; Sherk, C. S.; Sung, C. M.; Sutton, D.; Tummino, P. J.; Wegrzyn, R. J.; Auger, K. R.; Dhanak, D. ACS Med. Chem.Lett. 2010, 1, 39.
[31] Lv, X.-Q.; Ying, H.-Z.; Ma, X.-D.; Qiu, N.; Wu, P.; Yang, B.; Hu, Y.-Z., Eur. J. Med. Chem. 2015, 99, 36.
[32] De Simone, A.; La Pietra, V.; Betari, N.; Petragnani, N.; Conte, M.; Daniele, S.; Pietrobono, D.; Martini, C.; Petralla, S.; Casadei, R.; Davani, L.; Frabetti, F.; Russomanno, P.; Novellino, E.; Montanari, S.; Tumiatti, V.; Ballerini, P.; Sarno, F.; Nebbioso, A.; Altucci, L.; Monti, B.; Andrisano, V.; Milelli, A. ACS Med. Chem. Lett. 2019, 10, 469.
[33] Finnin, M. S.; Donigian, J. R.; Cohen, A.; Richon, V. M.; Rifkind, R. A.; Marks, P. A.; Breslow, R.; Pavletich, N. P. Nature 1999, 401, 188.
[34] Morphy, R.; Rankovic, Z. J. Med. Chem. 2005, 48, 6523.
[35] Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
[36] Andrianov, V.; Gailite, V.; Lola, D.; Loza, E.; Semenikhina, V.; Kalvinsh, I.; Finn, P.; Petersen, K. D.; Ritchie, J. W.; Khan, N.; Tumber, A.; Collins, L. S.; Vadlamudi, S. M.; Bjorkling, F.; Sehested, M. Eur. J. Med. Chem. 2009, 44, 1067.
[37] Lagger, G.; O'Carroll, D.; Rembold, M.; Khier, H.; Tischler, J.; Weitzer, G.; Schuettengruber, B.; Hauser, C.; Brunmeir, R.; Jenuwein, T.; Seiser, C. EMBO J. 2002, 21, 2672.
[38] Raynaud, F. I.; Eccles, S. A.; Patel, S.; Alix, S.; Box, G.; Chuckowree, I.; Folkes, A.; Gowan, S.; De Haven Brandon, A.; Di Stefano, F.; Hayes, A.; Henley, A. T.; Lensun, L.; Pergl-Wilson, G.; Robson, A.; Saghir, N.; Zhyvoloup, A.; McDonald, E.; Sheldrake, P.; Shuttleworth, S.; Valenti, M.; Wan, N. C.; Clarke, P. A.; Workman, P. Mol. Cancer Ther. 2009, 8, 1725.
[39] Botta, C. B.; Cabri, W.; Cini, E.; De Cesare, L.; Fattorusso, C.; Giannini, G.; Persico, M.; Petrella, A.; Rondinelli, F.; Rodriquez, M.; Russo, A.; Taddei, M. J. Med. Chem. 2011, 54, 2165.
[40] Crawford, T. D.; Vartanian, S.; Côté, A.; Bellon, S.; Duplessis, M.; Flynn, E. M.; Hewitt, M.; Huang, H.-R.; Kiefer, J. R.; Murray, J.; Nasveschuk, C. G.; Pardo, E.; Romero, F. A.; Sandy, P.; Tang, Y.; Taylor, A. M.; Tsui, V.; Wang, J.; Wang, S.; Zawadzke, L.; Albrecht, B. K.; Magnuson, S. R.; Cochran, A. G.; Stokoe, D. Bioorg. Med. Chem. Lett. 2017, 27, 3534.
[41] Ding, H.-W.; Deng, C.-L.; Li, D.-D.; Liu, D.-D.; Chai, S.-M.; Wang, W.; Zhang, Y.; Chen, K.; Li, X.; Wang, J.; Song, S.-J.; Song, H.-R. Eur. J. Med. Chem. 2018, 146, 460.
[42] Zhang, J.-K.; Lv, X.-Q.; Ma, X.-D.; Hu, Y.-Z. Eur. J. Med. Chem. 2017, 127, 509.
[43] Zhang, K.-H.; Lai, F.-F.; Lin, S.-W.; Ji, M.; Zhang, J.-B.; Zhang, Y.; Jin, J.; Fu, R.; Wu, D.-Y.; Tian, H.; Xue, N.-N.; Sheng, L.; Zou, X.-W.; Li, Y.; Chen, X.-G.; Xu, H. J. Med. Chem. 2019.
[44] Yao, L.-B.; Mustafa, N.; Tan, E. C.; Poulsen, A.; Singh, P.; Duong-Thi, M.-D.; Lee, J. X. T.; Ramanujulu, P. M.; Chng, W. J.; Yen, J. J. Y.; Ohlson, S.; Dymock, B. W. J. Med. Chem. 2017, 60, 8336.

新型吡啶苯磺酰胺联喹啉基异羟肟酸类PI3K/HDAC双靶点抑制剂的设计、合成和生物活性研究

Design, Synthesis and Biological Evaluation of Novel (Quinolinyl-3-pyridinyl)benzenesulfonamide-Based Hydroxamic Acids as PI3K and HDAC Dual Targeting Inhibitors

PDF

Supporting Info.

Knowledge

Abstract

Cite this article

share this article

References

Related Articles 15

Recommended Articles

Metrics

Comments

[1]	Jinyan He, Fuyun Tian, Qingqing Wu, Yueming Zheng, Yuting Chen, Haiyan Xu, Zhengsheng Jin, Li Zhan, Xinqiang Cheng, Yueling Gu, Zhaobing Gao, Guilong Zhao. Design, Synthesis and Bioactivity of [3.3.3]Propellane-Based Voltage-Gated Calcium Channel α2δ Subunit Ligands [J]. Chinese Journal of Organic Chemistry, 2023, 43(6): 2226-2238.
[2]	Yang Sun, Yang Wang, Zichan Zhang, Ye Qian, Guicheng Luo, Beibei Zhou, Lisha Miao, Yudie Chen, Hong Dai, Baolin Xu, Zhengguang Wu. Synthesis and Bioactivities of Novel Pyrazole Oxime Derivatives Containing 1,3,4-Oxadiazole Group [J]. Chinese Journal of Organic Chemistry, 2023, 43(4): 1584-1590.
[3]	Sha Zhou, Mukuo Wang, Weibin Xie, Shaa Zhou, Lixia Xiong, Yu Zhao, Zhengming Li. Synthesis and Insecticidal Activities of Novel Optically Active Dicarboxamides Containing N-Trifluoroacetyl Sulfulimiyl Substituents [J]. Chinese Journal of Organic Chemistry, 2021, 41(9): 3532-3538.
[4]	Jiyan Shao, Zhijie Li, Yajun Wang, Yuyan Xiong, Xiangdong Hu. Synthesis and Bioactivity of Tropone Derivatives as Potential Compounds against Human Gastric Cancer Cells Growth [J]. Chinese Journal of Organic Chemistry, 2021, 41(9): 3675-3681.
[5]	Chenhao Xu, Yunpeng Gong, Yaxin Chen, Qimeng Song, Jiao Li, Yichao Zheng, Wen Li, Kai Sun, Hongmin Liu. Design, Synthesis and Activity Evaluation of Novel Bromodomain-Containing Protein 4 (BRD4) Small Molecule Inhibitor Based on ABBV-075 [J]. Chinese Journal of Organic Chemistry, 2021, 41(4): 1712-1721.
[6]	Weinü Zeng, Guolei Huang, Bin Wang, Jin Cai, Caijuan Zheng. Secondary Metabolites and Bioactivities of Penicillium sp. Sourced from Mangrove from 2007 to 2020 [J]. Chinese Journal of Organic Chemistry, 2021, 41(11): 4255-4278.
[7]	Zhang Min, Zheng Dandan, Ni Yadan, Liang Kai, Xun Xiao, Hu Lanping, Chen Qingwen, Yang Bing, Liang Zhipeng, Ding Ying, Shi Jian, Dai Hong. Synthesis and Bioactivities of Novel Pyrazole Amides Carrying Oxazole Moiety [J]. Chinese Journal of Organic Chemistry, 2020, 40(6): 1772-1778.
[8]	Huang Jing, Yang Yihua, Feng Juan, Li Junzhang, Liu Shouxin. Research Progress on cis-/trans-Isomerization of Cyclic Peptide [J]. Chinese Journal of Organic Chemistry, 2020, 40(6): 1473-1483.
[9]	Xun Xiao, Ni Yadan, Li Jinfeng, Ding Ying, Zhang Min, Wang Yang, Hu Lanping, Zhou Huanyu, Yang Bing, Shi Jian, Gao Lei, Dai Hong. Synthesis and Bioactivities of Novel Pyrazole Oxime Derivatives Containing a N-Pyridylpyrazole Moiety [J]. Chinese Journal of Organic Chemistry, 2020, 40(6): 1638-1646.
[10]	Wang Yurong, Zheng Dandan, Wang Yang, Ye Hao, Yao Wei, Ding Ying, Gu Haiying, Feng Xia, Li Ling, Dai Hong. Synthesis and Bioactivities of Novel Pyrazole Oxime Ethers Containing 1,2,4-Triazole Moiety [J]. Chin. J. Org. Chem., 2019, 39(7): 2053-2061.
[11]	Shi Yujun, Zhou Qian, Wang Yang, Qian Hongwei, Ye Linyu, Feng Xia, Chen Hui, Li Yating, Dai Hong, Wei Zhonghao, Wu Jinming. Synthesis and Biological Activities of Novel Pyrazole Amide Derivatives Containing Substituted Pyridyl Group [J]. Chin. J. Org. Chem., 2018, 38(9): 2450-2457.
[12]	Yuan Rui, Wang Yuanjiang, Huang Shuying, Dou Pengfei, Zhang Longyan, Chen Wen, Ren Xuanxuan, Zhou Shengliang, Wan Yu, Wu Hui. Synthesis and Biological Evaluation of Novel Flavonoid-Substituted Tröger's Bases [J]. Chin. J. Org. Chem., 2018, 38(12): 3338-3344.
[13]	Lu Wenyu, Yu Wenjing, Sun Dequn. Advances in Application of Marine Bioactive Peptides in Drug Development [J]. Chin. J. Org. Chem., 2017, 37(7): 1681-1700.
[14]	Dai Hong, Ye Linyu, Li Yang, Fang Yuan, Shi Yujun, Liang Zhipeng, Shi Jian. Synthesis and Biological Activities of Novel Pyrazole Oximes Containing Substituted Pyrimidine Group [J]. Chin. J. Org. Chem., 2017, 37(4): 1020-1026.
[15]	Dai Hong, Huang Meiling, Ge Shushan, Sun Siyu, Shen Aibao, Cheng Xiaoyan, Li Chunjian, Shi Jian. Synthesis and Biological Activities of Novel Pyrazole Oxime Esters Containing Substituted Pyrazolyl Group [J]. Chin. J. Org. Chem., 2017, 37(12): 3289-3295.