Discovery of 2-methoxy-3-phenylsulfonamino-5-(quinazolin-6-yl or quinolin-6-yl)benzamides as novel PI3K inhibitors and anticancer agents by bioisostere.
作者： Teng Shao , Juan Wang , Jian-Gang Chen , Xiao-Meng Wang , Huan Li
DOI: 10.1016/J.EJMECH.2014.01.053
关键词:
摘要: Abstract 2-Substituted-3-sulfonamino-5-(quinazolin-6-yl or quinolin-6-yl)benzamides have been proposed as novel structures of PI3K inhibitors and anticancer agents based on bioisostere. In the present study, 2-substituted-3-sulfonamino-5-(4-morpholinoquinazolin-6-yl)benzamides 2-methoxy-3-sulfonamino-5-(4-morpholinoquinolin-6-yl)benzamides were synthesized. Their antiproliferative activities in vitro evaluated via MTT assay against four human cancer cell lines, including A549, HCT-116, U-87 MG KB. The SAR title compounds was preliminarily discussed. Compound 1a with potent activity tested for its inhibitory mTOR effect AKT p-AKT 473 . in established nude mice xenograft model. results suggest that compound can significantly inhibit PI3K/AKT/mTOR pathway tumor growth. These findings strongly support assumption are agents.
sci-hub.se 参考文章(24)
Xiao-Meng Wang, Jing Xu, Yi-Ping Li, Huan Li, Cong-Shan Jiang, Guang-De Yang, She-Min Lu, San-Qi Zhang, Synthesis and anticancer activity evaluation of a series of [1,2,4]triazolo[1,5-a]pyridinylpyridines in vitro and in vivo. European Journal of Medicinal Chemistry. ,vol. 67, pp. 243- 251 ,(2013) , 10.1016/J.EJMECH.2013.06.052
Pixu Liu, Hailing Cheng, Thomas M. Roberts, Jean J. Zhao, Targeting the phosphoinositide 3-kinase pathway in cancer Nature Reviews Drug Discovery. ,vol. 8, pp. 627- 644 ,(2009) , 10.1038/NRD2926
Adrian L. Smith, Noel D. D’Angelo, Yunxin Y. Bo, Shon K. Booker, Victor J. Cee, Brad Herberich, Fang-Tsao Hong, Claire L. M. Jackson, Brian A. Lanman, Longbin Liu, Nobuko Nishimura, Liping H. Pettus, Anthony B. Reed, Seifu Tadesse, Nuria A. Tamayo, Ryan P. Wurz, Kevin Yang, Kristin L. Andrews, Douglas A. Whittington, John D. McCarter, Tisha San Miguel, Leeanne Zalameda, Jian Jiang, Raju Subramanian, Erin L. Mullady, Sean Caenepeel, Daniel J. Freeman, Ling Wang, Nancy Zhang, Tian Wu, Paul E. Hughes, Mark H. Norman, Structure-Based Design of a Novel Series of Potent, Selective Inhibitors of the Class I Phosphatidylinositol 3-Kinases Journal of Medicinal Chemistry. ,vol. 55, pp. 5188- 5219 ,(2012) , 10.1021/JM300184S
Nobuko Nishimura, Aaron Siegmund, Longbin Liu, Kevin Yang, Marian C. Bryan, Kristin L. Andrews, Yunxin Bo, Shon K. Booker, Sean Caenepeel, Daniel Freeman, Hongyu Liao, John McCarter, Erin L. Mullady, Tisha San Miguel, Raju Subramanian, Nuria Tamayo, Ling Wang, Douglas A. Whittington, Leeanne Zalameda, Nancy Zhang, Paul E. Hughes, Mark H. Norman, Phospshoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dual inhibitors: discovery and structure-activity relationships of a series of quinoline and quinoxaline derivatives. Journal of Medicinal Chemistry. ,vol. 54, pp. 4735- 4751 ,(2011) , 10.1021/JM200386S
Daniel P. Sutherlin, Linda Bao, Megan Berry, Georgette Castanedo, Irina Chuckowree, Jenna Dotson, Adrian Folks, Lori Friedman, Richard Goldsmith, Janet Gunzner, Timothy Heffron, John Lesnick, Cristina Lewis, Simon Mathieu, Jeremy Murray, Jim Nonomiya, Jodie Pang, Niel Pegg, Wei Wei Prior, Lionel Rouge, Laurent Salphati, Deepak Sampath, Qingping Tian, Vickie Tsui, Nan Chi Wan, Shumei Wang, BinQing Wei, Christian Wiesmann, Ping Wu, Bing-Yan Zhu, Alan Olivero, Discovery of a Potent, Selective, and Orally Available Class I Phosphatidylinositol 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Kinase Inhibitor (GDC-0980) for the Treatment of Cancer Journal of Medicinal Chemistry. ,vol. 54, pp. 7579- 7587 ,(2011) , 10.1021/JM2009327
Hengmiao Cheng, Jacqui E. Hoffman, Phuong T. Le, Mason Pairish, Robert Kania, William Farrell, Shubha Bagrodia, Jing Yuan, Shaoxian Sun, Eric Zhang, Cathy Xiang, Deepak Dalvie, Sadayappan V. Rahavendran, Structure-based design, SAR analysis and antitumor activity of PI3K/mTOR dual inhibitors from 4-methylpyridopyrimidinone series. Bioorganic & Medicinal Chemistry Letters. ,vol. 23, pp. 2787- 2792 ,(2013) , 10.1016/J.BMCL.2013.02.020
Noel D D’Angelo, Tae-Seong Kim, Kristin Andrews, Shon K Booker, Sean Caenepeel, Kui Chen, Derin D’Amico, Dan Freeman, Jian Jiang, Longbin Liu, John D McCarter, Tisha San Miguel, Erin L Mullady, Michael Schrag, Raju Subramanian, Jin Tang, Robert C Wahl, Ling Wang, Douglas A Whittington, Tian Wu, Ning Xi, Yang Xu, Peter Yakowec, Kevin Yang, Leeanne P Zalameda, Nancy Zhang, Paul Hughes, Mark H Norman, None, Discovery and Optimization of a Series of Benzothiazole Phosphoinositide 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Dual Inhibitors Journal of Medicinal Chemistry. ,vol. 54, pp. 1789- 1811 ,(2011) , 10.1021/JM1014605
Matthew T. Burger, Sabina Pecchi, Allan Wagman, Zhi-Jie Ni, Mark Knapp, Thomas Hendrickson, Gordana Atallah, Keith Pfister, Yanchen Zhang, Sarah Bartulis, Kelly Frazier, Simon Ng, Aaron Smith, Joelle Verhagen, Joshua Haznedar, Kay Huh, Ed Iwanowicz, Xiaohua Xin, Daniel Menezes, Hanne Merritt, Isabelle Lee, Marion Wiesmann, Susan Kaufman, Kenneth Crawford, Michael Chin, Dirksen Bussiere, Kevin Shoemaker, Isabel Zaror, Sauveur-Michel Maira, Charles F. Voliva, Identification of NVP-BKM120 as a Potent, Selective, Orally Bioavailable Class I PI3 Kinase Inhibitor for Treating Cancer ACS Medicinal Chemistry Letters. ,vol. 2, pp. 774- 779 ,(2011) , 10.1021/ML200156T
Adrian J. Folkes, Khatereh Ahmadi, Wendy K. Alderton, Sonia Alix, Stewart J. Baker, Gary Box, Irina S. Chuckowree, Paul A. Clarke, Paul Depledge, Suzanne A. Eccles, Lori S. Friedman, Angela Hayes, Timothy C. Hancox, Arumugam Kugendradas, Letitia Lensun, Pauline Moore, Alan G. Olivero, Jodie Pang, Sonal Patel, Giles H. Pergl-Wilson, Florence I. Raynaud, Anthony Robson, Nahid Saghir, Laurent Salphati, Sukhjit Sohal, Mark H. Ultsch, Melanie Valenti, Heidi J.A. Wallweber, Nan Chi Wan, Christian Wiesmann, Paul Workman, Alexander Zhyvoloup, Marketa J. Zvelebil, Stephen J. Shuttleworth, The Identification of 2-(1H-Indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a Potent, Selective, Orally Bioavailable Inhibitor of Class I PI3 Kinase for the Treatment of Cancer† Journal of Medicinal Chemistry. ,vol. 51, pp. 5522- 5532 ,(2008) , 10.1021/JM800295D
Wenjuan Yang, Mao Shu, Yuanqiang Wang, Rui Wang, Yong Hu, Lingxin Meng, Zhihua Lin, 3D-QSAR and docking studies of 3-Pyridine heterocyclic derivatives as potent PI3K/mTOR inhibitors Journal of Molecular Structure. ,vol. 1054, pp. 107- 116 ,(2013) , 10.1016/J.MOLSTRUC.2013.09.049