Chinese Journal of Organic Chemistry >
Synthesis and Anticancer Activity Evaluation of Benzo[f][1,4]oxazepinone Derivatives
Received date: 2015-12-23
Revised date: 2016-01-22
Online published: 2016-02-18
Supported by
Project supported by the National Natural Science Foundation of China (No. 81302643), and the China Postdoctoral Science Foundation (No. 2014M552374).
The telomere-associated protein tankyrase is a poly(adenosine diphosphate-ribose) polymerase and is considered to be a promising target for cancer therapy, especially selective lethality on breast cancer associated (BRCA) cell lines, including breast cancer as well as malignancies of the ovaries, pancreas, and prostate gland. A variety of drug candidates have been developed and investigated, such as XAV-939, which was identified as a tankyrase inhibitor during screening for a small-mole- cule inhibitor of the Wnt/β-catenin pathway, and it exhibits nanomolar activity in the tankyrase-2 biochemical assay. Coincidentally, almost all compounds which exhibit excellent activity in the tankyrase-2 biochemical assay showed the common structure: lactam ring or amide structure. According to the reported co-crystal structure of inhibitors with tankyrase-2 analysis, it was found that the lactam ring or amide of the compounds forms three conserved hydrogen bonds to Gly1032 and Ser1068 and a π-stacking interaction with Tyr1071. Thus the lactam ring or amide was identified to be a key structure of tankyrase inhibitors. So a new class of structure based on benzo[f][1,4]oxazepinone scaffold was designed through computer-aided virtual drug screening, and 12 new compounds were synthesized via Mannich reactions of aromatic aldehydes with aromatic amines and aromatic ketones, ring expansion, reduction and condensation. The target compound was confirmed by 1H NMR, 13C NMR, HRMS. Followed by the methyl thiazolyl tetrazolium (MTT) assay [A1] to test in vitro anti-tumor activity, part compounds showed potent inhibitory effect on tumor cells. This study culminates in compound 3h, an inhibitor with potent activity against Hep-3B (IC50=3.5 μmol/L). Here, the synthesis and structure-activity relationship (SAR) of this novel series were described. To explore the anti-tumor mechanism of benzo[f][1,4]oxazepinone compounds, we explored the interaction of the compound 3h complex with the Gly1032, Ser1068 and Tyr1071 binding site of tankyrase-2, which confirms the three conserved hydrogen and π-stacking binding mode, as supporting information for the in vitro anti-tumor activity.
Li Fengqiong, Mu Minjie, Yang Na, Zhong Ling, Hu Rong, Li Jinqi, Bai Lan, Shi Jianyou, Zhang Mei . Synthesis and Anticancer Activity Evaluation of Benzo[f][1,4]oxazepinone Derivatives[J]. Chinese Journal of Organic Chemistry, 2016 , 36(6) : 1419 -1425 . DOI: 10.6023/cjoc201512034
[1] Amé, J. C.; Spenlehauer, C.; de Murcia, G. BioEssays 2004, 26, 882.
[2] Hottiger, M. O.; Hassa, P. O.; Lüscher, B.; Lüscher, H.; Koch-Nolte, F. Trends Biochem. Sci. 2010, 35, 208.
[3] Hsiao ,S. J.; Smith, S. Biochimie 2008, 90, 83.
[4] Dregalla, R. C.; Zhou, J.; Idate, R. R.; Battaglia, C. L.; Liber, H. L.; Bailey, S. M. Aging (Albany NY), 2010, 2, 691.
[5] Muramatsu, Y.; Ohishi, T.; Sakamoto, M.; Tsuruo, T.; Seimiya, H. Cancer Sci. 2007, 98, 850.
[6] Huang, S. M.; Mishina, Y. M.; Liu, S.; Cheung, A.; Stegmeier, F.; Michaud, G. A.; Charlat, O.; Wiellette, E.; Zhang ,Y.; Wiessner, S.; Hild, M.; Shi, X.; Wilson, C. J.; Mickanin, C.; Myer, V.; Fazal, A.; TomLinson, R.; Serluca, F.; Shao, W.; Cheng, H.; Shultz, M.; Rau, C.; Schirle, M.; Schlegl, J.; Ghidelli, S.; Fawell, S.; Lu, C.; Curtis, D.; Kirschner, M. W.; Lengauer, C.; Finan, P. M.; Tallarico, J. A.; Bouwmeester, T.; Porter, J. A.; Bauer, A.; Cong, F. Nature 2009, 461, 614．
[7] Karlberg, T.; Markova, N.; Johansson, I.; Hammarström, M.; Schutz, P.; Weigelt, J.; Schüler, H. J. Med. Chem. 2010, 53, 5352.
[8] Lehtiö, L.; Jemth, A. S.; Collins, R.; Loseva, O.; Johansson, A.; Markova, N.; Hammarström, M.; Flores, A.; Holmberg-Schiavone, L.; Weigelt, J.; Helleday, T.; Schüler, H.; Karlberg, T. J. Med. Chem. 2009, 52, 3108.
[9] Liu, D. Z.; Qian, Y.; Nie, Z. F．Dyestuffs Coloration 1998, 35, 35 (in Chinese). (刘东志, 钱颖, 聂中方, 染料工业, 1998, 35, 35.)
[10] Veerababurao, Kavala.; Lin, C. C.; Kuo, C. W.; Fang, H. L.; Yao, C. F. Tetrahedron 2012, 68, 1321.
[11] Krapcho, J.; Turk, C. F. J. Med. Chem. 1966, 9, 191.
[12] Huang, P.; Wang, P. P.; Huang, L. P. J. Nanjing Univ. Technol. 2007, 29, 101 (in Chinese). (黄培, 王朋朋, 黄丽萍, 南京工业大学学报, 2007, 29, 101.)
[13] Qiu, N. N.; Huang, J. C.; Li, X. J.; Dong, Y. X.; Chen, G. L.; Wu, Z. R.; He, D. Chem. Reag. 2010, 32. 1045 (in Chinese). (邱楠楠, 黄金程, 李晓军, 董永喜, 陈桂玲, 吴争荣, 贺殿, 化学试剂, 2010, 32, 1045.)
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