Design, synthesis and biological evaluation of indole derivatives as novel inhibitors targeting B-Raf kinase

注册 English

Design, synthesis and biological evaluation of indole derivatives as novel inhibitors targeting B-Raf kinase

Zeng Wu , Ming Yan , Shi-He Hu , Zhi-Cheng Yu , Yong Zhu , Ya-Dong Cheng , Hai-Chun Liu , Yan-Min Zhang , Si-Hui Yao , Wei-Fang Tang , Tao Lu

Citation: Zeng Wu, Ming Yan, Shi-He Hu, Zhi-Cheng Yu, Yong Zhu, Ya-Dong Cheng, Hai-Chun Liu, Yan-Min Zhang, Si-Hui Yao, Wei-Fang Tang, Tao Lu. Design, synthesis and biological evaluation of indole derivatives as novel inhibitors targeting B-Raf kinase[J]. Chinese Chemical Letters, 2014, 25(2): 351-354. shu

shu

Design, synthesis and biological evaluation of indole derivatives as novel inhibitors targeting B-Raf kinase

通讯作者: Wei-Fang Tang,
Tao Lu,

基金项目:
This work was financially supported by the Natural Science Foundation of Jiangsu Province (No. BK2009303) (No. BK2009303)

the National Natural Science Foundation of China (No. 30973609) (No. 30973609)

Fundamental Research Funds for the Central Universities (No. JKZ2011004) (No. JKZ2011004)

Specialized Research Fund for the Doctoral Program of Higher Education (No. 20100096110007). (No. 20100096110007)

摘要: A series of novel indole derivatives were designed and synthesized and their inhibitory activity against B-Raf and HepG2 cell were also described. Among them, compounds 7a and 7b exhibited excellent potency, which showed the potential for further research as lead compounds.

关键词:

English

Design, synthesis and biological evaluation of indole derivatives as novel inhibitors targeting B-Raf kinase

1.
a Department of Organic Chemistry, China Pharmaceutical University, Nanjing 210009, China;
2.
b National Nanjing Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, China;
3.
c Laboratory of Molecular Design and Drug Discovery, School of Sciences, China Pharmaceutical University, Nanjing 210009, China;
4.
d State Key laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China;
5.
e The Headmaster's Office, China Pharmaceutical University, Nanjing 210009, China

Corresponding author: Wei-Fang Tang, Tao Lu,

Received Date: 10 July 2013
Fund Project:

Abstract: A series of novel indole derivatives were designed and synthesized and their inhibitory activity against B-Raf and HepG2 cell were also described. Among them, compounds 7a and 7b exhibited excellent potency, which showed the potential for further research as lead compounds.

Key words:

1. [1] L.R. Howe, S.J. Leevers, N. Gomez, et al., Activation of the MAP kinase pathway, Cell 71 (1992) 335-342.[1] L.R. Howe, S.J. Leevers, N. Gomez, et al., Activation of the MAP kinase pathway, Cell 71 (1992) 335-342.
2. [2] M. Garnett, R. Marais, Guilty as charged: B-RAF is a human oncogene, Cancer Cell 6 (2004) 313-319.[2] M. Garnett, R. Marais, Guilty as charged: B-RAF is a human oncogene, Cancer Cell 6 (2004) 313-319.
3. [3] C. Hagemann, U.R. Rapp, Isotype-specific functions of Raf kinases, Exp. Cell Res. 253 (1999) 34-46.[3] C. Hagemann, U.R. Rapp, Isotype-specific functions of Raf kinases, Exp. Cell Res. 253 (1999) 34-46.
4. [4] M. Malumbres, M. Barbacid, RAS oncogenes: the first 30 years, Nat. Rev. Cancer 3 (2003) 459-465.[4] M. Malumbres, M. Barbacid, RAS oncogenes: the first 30 years, Nat. Rev. Cancer 3 (2003) 459-465.
5. [5] H. Davies, G.P. Bignell, C. Cox, Mutation of the BRAF gene in human cancer, Nature 417 (2002) 949-954.[5] H. Davies, G.P. Bignell, C. Cox, Mutation of the BRAF gene in human cancer, Nature 417 (2002) 949-954.
6. [6] C. Michaloglou, L.C.W. Verdevedld, W.J. Mooi, BRAFE600 in benign and malignant human tumours, Oncogene 27 (2008) 877-895.[6] C. Michaloglou, L.C.W. Verdevedld, W.J. Mooi, BRAFE600 in benign and malignant human tumours, Oncogene 27 (2008) 877-895.
7. [7] J. Xing, R.X. Liu, M.Z. Xing, The BRAF^T1799A mutation confers sensitivity of thyroid cancer cells to the BRAF^V600E inhibitor PLX4032(RG7204), Biochem. Biophys. Res. Commun. 404 (2011) 958-962.[7] J. Xing, R.X. Liu, M.Z. Xing, The BRAF^T1799A mutation confers sensitivity of thyroid cancer cells to the BRAF^V600E inhibitor PLX4032(RG7204), Biochem. Biophys. Res. Commun. 404 (2011) 958-962.
8. [8] A. Gopalsamy, G. Ciszewski, Y.B. Hu, Hit to lead optimization of pyrazolo[1,5- a]pyrimidines as B-Raf kinase inhibitors, Bioorg. Med. Chem. Lett. 19 (2009) 2735-2738.[8] A. Gopalsamy, G. Ciszewski, Y.B. Hu, Hit to lead optimization of pyrazolo[1,5- a]pyrimidines as B-Raf kinase inhibitors, Bioorg. Med. Chem. Lett. 19 (2009) 2735-2738.
9. [9] F. Minisci, R. Galli, M. Cecere, et al., Nucleopphilic character of alkyl radicals generated in redox processes, Tetrahedron Lett. 9 (1968) 5609-5612.[9] F. Minisci, R. Galli, M. Cecere, et al., Nucleopphilic character of alkyl radicals generated in redox processes, Tetrahedron Lett. 9 (1968) 5609-5612.
10. [10] I. Martin, J. Anvelt, L. Vares, An alternative synthesis of the NMDA antagonist CGS 19755 via free radical carbonylation of theyl isonicotinate, Acta Chem. Scand. 49 (1995) 230-232.[10] I. Martin, J. Anvelt, L. Vares, An alternative synthesis of the NMDA antagonist CGS 19755 via free radical carbonylation of theyl isonicotinate, Acta Chem. Scand. 49 (1995) 230-232.
11. [11] C. Brennan, J.A. Dixon, W.J. Scott, 2-Aminoarylcarboxamides useful as cancer chemotherapeutic agengs, US/05/022518 2005.[11] C. Brennan, J.A. Dixon, W.J. Scott, 2-Aminoarylcarboxamides useful as cancer chemotherapeutic agengs, US/05/022518 2005.
12. [12] J.M. Frost, M.J. Dart, K.R. Tietje, Indol-3-ylcucloalkyl ketones: effects of N1 substituted indole side chain variations on CB2 cannabinoid receptor activity, J. Med. Chem. 53 (2006) 295-315.[12] J.M. Frost, M.J. Dart, K.R. Tietje, Indol-3-ylcucloalkyl ketones: effects of N1 substituted indole side chain variations on CB2 cannabinoid receptor activity, J. Med. Chem. 53 (2006) 295-315.
13. [13] L. Liu, Y.C. Cao, C. Chen, Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumors angiogenesis, and induces tumor cell apotosis in hepatocellular carcinoma model PLC/PRF/5, Cancer Res. 66 (2006) 11851-11859.[13] L. Liu, Y.C. Cao, C. Chen, Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumors angiogenesis, and induces tumor cell apotosis in hepatocellular carcinoma model PLC/PRF/5, Cancer Res. 66 (2006) 11851-11859.

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