Abstract
Two series of phenylpicolinamide sorafenib derivatives (14a–k, 15a–k) were designed and synthesized. They were evaluated for IC50 values against three cancer cell lines (A549, Hela, and MCF-7) and VEGFR2/KDR, BRAF, and CRAF kinases. Fourteen target compounds showed moderate to excellent cytotoxicity activity against the different cancer cells with potency from the single-digit μM to nanomole range. What’s more, six of them were equal to more potent than sorafenib against one or more cell lines. Most of the compounds showed bad activity against VEGFR2/KDR, BRAF, or CRAF kinases. The most promising compound 15f showed strong antitumor activities against A549 and MCF-7 cell lines with IC50 values of 5.43 ± 0.74 and 0.62 ± 0.21 μM, which were 1.29–6.79-fold more active than sorafenib (6.53 ± 0.82, 4.21 ± 0.62 μM), respectively and it exhibited moderate IC50 (7.1 μM) than 14f (IC50 = 3.1 μM). Structure–activity relationships (SARs) and docking studies indicated that replacement of diarylurea of sorafenib with phenylpicolinamide moiety benefits to the activity. The position of aryl group and the substitutions of aryl group have a great influence on antitumor activity and selectivity. Small volume groups of aryl group such as (substituted) alkyl groups (–CH3, –CF3), halogen atoms (–F) were favorable to the cytotoxicity. Exact action mechanism of target compounds is not quite clear and further study will be carried out to identify the target in near future.
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References
Harris PA, Boloor A, Cheung M, Kumar R, Crosby RM, Davis-Ward RG, Epperly AH, Hinkle KW, Hunter III RN, Johnson JH, Knick VB, Laudeman CP, Luttrell DK, Mook RA, Nolte RT, Rudolph SK, Szewczyk JR, Truesdale AT, Veal JM, Wang L, Stafford JA (2008) Discovery of 5-[[4-[(2, 3-dimethyl-2 H-indazol-6-yl) methylamino]-2-pyrimidinyl] amino]-2-methyl-benzenesulfonamide (Pazopanib), a novel and potent vascular endothelial growth factor receptor inhibitor[J]. J Med Chem 51(15):4632–4640
Keating GM, Santoro A (2009) Sorafenib[J]. Drugs 69(2):223–240
Lyons JF, Wilhelm S, Hibner B, Bollag G (2001) Discovery of a novel Raf kinase inhibitor[J]. Endocr Relat Cancer 8(3):219–225
Motzer RJ, Michaelson MD, Redman BG, Hudes GR, Wilding G, Figlin RA, Ginsberg MS, Kim ST, Baum CM, DePrimo SE, Li JZ, Bello CL, Theuer CP, George DJ, Rini BI (2006) Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma[J]. J Clin Oncol 24(1):16–24
Roper J, Richardson MP, Wang WV, Richard LG, Chen W, Coffee EM, Sinnamon MJ, Lee L, Chen PC, Bronson RT, Martin ES, Hung KE (2011) The dual PI3K/mTOR inhibitor NVP-BEZ235 induces tumor regression in a genetically engineered mouse model of PIK3CA wild-type colorectal cancer[J]. PLoS One 6(9):e25132
Strumberg D (2005) Preclinical and clinical development of the oral multikinase inhibitor sorafenib in cancer treatment[J]. Drugs Today 41(12):773–784
Tang Q, Zhao Y, Du X, Chong L, Gong P, Guo C (2013) Design, synthesis, and structure–activity relationships of novel 6, 7-disubstituted-4-phenoxyquinoline derivatives as potential antitumor agents[J]. Eur J Med Chem 69:77–89
Wan PT, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM, Jones CM, Marshall CJ, Springer CJ, Barford D, Marais R (2004) Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF[J]. Cell 116(6):855–867
Wang C, Gao H, Dong J, Zhang YM, Su P, Shi YL, Zhang J (2014) Biphenyl derivatives incorporating urea unit as novel VEGFR-2 inhibitors: Design, synthesis and biological evaluation[J]. Bioorg Med Chem 22(1):277–284
Wilhelm S, Carter C, Lynch M, Lowinger T, Dumas J, Smith RA, Schwartz B, Simantov R, Kelley S (2006) Discovery and development of sorafenib: a multikinase inhibitor for treating cancer[J]. Nat Rev Drug Discov 5(10):835–844
Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M (2008) Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling[J]. Mol Cancer Ther 7(10):3129–3140
Wilhelm SM, Carter C, Tang LY, Wilkie D, McNabola A, Rong H, Chen C, Zhang XM, Vincent P, McHugh M, Cao YC, Shujath J, Gawlak S, Eveleigh D, Rowley B, Liu L, Adnane L, Lynch M, Auclair D, Taylor I, Gedrich R, Voznesensky A, Riedl B, Post LE, Bollag G, Trail PA (2004) BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis[J]. Cancer Res 64(19):7099–7109
Zhu WF, Wu CJ, Xu S, Li W, Fang HH, Chen ZC, Tu XH, Zheng PW (2014) Design, synthesis, and biological evaluation of sorafenib analogs bearing a sulfonylurea unit as novel VEGFR2 kinase inhibitors[C]. Adv Mater Res 989:1048–1051
Acknowledgements
This work is supported by National Natural Science Foundation of China (No.81460527, 21662014), Project supported by the Natural Science Foundation of Jiangxi, China (20161BAB215216,20171ACB21052,20171BCB23078), Doctoral Scientific Research Foundation of Jiangxi Science & Technology Normal University and Program of Key Laboratory of Drug Design and Optimization, Jiangxi Science & Technology Normal University (300098010306) and College Students’ science and Technology Innovation Project of Jiangxi Province (201411318033)
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Chunjiang Wu and Shan Xu contribute equally to this work.
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Wu, C., Xu, S., Guo, Y. et al. Design, synthesis and biological evaluation of phenylpicolinamide sorafenib derivatives as antitumor agents. Med Chem Res 27, 374–387 (2018). https://doi.org/10.1007/s00044-017-2045-0
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DOI: https://doi.org/10.1007/s00044-017-2045-0