Abstract
Guided by bioisosterism and pharmacokinetic parameters, we designed and synthesized a series of novel benzamide derivatives. Preliminary in vitro studies indicated that compounds 10b and 10j show significant inhibitory bioactivity in HepG2 cells (IC50 values of 0.12 and 0.13 μM, respectively). Compounds 10b and 10j induced the expression of HIF-1α protein and downstream target gene p21, and upregulated the expression of cleaved caspase-3 to promote tumor cells apoptosis.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Adeniji AO, Twenter BM, Byrns MC, Jin Y, Chen M, Winkler JD, Penning TM (2012) Development of potent and selective inhibitors of aldo-keto reductase 1C3 (Type 5 17 beta-hydroxysteroid dehydrogenase) based on N-phenyl-aminobenzoates and their structure-activity relationships. J Med Chem 55:2311–2323
Brahimi-Horn MC, Chiche J, Pouysségur J (2007) Hypoxia and cancer. J Mol Med 85:1301–1307
Carato P, Graulich A, Jensen N, Roth BL, Liégeois JF (2007) Synthesis and in vitro binding studies of substituted piperidine naphthamides. Part II: influence of the substitution on the benzyl moiety on the affinity for D 2L, D 4.2, and 5-HT 2A receptors. Bioorgan Med Chem Lett 17:1570–1574
Guo LY, Zhu P, Jin XP (2016) Association between the expression of HIF-1α and VEGF and prognostic implications in primary liver cancer. Genet Mol Res 15:1–6
Hou J, Zhao W, Huang ZN, Yang SM, Wang LJ, Jiang Y, Zhou ZS, Zheng MY, Jiang JL, Li SH (2015) Evaluation of novel N-(piperidine-4-yl)benzamide derivatives as potential cell cycle inhibitors in HepG2 cells. Chem Biol Drug Des 86:223–231
Lina J, Brown EA (2006) Bafilomycin induces the p21-mediated growth inhibition of cancer cells under hypoxic conditions by expressing hypoxia-inducible factor-1alpha. Mol Pharmacol 70:1856–1865
Majmundar AJ, Wong WJ, Simon MC (2010) Hypoxia-inducible factors and the response to hypoxic stress. Mol Cell 40:294–295
Rankin EB, Giaccia AJ (2008) The role of hypoxia-inducible factors in tumorigenesis. Cell Death Differ 15:678–685
Sendoel A, Kohler I, Fellmann C, Lowe SW, Hengartner MO (2010) HIF-1 antagonizes p53-mediated apoptosis through a secreted neuronal tyrosinase. Nature 465:577–581
Sun HX, Xu Y, Yang XR, Wang WM, Bai HB, Shi RY, Nayar Suresh K, Ranjan PD, He YZ, Zhu QF, Sun YF, Hu B, Mehtab K, Robert AA, Fan J (2013) Hypoxia inducible factor 2 alpha inhibits hepatocellular carcinoma growth through the transcription factor dimerization partner 3/E2F transcription factor 1-dependent apoptotic pathway. Hepatology 57:1088–1097
Yang LL, Li GB, Ma S, Zou C, Zhou S, Sun QZ, Cheng C, Chen X, Wang LJ, Feng S (2013) Structure-activity relationship studies of pyrazolo 3,4-d pyrimidine derivatives leading to the discovery of a novel multikinase inhibitor that potently inhibits FLT3 and VEGFR2 and evaluation of its activity against acute myeloid leukemia in vitro and in vivo. J Med Chem 56:1641–1655
Yang SM, Huang ZN, Zhou ZS, Hou J, Zheng MY, Wang LJ, Jiang Y, Zhou XY, Chen QY, Li SH (2015) Structure-based design, structure–activity relationship analysis, and antitumor activity of diaryl ether derivatives. Arch Pharm Res 38:1761–1773
Acknowledgements
This work was supported by the National Natural Science Foundation of China (NSFC-81472230), the National Training Program of Innovation and Entrepreneurship for Undergraduates (2016x0644), and the Natural Science Foundation of Fujian Province of China (2015Y0081, 2015J01350, 2015J01545).
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Huang, ZN., Liang, H., Qiao, H. et al. Synthesis and structure–activity relationship of N-(piperidin-4-yl)benzamide derivatives as activators of hypoxia-inducible factor 1 pathways. Arch. Pharm. Res. 41, 1149–1161 (2018). https://doi.org/10.1007/s12272-018-1050-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12272-018-1050-2