Abstract
A new series of cinnamide derivatives 6a–l were synthesized by the reaction of acyl chlorides with various substituted benzylpiperazines. The structures were characterized by 1H NMR, 13C NMR, and HRMS. The potential neuroprotective activities of cinnamide analogs were evaluated in differentiated rat pheochromocytoma cells (PC12 cells) and in mice subjected to acute cerebral ischemia. Among the series, 6a, 6b, and 6c, featuring a 1,3-benzodioxole moiety, showed potent neuroprotection both in vivo and in vitro. The three compounds were selected and further studied to determine their mechanism of action. MTT assay, Hoechst 33342/PI double staining, and high content screening (HCS) revealed that pretreatment of the cells with 6a, 6b, and 6c has significantly decreased the extent of cell apoptosis in a dose-dependent manner. The results of western blot analysis demonstrated these compounds suppressed apoptosis of glutamate-induced PC12 cells via caspase-3 pathway. These compounds can be lead compounds for further discovery of neuroprotective agents for treating cerebral ischemic stroke.
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References
Alexandrov AV, Hall CE, Labiche LA, Wojner AW, Grotta JC (2004) Ischemic stunning of the brain: early recanalization without immediate clinical improvement in acute ischemic stroke. Stroke 35:449–452
Beresford IJ, Parsons AA, Hunter AJ (2003) Treatments for stroke. Expert Opin Emerg Drugs 8:103–122
de Keyser J, Sulter G, Luiten PG (1999) Clinical trials with neuroprotective drugs in acute ischaemic stroke: are we doing the right thing? Trends Neurosci 22:535–540
Jia Q, Liu LP, Wang YJ (2011) Risk factors and prevention of stroke in the Chinese population. J Stroke Cerebrovasc Dis 20:395–400
Li ZY, Jiang YM, Liu YM, Guo Z, Shen SN, Liu XM, Pan RL (2014) Saikosaponin D acts against corticosterone-induced apoptosis via regulation of mitochondrial GR translocation and a GR-dependent pathway. Prog Neuropsychopharmacol Biol Psychiatry 53:80–89
Liu M, Wu B, Wang WZ, Lee LM, Zhang SH, Kong LZ (2007) Stroke in China: epidemiology, prevention, and management strategies. Lancet Neurol 6:456–464
Liu XD, Lv YL, Wang B, Zhao G, Yan YP, Xu DZ (2007) Prediction of functional outcome of ischemic stroke patiants in northwest China. Clin Neurol Neurosurg 109:571–577
Long JZ, Jin X, Adibekian A, Li WW, Cravatt BF (2010) Characterization of tunable piperidine and piperazine carbamates as inhibitors of endocannabinoid hydrolases. J Med Chem 53:1830–1842
Ma SW, Liu HX, Jiao HY, Wang LY, Chen LY, Liang J, Zhao M, Zhang XT (2012) Neuroprotective effect of ginkgolide K on glutamate-induced cytotoxicity in PC 12 cells via inhibition of ROS generation and Ca(2+) influx. Neurotoxicology 33:59–69
Maki S, Osamu T, Ryo T, Aki S (2013) Synthesis and biological evaluation of pyrrolidine derivatives as novel and potent sodium channel blockers for the treatment of ischemic stroke. Bioorg Med Chem Lett 23:4230–4234
Meng Y, Guo YB, Ling Y, Zhao YH, Zhang Q, Zhou XY, Ding F, Yang YM (2011) Synthesis and protective effects of aralkyl alcoholic 2-acetamido-2-deoxy-β-d-pyranosides on hypoglycemia and serum limitation induced apoptosis in PC12 cell. Bioorg Med Chem 19:5577–5584
Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63
Park SJ, Nam KW, Lee HJ, Cho EY, Koo U, Mar W (2009) Neuroprotective effects of an alkaloid-free ethyl acetate extract from the root of Sophora flavescens Ait. against focal cerebral ischemia in rats. Phytomedicine 16:1042–1051
Sahin A, Cakmak O, Demirtas I, Okten S, Tutar A (2008) Efficient and selective synthesis of quinoline deravatives. Tetrahedron 64:10068–10074
Šterk D, Časar Z, Jukič M, Košmrlj J (2012) Concise and highly efficient approach to three key pyrimidine precursors for rosuvastatin synthesis. Tetrahedron 68:2155–2160
Tanaka K, Matsuo K, Nakanishi A, Hatano T, Izeki H, Ishida Y, Mori W (1983) Syntheses and anti-inflammatory and analgesic activities of hydroxamic acids and acid hydrazides. Chem Pharm Bull 31:2810–2819
Wang CJ, Hu CP, Xu KP, Yuan Q, Li FS, Zou H, Tan GS, Li YJ (2010) Protective effect of selaginellin on glutamate-induced cytotoxicity and apoptosis in differentiated PC12 Cells. Naunyn Schmied Arch Pharmacol 381:73–81
Wang DR, Hao ZL, Tao WD, Kong FY, Zhang SH, Wu B, Lin S, Liu M (2011) Acute ischemic stroke in the very elderly Chinese: risk factors, hospital management and one-year outcome. Clin Neurol Neurosurg 113:442–446
Warach S, Latour LL (2004) Evidence of reperfusion injury, exacerbated by thrombolytic therapy, in human focal brain ischemia using a novel imaging marker of early blood-brain barrier disruption. Stroke 35:2659–2661
Wu B, Zhou L, Cai HH (2008) Synthesis and neuroprotective properties of novel cinnamide derivatives. Chin Chem Lett 19:1163–1166
Wu B, Zhu DY, Li F (2012) Preparation and use of a novel substituted cinnamide derivatives as neuroprotective agents C.N. Patent No. ZL200810020419.8
Yanpallewar SU, Hota D, Rai S, Kumar M, Acharya SB (2004) Nimodipine attenuates biochemical, behavioral and histopathological alterations induced by acute transient and long-term bilateral common carotid occlusion in rats. Pharmacol Res 49:143–150
Yousef MM, Afshin AD, Jawad FK, Pansy HL, Adnan IQ (2004) Acute treatment for ischemic stroke in 2004. Emerg Radiol 11:83–86
Zhang YY, Wang XY, Wang XR, Xu ZH, Liu Z, Ni Q, Chu XP, Qiu MF, Zhao AH, Jia W (2006) Protective effect of flavonoids from Scutellaria baicalensis Georgi on cerebral ischemia injury. J Ethnopharmacol 108:355–360
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The authors are grateful to the support from the National Natural Science Foundation of China (No. 81371451) and the Natural Science Foundation of Jiangsu Province (No. BK20131390).
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Zhong, Y., Li, X., Zhang, A. et al. Design, synthesis and neuroprotective activities of novel cinnamide derivatives containing benzylpiperazine moiety. Med Chem Res 27, 1366–1373 (2018). https://doi.org/10.1007/s00044-018-2153-5
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DOI: https://doi.org/10.1007/s00044-018-2153-5