Abstract
A series of N-alkyl-1,4-dihydroquinoline prodrugs of scutellarin methyl ester have been synthesized (4a–4f). Compared to the parent compound scutellarin, we demonstrated that these prepared compounds had higher water solubility, more appropriate logP and better stability. Importantly, compounds 4a–4e showed improved neuroprotective activity against the H2O2-induced cell death in PC12 cells, and higher cell permeability (Papp AP–BL) and lower efflux ratio were observed for compounds 4d and 4e. The optimized compound 4d was further evaluated by cerebral ischemia/reperfusion in the middle cerebral artery occlusion (MCAO) model and could decrease the neuronal cell damage in CA1 pyramidal neurons in rats, inhibit the activation of autophagy protein beclin 1 and downregulate the expression of apoptotic protein caspase-3.
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References
Bodor N, Buchwald P (1999) Recent advances in the brain targeting of neuropharmaceuticals by chemical delivery systems. Adv Drug Deliv Rev 36:229–254
Bodor N, Buchwald P (2002) Barriers to remember: brain-targeting chemical delivery systems and Alzheimer’s disease. Drug Discov Today 7:766–774
Cao F, Guo JX, Ping QN, Shao Y, Liang J (2006) Prodrugs of scutellarin: ethyl, benzyl and N,N-diethylglycolamide ester synthesis, physicochemical properties, intestinal metabolism and oral bioavailability in the rats. Eur J Pharm Sci 29:385–393
Cha YF, Zhang S, Su H, Ou Y, Fu XZ, Jiang FJ, Zhao YL, Dong YX, Luo M, Huang Y, Lan YY, Wang AM, Wang YL (2015) L-Amino acid carbamate prodrugs of scutellarin: synthesis, physiochemical property, Caco-2 cell permeability, and in vitro anti-oxidative activity. Med Chem Res 24:2238–2246
Djeddi A, Michelet X, Culetto E, Alberti A, Barois N, Legouis R (2012) Induction of autophagy in escrt mutants is an adaptive response for cell survival in c. elegans. J Cell Sci 125:685–694
Eisenberglerner A, Bialik S, Simon HU, Kimchi A (2009) Life and death partners: apoptosis, autophagy and the cross-talk between them. Cell Death Differ 16:966–975
Eigenmann DE, Xue G, Kim KS, Moses AV, Hamburger M, Oufir M (2013) Comparative study of four immortalized human brain capillary endothelial cell lines, hcmec/d3, hbmec, ty10, and bb19, and optimization of culture conditions, for an in vitro, blood–brain barrier model for drug permeability studies. Fluids Barriers CNS 10:33–49
Hong L, Yang X, Ren T, Jie L, Xu H (2005) Effect of scutellarin on nitric oxide production in early stages of neuron damage induced by hydrogen peroxide. Pharmacol Res 51:205–210
Hu XM, Zhou MM, Hu XM, Zeng FD (2005) Neuroprotective effects of scutellarin on rat neuronal damage induced by cerebral ischemia/reperfusion. Acta Pharmacol Sin 26:1454–1459
Levine B, Mizushima N, Virgin HW (2011) Autophagy in immunity and inflammation. Nature 469:323–335
Li NG, Shen MZ, Wang ZJ, Tang YP, Shi ZH, Fu YF, Shi QP, Tang H, Duan JA (2013) Design, synthesis and biological evaluation of glucose-containing scutellarein derivatives as neuroprotective agents based on metabolic mechanism of scutellarin in vivo. Bioorg Med Chem Lett 23:102–106
Longa EZ, Weinstein PR, Carlson S, Cummins R (1989) Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20:84–91
Pan Z, Feng T, Shan L, Cai B, Chu W, Niu H, Lu Y, Yang B (2008) Scutellarin-induced endothelium-independent relaxation in rat aorta. Phytother Res 22:1428–1433
Prokai L, Prokai-Tatrai K, Bodor N (2000) Cheminform abstract: targeting drugs to the brain by redox chemical delivery systems. Med Res Rev 20:367–416
Shi ZH, Li NG, Shi QP, Zhang W, Dong ZX, Tang YP, Zhang PX, Gu T, Wu WY, Fang F, Xue X, Li HM, Yang JP, Duan JA (2015a) Synthesis of scutellarein derivatives to increase biological activity and water solubility. Bioorg Med Chem 23:6875–6884
Shi ZH, Li NG, Wang ZJ, Tang YP, Dong ZX, Zhang W, Zhang PX, Gu T, Wu WY, Yang JP, Duan JA (2015b) Synthesis and biological evaluation of methylated scutellarein analogs based on metabolic mechanism of scutellarin in vivo. Eur J Med Chem 106:95–105
Tang H, Tang YP, Li NG, Shi QP, Guo JM, Shang EX, Duan JA (2014) Neuroprotective effects of scutellarin and scutellarein on repeatedly cerebral ischemia-reperfusion in rats. Pharm Biochem Behav 118:51–59
Ţînţaş ML, Foucout L, Petit S, Oudeyer S, Gourand F, Barré L, Papamicaël C, Levacher V (2014) New developments in redox chemical delivery systems by means of 1,4-dihydroquinoline-based targetor: application to galantamine delivery to the brain. Eur J Med Chem 81:218–226
Wu WM, Pop E, Shek E, Bodor N (1989) Improved delivery through biological membranes. 39. brain-specific chemical delivery systems for. beta.-lactam antibiotics. in vitro and in vivo studies of some dihydropyridine and dihydroisoquinoline derivatives of benzylpenicillin in rats. J Med Chem 32:1782–1788
Xuan S, Zhao N, Zhou Z, Fronczek FR, Vicente MG (2016) Synthesis and in vitro studies of a series of carborane-containing boron dipyrromethenes (bodipys). J Med Chem 59:2109–2117
Yang XF, Wang NP, Lu WH, Zeng FD (2003) Effects of ginkgo biloba extract and tanshinone on cytochrome P-450 isozymes and glutathione transferase in rats. Acta Pharmacol Sin 24:1033–1038
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This work was supported by National Natural Science Foundation of China (Nos. 81260473 and 81460523), Natural Science Foundation of Guizhou Province (No. 2016-1127).
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Dong, Y., Dong, L., Chen, J. et al. Synthesis and biological evaluation of N-alkyl-1,4-dihydroquinoline prodrugs of scutellarin methyl ester as neuroprotective agents. Med Chem Res 27, 1111–1121 (2018). https://doi.org/10.1007/s00044-018-2134-8
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DOI: https://doi.org/10.1007/s00044-018-2134-8