Synthesis and Biological Evaluation of Scutellarein Alkyl Derivatives as Preventing Neurodegenerative Agents with Improved Lipid Soluble Properties

Author(s): He-Min Li, Ting Gu, Wen-Yu Wu, Shao-Peng Yu, Tian-Yuan Fan, Yue Zhong, Nian-Guang Li*.

Journal Name: Medicinal Chemistry

Volume 15 , Issue 7 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Exogenous antioxidants are considered as a promising therapeutic approach to treat neurodegenerative diseases since they could prevent and/or minimize the neuronal damage by oxidation.

Objective: Three series of lipophilic compounds structurally based on scutellarein (2), which is one metabolite of scutellarin (1) in vivo, have been designed and synthesized.

Methods: Their antioxidant activity was evaluated by detecting the 2-thiobarbituric acid reactive substance (TBARS) produced in the ferrous salt/ascorbate-induced autoxidation of lipids, which were present in microsomal membranes of rat hepatocytes. The lipophilicity of these compounds indicated as partition coefficient between n-octanol and buffer was investigated by ultraviolet (UV) spectrophotometer.

Results: This study indicated that compound 5e which had a benzyl group substituted at the C4'- OH position showed a potent antioxidant activity and good lipophilicity.

Conclusion: 5e could be an effective candidate for preventing or reducing the oxidative status associated with the neurodegenerative processes.

Keywords: Alzhei-mer's disease, scutellarin, scutellarein, antioxidant, lipophilicity, neurodegenerative.

[1]
Rao, J.; Chiappelli, J.; Kochunov, P.; Regenold, W.T.; Rapoport, S.I.; Hong, L.E. Is schizophrenia a neurodegenerative disease? Evidence from age-related decline of brain-derived neurotrophic factor in the brains of schizophrenia patients and matched nonpsychiatric controls. Neurodegener. Dis., 2015, 15, 38-44.
[2]
Delle, C.R.; Minichino, A.; Salviati, M.; Fiorentini, S.; Tonini, A.; Bersani, F.S.; De Michele, F.; Caredda, M.; Biondi, M. Bipolar spectrum disorders in patients with cerebellar lesions: A comparison with Parkinson’s disease. J. Nerv. Ment. Dis., 2015, 203, 725-729.
[3]
Millán-Calenti, J.C.; Lorenzo-López, L.; Alonso-Búa, B.; de Labra, C.; González-Abraldes, I.; Maseda, A. Optimal nonpharmacological management of agitation in Alzheimer’s disease: Challenges and solutions. Clin. Interv. Aging, 2016, 11, 175-184.
[4]
Foltynie, T.; Kahan, J. Parkinson’s disease: An update on pathogenesis and treatment. J. Neurol., 2013, 260, 1433-1440.
[5]
Saudou, F.; Humbert, S. The biology of Huntingtin. Neuron, 2016, 89, 910-926.
[6]
Buendia, I.; Michalska, P.; Navarro, E.; Gameiro, I.; Egea, J.; León, R. Nrf2-ARE pathway: An emerging target against oxidative stress and neuroinflammation in neurodegenerative diseases. Pharmacol. Ther., 2016, 157, 84-104.
[7]
Williams, S.; Hamil, N.; Abramov, A.Y.; Walker, M.C.; Kovac, S. Status epilepticus results in persistent overproduction of reactive oxygen species, inhibition of which is neuroprotective. Neuroscience, 2015, 303, 160-165.
[8]
Pardillo-Díaz, R.; Carrascal, L.; Ayala, A.; Nunez-Abades, P. Oxidative stress induced by cumene hydroperoxide evokes changes in neuronal excitability of rat motor cortex neurons. Neuroscience, 2015, 289, 85-98.
[9]
Liguori, I.; Russo, G.; Curcio, F.; Bulli, G.; Aran, L.; Della-Morte, D.; Gargiulo, G.; Testa, G.; Cacciatore, F.; Bonaduce, D.; Abete, P. Oxidative stress, aging, and diseases. Clin. Interv. Aging, 2018, 13, 757-772.
[10]
Nuzzo, D.; Amato, A.; Picone, P.; Terzo, S.; Galizzi, G.; Bonina, F.P.; Mulè, F.; Di Carlo, M. A natural dietary supplement with a combination of nutrients prevents neurodegeneration induced by a high fat diet in mice. Nutrients, 2018, 10E1130
[11]
Sun, J.B.; Li, Y.; Cai, Y.F.; Huang, Y.; Liu, S.; Yeung, P.K.; Deng, M.Z.; Sun, G.S.; Zilundu, P.L.; Hu, Q.S.; An, R.X.; Zhou, L.H.; Wang, L.X.; Cheng, X. Scutellarin protects oxygen/glucose-deprived astrocytes and reduces focal cerebral ischemic injury. Neural Regen. Res., 2018, 13, 1396-1407.
[12]
Wang, W.W.; Lu, L.; Bao, T.H.; Zhang, H.M.; Yuan, J.; Miao, W.; Wang, S.F.; Xiao, Z.C. Scutellarin alleviates behavioral deficits in a mouse model of multiple sclerosis, possibly through protecting neural stem cells. J. Mol. Neurosci., 2016, 58, 210-220.
[13]
Tang, H.; Tang, Y.; Li, N.; Shi, Q.; Guo, J.; Shang, E.; Duan, J.A. Neuroprotective effects of scutellarin and scutellarein on repeatedly cerebral ischemia-reperfusion in rats. Pharmacol. Biochem. Behav., 2014, 118, 51-59.
[14]
Cao, F.; Guo, J.X.; Ping, Q.N.; Liao, Z.G. 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., 2006, 29, 385-393.
[15]
Ge, Q.H.; Zhou, Z.; Zhi, X.J.; Ma, L.L.; Chen, X.H. Pharmacokinetics and absolute bioavailability of breviscapine in beagle dogs. Chin. J. Pharm., 2003, 34, 618-632.
[16]
Zhang, H.Y.; Ping, Q.N.; Guo, J.X.; Cao, F. Pharmacokinetics of breviscapine and its beta-cyclodextrin complex in rats. Acta Pharm. Sin., 2005, 40, 563-567.
[17]
Chen, X.; Cui, L.; Duan, X.; Ma, B.; Zhong, D. Pharmacokinetics and metabolism of the flavonoid scutellarin in humans after a single oral administration. Drug Metab. Dispos., 2006, 34, 1345-1352.
[18]
Qian, L.; Shen, M.; Tang, H.; Tang, Y.; Zhang, L.; Fu, Y.; Shi, Q.; Li, N.G. Synthesis and protective effect of scutellarein on focal cerebral ischemia/reperfusion in rats. Molecules, 2012, 17, 10667-10674.
[19]
Qian, L-H.; Li, N-G.; Tang, Y-P.; Zhang, L.; Tang, H.; Wang, Z-J.; Liu, L.; Song, S-L.; Guo, J-M.; Ding, A-W. Synthesis and bio-activity evaluation of scutellarein as a potent agent for the therapy of ischemic cerebrovascular disease. Int. J. Mol. Sci., 2011, 12, 8208-8216.
[20]
Song, S-L.; Li, N-G.; Tang, Y-P.; Wang, Z-J.; Qian, L-H.; Tang, H.; Duan, J-A. Design, synthesis and biological evaluation of scutellarein derivatives as potential anti-Alzheimer’s disease candidates based on metabolic mechanism. Lett. Drug Des. Discov., 2012, 9, 78-83.
[21]
Bicker, J.; Alves, G.; Fortuna, A.; Falcão, A. Blood-brain barrier models and their relevance for a successful development of CNS drug delivery systems: A review. Eur. J. Pharm. Biopharm., 2014, 87, 409-432.
[22]
Li, N-G.; Wang, R.; Tang, Y-P.; Shi, Z-H.; Li, B-Q.; Li, W.; Yang, J-P.; Wang, Z-J.; Song, S-L.; Qian, L-H.; Yao, L-J.; Xi, J-Z.; Xu, J.; Feng, F.; Qian, D-W.; Duan, J-A. Design, synthesis and biological study of novel NO-donor-caffeic acid hybrids as potential anti-atherosclerotic drug candidates. Lett. Drug Des. Discov., 2011, 8, 550-557.
[23]
Li, N-G.; Wang, R.; Shi, Z-H.; Tang, Y-P.; Li, B-Q.; Wang, Z-J.; Song, S-L.; Qian, L-H.; Yang, J-P.; Yao, L-J.; Xi, J-Z.; Xu, J.; Feng, F.; Qian, D-W.; Duan, J-A. Design and synthesis of novel NO-donor-ferulic acid hybrids as potential antiatherosclerotic drug candidates. Drug Dev. Res., 2011, 72, 405-415.
[24]
Abdel-Aziz, M.; Park, S.E.; Abuo-Rahma, G.A.; Sayed, M.A.; Kwon, Y. Novel N-4-piperazinyl-ciprofloxacin-chalcone hybrids: Synthesis, physicochemical properties, anticancer and topoisomerase I and II inhibitory activity. Eur. J. Med. Chem., 2013, 69, 427-438.
[25]
Shi, Z-H.; Li, N-G.; Wang, Z-J.; Tang, Y-P.; Dong, Z-X.; Zhang, W.; Zhang, P-X.; Gu, T.; Wu, W-Y.; Yang, J-P.; Duan, J-A. Synthesis and biological evaluation of methylated scutellarein analogs based on metabolic mechanism of scutellarin in vivo. Eur. J. Med. Chem., 2015, 106, 95-105.
[26]
Li, N.G.; Song, S.L.; Shen, M.Z.; Tang, Y.P.; Shi, Z.H.; Tang, H.; Shi, Q.P.; Fu, Y.F.; Duan, J.A. Mannich bases of scutellarein as thrombin-inhibitors: Design, synthesis, biological activity and solubility. Bioorg. Med. Chem., 2012, 20, 6919-6923.
[27]
Li, N.G.; Shen, M.Z.; Wang, Z.J.; Tang, Y.P.; Shi, Z.H.; Fu, Y.F.; Shi, Q.P.; Tang, H.; Duan, J.A. 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., 2013, 23, 102-106.
[28]
Zhang, W.; Dong, Z-X.; Gu, T.; Li, N-G.; Zhang, P-X.; Wu, W-Y.; Yu, S-P.; Tang, Y-P.; Yang, J-P.; Shi, Z-H. A new and efficient synthesis of 6-O-methylscutellarein, the major metabolite of the natural medicine scutellarin. Molecules, 2015, 20, 10184-10191.
[29]
Lin, H.; Zhang, W.; Dong, Z-X.; Gu, T.; Li, N-G.; Shi, Z-H.; Kai, J.; Qu, C.; Shang, G-X.; Tang, Y-P.; Fang, F.; Li, H-M.; Yang, J-P.; Duan, J-A. A new and practical synthetic method for the synthesis of 6-O-methyl-scutellarein: One metabolite of scutellarin in vivo. Int. J. Mol. Sci., 2015, 16, 7587-7594.
[30]
Li, N-G.; Wang, J-X.; Liu, X-R.; Lin, C-J.; You, Q-D.; Guo, Q-L. A novel and efficient route to the construction of 4-oxa-tricyclo [4.3.1.0]decan-2-one scaffold. Tetrahedron Lett., 2007, 48, 6586-6589.
[31]
Tisdale, E.J.; Slobodov, I.; Theodorakis, E.A. Unified synthesis of caged Garcinia natural products based on a site-selective Claisen/Diels-Alder/Claisen rearrangement. Proc. Natl. Acad. Sci. USA, 2004, 101, 12030-12035.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 15
ISSUE: 7
Year: 2019
Page: [771 - 780]
Pages: 10
DOI: 10.2174/1573406414666181015143551
Price: $65

Article Metrics

PDF: 28
HTML: 2