Multi-target compounds acting in the central nervous system designed from natural products

Current Medicinal Chemistry

Volumn 20, Issue 13, 2013, Pages 1673-1685

  Chen, X ^a   Decker, M ^a  

^a UNIVERSITY OF WÜRZBURG   (Germany)

Author keywords

Alzheimer's disease; Antioxidants; Central nervous system disorders; Multi target directed ligands; Natural products; Neurodegenerative disorders

Indexed keywords

ANTIOXIDANT; BERBERINE; CAFFEIC ACID; CATECHIN; CHROMAN DERIVATIVE; CURCUMIN; EPIGALLOCATECHIN GALLATE; FERULIC ACID; FLAVONE; HUPRINE X; LINARIN; LIPOCRIN; MELATONIN; MEMOQUIN; NATURAL PRODUCT; QUERCETIN; RESVERATROL; SILIBININ; TACRINE; THIOCTIC ACID; TILIANIN; UNCLASSIFIED DRUG; VITISIN A;

ALZHEIMER DISEASE; ARTICLE; BIOLOGICAL ACTIVITY; CENTRAL NERVOUS SYSTEM DISEASE; DRUG CYTOTOXICITY; DRUG STRUCTURE; HUMAN; IC 50; NEUROPROTECTION; NONHUMAN; PARKINSON DISEASE;

ANIMALS; BIOLOGICAL AGENTS; CENTRAL NERVOUS SYSTEM; DRUG DESIGN; HUMANS; NEURODEGENERATIVE DISEASES;

EID: 84877982789     PISSN: 09298673     EISSN: 1875533X     Source Type: Journal    
DOI: 10.2174/0929867311320130007     Document Type: Article

References (88)

1. Enna, S.J.; Williams, M. Challenges in the search for drugs to treat central nervous system disorders. J. Pharmacol. Exp. Ther., 2009, 329, 404-411.
2. Geldenhuys, W.J.; Youdim, M.B.H.; Carroll, R.T.; Van der Schyf, C.J. The emergence of designed multiple ligands for neurodegenerative disorders. Prog. Neurobiol., 2011, 94, 347-359.
3. Ballard, C.; Gauthier, S.; Corbett, A.; Brayne, C.; Aarsland, D.; Jones, E. Alzheimer's disease. Lancet, 2011, 377, 1019-1031.
4. Geerts, H. Mechanistic disease modeling as a useful tool for improving CNS drug research and development. Drug Dev. Res., 2011, 72, 66-73.
5. Decker, M. Hybrid molecules incorporating natural products: Applications in cancer therapy, neurodegenerative disorders and beyond. Curr. Med. Chem., 2011, 18, 1464-1475.
6. Mohamed, T.; Rao P., P.N. Alzheimer's disease: Emerging trends in small molecule therapies. Curr. Med. Chem., 2011, 18, 4299-4320.
7. Cavalli, A.; Bolognesi, M.L.; Minarini, A.; Rosini, M.; Tumiatti, V.; Recanatini, M.; Melchiorre, C. Multi-target-directed ligands to combat neurodegenerative diseases. J. Med. Chem., 2008, 51, 347-372.
8. Zhang, H.-Y. One-compound-multiple-targets strategy to combat Alzheimer's disease. FEBS Lett., 2005, 579, 5260-5264.
9. Tumiatti, V.; Minarini, A.; Bolognesi, M.L.; Milelli, A.; Rosini, M.; Melchiorre, C. Tacrine derivatives and Alzheimer's disease. Curr. Med. Chem., 2010, 17, 1825-1838.
10. León, R.; Garcia, A.G.; Maro-Contelles, J. Recent advances in the multitarget-directed ligands approach for the treatment of Alzheimer's disease. Med. Res. Rev., 2011, DOI: 10.1002/med.20248. Available from: Http://onlinelibrary.wiley.com/doi/10.1002/med.20248/pdf.
11. Bajda, M.; Guzior, N.; Ignasik, M.; Malawska, B. Multi-targetdirected ligands in Alzheimer's disease treatment. Curr. Med. Chem., 2011, 18, 4949-4975.
12. Paterson, I.; Anderson, E.A. The renaissance of natural products as drug candidates. Science, 2005, 310, 451-453.
13. Newman, D.J., Cragg, G.M. Natural products sources of new drugs over the last 25 years. J. Nat. Prod., 2007, 70, 461-477.
14. Williams, P.; Sorribas, A.; Howes, M.-J.R. Natural products as a source of Alzheimer's drug leads. Nat. Prod. Rep., 2011, 28, 48-77.
15. Joyner, P.M.; Cichewicz, R.H. Bringing natural products into the fold-exploring the therapeutic lead potential of secondary metabolites for the treatment of protein-misfolding-related neurodegenerative diseases. Nat. Prod. Rep., 2011, 28, 26-47.
16. Tsogoeva, S.B. Recent progress in the development of synthetic hybrids of natural or unnatural bioactive compounds for medicinal chemistry. Mini-Rev. Med. Chem., 2010, 10, 773-793.
17. Tietze, L. F.; Bell, H. P.; Chandrasekhar, S. Natural product hybrids as new leads for drug discovery. Angew. Chem. Int. Ed., 2003, 42, 3996-4028.
18. Pohanka, M. Alzheimer's disease and related neurodegenerative disorders: Implication and counteracting of melatonin. J. Appl. Biomed., 2011, 9, 185-196.
19. Srinivasan, V.; Spence, D.W.; Pandi-Perumal, S.R.; Brown, G.M.; Cardinali, D.P. Melatonin in mitochondrial dysfunction and related disorders. Int. J. Alzheimers Dis., 2011, 326320.
20. Ionov, M.; Burchell, V.; Klajnert, B.; Bryszewska, M.; Abramov, A.Y. Mechanism of neuroprotection of melatonin against betaamyloid neurotoxicity. Neuroscience, 2011, 180, 229-237.
21. Rodríguez-Franco, M.I.; Fernández-Bachiller, M.I.; Pérez, C.; Hernández-Ledesma, B.; Bartolomé, B. Novel tacrine-melatonin hybrids as dual-acting drugs for Alzheimer's disease, with improved acetylcholinesterase inhibitory and antioxidant properties. J. Med. Chem., 2006, 49, 459-462.
22. Inestrosa, N.C.; Alvarez, A.; Pérez, C.A.; Moreno, R.D.; Vicente, M.; Linker, C.; Casanueva, O.I.; Soto, C.; Garrido, J. Acetylcholinesterase accelerates assembly of amyloid-β-peptides into Alzheimer's fibrils: Possible role of the peripheral site of the enzyme. Neuron, 1996, 16, 881-891.
23. Fernández-Bachiller, M.I.; Pérez, C.; Campillo, N.E.; Páez, J.A.; González-Munoz, G.C.; Usán, P.; García-Palomero, E.; López, M.G.; Villarroya, M.; García, A.G.; Martínez, A.; Rodríguez-Franco, M.I. Tacrine-melatonin hybrids as multifunctional agents for Alzheimer's disease, with cholinergic, antioxidant, and neuroprotective properties. ChemMedChem, 2009, 4, 828-841.
24. Spuch, C.; Antequera, D.; Fernández-Bachiller, M.I.; Rodríguez-Franco, M.I.; Carro, E. A new tacrine-melatonin hybrid reduces amyloid burden and behavioral deficits in a mouse model of Alzheimer's disease. Neurotox. Res., 2010, 17, 421-431.
25. Fang, L.; Kraus, B.; Lehmann, J.; Heilmann, J.; Zhang, Y.; Decker, M. Design and synthesis of tacrine-ferulic acid hybrids as multipotent anti-Alzheimer drug candidates. Bioorg. Med. Chem. Lett., 2008, 18, 2905-2909.
26. Deng, Y.; Wang, N.; Zhu, Q.; Xie, X.; Duan, J.; Ding, A. Neuroprotective effects of ferulic acid against glutamate induced neurotoxicity in PC12 cells. Pharmacol. Clin. Chin. Materia Medica, 2008, 24, 32-34.
27. Zhang, Y.; Yu, L.; Ma, R.; Zeng, R.; Fang, J.; Zhang, X.; Yu, T. Potent protective effect of ferulic acid on glutamate-induced neurotoxicity in adult mice. Chin. J. Neuromed., 2008, 7, 596-599.
28. Lupp, A.; Appenroth, D.; Fang, L.; Decker, M.; Lehmann, J.; Fleck, C. Tacrine-NO and tacrine-ferulic acid hybrid molecules as new anti-Alzheimer agents: Hepatotoxicity and influence on the cytochrome P450 system in comparison to tacrine. Arzneim.-Forsch., 2010, 60, 229-237.
29. Fleck, C.; Appenroth, D.; Fang, L.; Schott, Y.; Lehmann, J.; Decker, M. Investigation into the in vivo effects of five newly synthesized tacrine/ferulic acid and ββcarboline derivatives on scopolamine-induced cognitive impairments in rats using radial maze experiments. Arzneim.-Forsch., 2010, 60, 299-307.
30. Zhang, H.; Mak, S.; Cui, W.; Han, R.; Hu, S.; Ye, M.; Pi, R.; Han, Y. Tacrine(2)-ferulic acid, a novel multifunctional dimer, attenuates 6-hydroxydopamine-induced apoptosis in PC12 cells by activating Akt pathway. Neurochem. Int., 2011, 59, 981-988.
31. Chen, X.; Zenger, K.; Lupp, A.; Kling, B.; Heilmann, J.; Fleck, C.; Kraus, B.; Decker, M. Tacrine-silibinin codrug shows neuro-and hepatoprotective effects in vitro and pro-cognitive and hepatoprotective effects in vivo. J. Med. Chem., 2012, 55, 5231-5242.
32. Abenavoli, L.; Capasso, R.; Milic, N.; Capasso, F. Milk thistle in liver diseases: Past, present, future. Phytother. Res., 2010, 24, 1423-1432.
33. Gazák, R.; Svobodová, A.; Psotová, J.; Sedmera, P.; Prikrylová, V.; Walterová, D.; Kren, V. Oxidised derivatives of silybin and their antiradical and antioxidant activity. Bioorg. Med. Chem., 2004, 12, 5677-5687.
34. Trouillas, P.; Marsal, P.; Svobodová, A.; Vostálová, J.; Gazák, R.; Hrbá, J.; Sedmera, P.; Kren, V.; Lazzaroni, R.; Duroux, J.; Walterová, D. Mechanism of the antioxidant action of silybin and 2,3-dehydrosilybin flavonolignans: A joint experimental and theoretical study. J. Phys. Chem. A, 2008, 112, 1054-1063.
35. Fu, H.; Lin, M.; Muroya, Y.; Hata, K.; Katsumura, Y.; Yokoya, A.; Shikazono, N.; Hatano, Y. Free radical scavenging reactions and antioxidant activities of silybin: Mechanistic aspects and pulse radiolytic studies. Free Radical Res., 2009, 43, 887-897.
36. Nencinia, C.; Giorgia, G.; Micheli, L. Protective effect of silymarin on oxidative stress in rat brain. Phytomedicine, 2007, 14, 129-135.
37. Yang, L. X.; Huang, K.X.; Li, H.B.; Gong, J.X.; Wang, F.; Feng, Y.B.; Tao, Q.F.; Wu, Y.H.; Li, X.K.; Wu, X.M.; Zeng, S.; Spencer, S.; Zhao, Y.; Qu, J. Design, synthesis, and examination of neuron protective properties of alkenylated and amidated dehydro-silybin derivatives. J. Med. Chem., 2009, 52, 7732-7752.
38. Loguericio, C.; Festi, D. Silybin and the liver: From basic research to clinical practice. World J. Gastroenterol., 2011, 17, 2288-2301 and references therein.
39. Pocernich, C.B.; Lange, M.L.B.; Sultana, R.; Butterfield, D.A. Nutritional approaches to modulate oxidative stress in Alzheimer's disease. Curr. Alzheimers Res., 2011, 8, 452-469.
40. Ono, K.; Hirohata, M.; Yamada, M. Alpha-lipoic acid exhibits antiamyloidogenicity for beta-amyloid fibrils in vitro. Biochem. Biophys. Res. Commun., 2006, 341,1046-1052.
41. Holmquist, L.; Stuchbury, G.; Berbaum, K.; Muscat, S.; Young, S.; Hager, K.; Engel, J.; Munch, G. Lipoic acid as a novel treatment for Alzheimer's disease and related dementias. Pharmacol. Ther., 2007, 113, 145-164.
42. Rosini, M.; Andrisano, V.; Bartolini, M.; Bolognesi, M.L.; Hrelia, P.; Minarini, A.; Tarozzi, A.; Melchiorre, C. Rational approach to discover multipotent anti-Alzheimer drugs. J. Med. Chem., 2005, 48, 360-363.
43. Decker, M.; Krauth, F.; Lehmann, J. Novel tricyclic quinazolinimines and related tetracyclic nitrogen bridgehead compounds as cholinesterase inhibitors with selectivity towards butyrylcholinesterase. Bioorg. Med. Chem., 2006, 14, 1966-1977.
44. Decker, M.; Kraus, B.; Heilmann, J. Design, synthesis and pharmacological evaluation of hybrid molecules out of quinazoliminines and lipoic acid lead to highly potent and selective butyrylcholinesterase inhibitors with antioxidant properties. Bioorg. Med. Chem., 2008, 16, 4252-4261.
45. Bongarzone, S.; Tran, H.N.A.; Cavalli, A.; Roberti, M.; Rosini, M.; Carloni, P.; Legname, G.; Bolognesi, M.L. Hybrid lipoic acid derivatives to attack prion disease on multiple fronts. ChemMed-Chem, 2011, 6, 601-605.
46. Koufaki, M.; Kiziridi, C.; Nikoloudaki, F.; Alexis, M.N. Design and synthesis of 1,2-dithiolane derivatives and evaluation of their neuroprotective activity. Bioorg. Med. Chem. Lett., 2007, 17, 4223-4227.
47. Koufaki, M.; Kiziridi, C.; Alexi, X.; Alexis, M.N. Design and synthesis of novel neuroprotective 1,2-dithiolane/chroman hybrids. Bioorg. Med. Chem., 2009, 17, 6432-6441.
48. Koufaki, M.; Theodorou, E.; Galaris, D.; Nousis, L.; Katasanou, E.S.; Alexis, M.N. Chroman/catechol hybrids: Synthesis and evaluation of their activity against oxidative stress induced cellular damage. J. Med. Chem., 2006, 49, 300-306.
49. Koufaki, M.; Theodorou, E.; Alexi, X.; Alexis, M.N. Synthesis of a second generation chroman/catechol hybrids and evaluation of their activity in protecting neuronal cells from oxidative stress-induced cell death. Bioorg. Med. Chem., 2010, 18, 3898-3909.
50. Koufaki, M.; Tsatsaroni, A.; Alexi, X.; Guerrand, H.; Zerva, S.; Alexis, M.N. Isoxazole substituted chromans against oxidative stress-induced neuronal damage. Bioorg. Med. Chem., 2011, 19, 4841-4850.
51. Cavalli, A.; Bolognesi, M.L.; Capsoni, S.; Andrisano, V.; Bartolini, M.; Margotti, E.; Cattaneo, A.; Recanatini, M.; Melchiorre, C. A small molecule targeting the multifactorial nature of Alzheimer's disease. Angew. Chem. Int. Ed., 2007, 46, 3689-3692.
52. Bolognesi, M.L.; Banzi, R.; Bartolini, M.; Cavalli, A.; Tarozzi, A.; Andrisano, V.; Minartini, A.; Rosini, M.; Tumiatti, V.; Bergamini, C.; Fato, R.; Lenaz, G.; Hrelia, P.; Cattaneo, A.; Recanatini, M.; Melchiorre, C. Novel class of quinone-bearing polyamines as multi-target-directed ligands to combat Alzheimer's disease. J. Med. Chem., 2007, 50, 4882-4897.
53. Bolognesi, M.L.; Bartolini, M.; Rosini, M.; Andrisano, V.; Melchiorre, C. Structure-activity relationships of memoquin: Influence of the chain chirality in the multi-target mechanism of action. Bioorg. Med. Chem. Lett., 2009, 19, 4312-4315.
54. Mancini, F.; Bolognesi, M.L.; Melchiorre, C.; Andrisano, V. Investigation of the photostability properties of memoquin, a quinone derivative for the treatment of Alzheimer's disease. J. Pharm. Biomed. Anal., 2009, 50, 164-170.
55. Bolognesi, M.L.; Cavalli, A.; Melchiorre, C. Memoquin: A multitarget directed ligand as an innovation therapeutic opportunity for Alzheimer's disease. Neurother., 2009, 6, 152-162.
56. Bolognesi, M.L.; Chiriano, G.; Bartolini, M.; Mancini, F.; Bottegoni, G.; Maestri, V.; Czvitkovich, S.; Windisch, M.; Cavalli, A.; Minarini, A.; Rosini, M.; Tumiatti, V.; Andrisano, V.; Melchiorre, C. Synthesis of monomeric derivatives to probe memoquin's bivalent interactions. J. Med. Chem., 2011, 54, 8299-8304.
57. Bolognesi, M.L.; Cavalli, A.; Bergamini, C.; Fato, R.; Lenaz, G.; Rosini, M.; Bartolini, M.; Andrisano, V.; Melchiorre, C. Toward a rational design of multitarget-directed antioxidants: Merging memoquin and lipoic acid molecular frameworks. J. Med. Chem., 2009, 52, 7883-7886.
58. Rosini, M.; Simoni, E.; Bartolini, M.; Tarozzi, A.; Matera, R.; Milelli, A.; Hrelia, P.; Andrisano, V.; Bolognesi, M.L.; Melchiorre, C. Exploiting the lipoic acid structure in the search for novel multitarget ligands against Alzheimer's disease. Eur. J. Med. Chem., 2011, 46, 5435-5442.
59. Kulkarni, S.K.; Dhir, A. Berberine: A plant alkaloid with therapeutic potential for central nervous system disorders. Phytother. Res., 2010, 24, 317-324.
60. Ji, H.-F.; Shen, L. Berberine: A potential multipotent natural product to combat Alzheimer's disease. Molecules, 2011, 16, 6732-6740.
61. Jung, H.A.; Min, B.-S.; Yokozawa, T.; Lee, J.-H.; Kim, Y.S.; Choi, J.S. Anti-Alzheimer and antioxidant activities of Coptidis Rhizoma alkaloids. Biol. Pharm. Bull., 2009, 32, 1433-1438.
62. Jiang, H.; Wang, X.; Huang, L.; Luo, Z.; Su, T.; Ding, K.; Li, H. Benzenediol-berberine hybrids: Multifunctional agents for Alzheimer's disease. Bioorg. Med. Chem., 2011, 19, 7228-7235.
63. Huang, L.; Luo, Z.; He, F.; Lu, J.; Li, X. Synthesis and biological evaluation of a new series of berberine derivatives as dual inhibitors of acetylcholinesterase and butyrylcholinesterase. Bioorg. Med. Chem., 2010, 18, 4475-4484.
64. Shi, A.; Huang, L.; Lu, C.; He, F.; Li, X. Synthesis, biological evaluation and molecular modeling of novel triazole-contating berberine derivatives as acetylcholinesterase and-amyloid aggregation inhibitors. Bioorg. Med. Chem., 2011, 19, 2298-2305.
65. Hamaguchi, T.; Ono, K.; Yamada, M. Curcumin and Alzheimer's disease. CNS Neurosci. Ther., 2010, 16, 285-297.
66. Kim, J.; Lee, H.J.; Lee, K.W. Naturally occurring phytochemicals for the prevention of Alzheimer's disease. J. Neurochem., 2010, 112, 1415-1430.
67. Lenhart, J.A.; Ling, X.; Gandhi, R.; Guo, T.L.; Gerk, P.M.; Brunzell, D.H.; Zhang, S. "Clicked" bivalent ligands containing curcumin and cholesterol as multifunctional A-oligomerization inhibitors: Design, synthesis, and biological characterization. J. Med. Chem., 2010, 53, 6198-6209.
68. Liu, K.; Guo, T.L.; Chojnackinta J.; Lee, H.-G.; Wang, X.; Sandra, L.S.; Rao, W.; Zhu, X.; Zhang, S. Bivalent ligand containing curcumin and cholesterol as a fluorescence probe for A-plagues in Alzheimer's disease. ACS Chem. Neurosci., 2012, 3, 141-146.
69. Dolai, S.; Shi, W.; Corbo, C.; Sun, C.; Averick, S.; Obeysekera, D.; Farid, M.; Alonso, A.; Banerjee, P.; Raja, K. "Clicked" sugarcurcumin conjugate: Modulator of amyloid-and tau peptide aggregation at ultralow concentrations. ACS Chem. Neurosci., 2011, 2, 694-699.
70. Zhou, H.; Beevers, C.S.; Huang, S. The targets of curcumin. Curr. Drug Targets, 2011, 12, 322-347.
71. Chen, S.-Y.; Chen, Y.; Li, Y.-P.; Chen, S.H.; Tan, J.-H.; Ou, T.-M.; Gu, L.-Q.; Huang, Z.-S. Design, synthesis, and biological evaluation of curcumin analogues as multifunctional agents for the treatment of Alzheimer's disease. Bioorg. Med. Chem., 2011, 19, 5596-5604.
72. Simoni, E.; Bergamino, C.; Fato, R.; Tarozzi, A.; Bains, S.; Motterlini, R.; Cavalli, A.; Bolognesi, M.L.; Minarini, A.; Hrelia, P.; Lenaz, G.; Rosini, M.; Melchiorre, C. Polyamine conjugation of curcumin analogues toward the discovery of mitochondria-directed neuroprotective agents. J. Med. Chem., 2010, 53, 7264-7268.
73. Jang, M.H.; Piao, X.L.; Kim, J.M.; Kwon, S.W.; Park, J.H. Inhibition of cholinesterase and amyloid-aggregation by resveratrol oligomers from Vitis amurensis. Phytother. Res., 2008, 22, 544-549.
74. Chung, I.-M.; Yeo, M.-A; Kim, S.-J.; Moon, H.-I. Neuroprotective effects of resveratrol derivatives from the roots of Vitis thunbergii var. sinuate against glutamate-induced neurotoxicity in primary cultured rat cortical cells. Hum. Exp. Toxicol., 2011, 30, 1404-1408.
75. Olnonen, P.P.; Jokela, J.K.; Hatakka, A.I.; Vuorela, P.M. Linarin, a selective acetylcholinesterase inhibitor from Mentha arvensis. Fitoterapia, 2006, 77, 429-434.
76. Fan, P.; Hay, A.-E.; Marston, A.; Hostettmann, K. Acetylcholinesterase- inhibitory activity of linarin from Buddleja davidii, structure-activity relationships of related flavonoids, and chemical investigation of Buddleja nitida. Pharm. Biol., 2008, 46, 596-601.
77. Lou, H.; Fan, P.; Perez, R.G.; Lou, H. Neuroprotective effects of linarin through activiation of the PI3K/Akt pathway in amyloid-induced neuronal cell death. Bioorg. Med. Chem., 2011, 19, 4021-4027.
78. Camps, P.; El Achab, R.; Morral, J.; Muñoz-Torrero, D.; Badia, A.; Baños, J.E.; Vivas, N.M.; Barril, X.; Orozco, M.; Luque, F.J. New Tacrine-Huperzine A hybrids (Huprines): Highly potent tightbinding acetylcholinesterase inhibitors of interest for the treatment of Alzheimer's disease. J. Med. Chem., 2000, 43, 4657-4666.
79. Viayna, E.; Gómez, T.; Galdeano, C.; Ramírez, L.; Ratia, M.; Badia, A.; Clos, M.V.; Verdaguer, E.; Junyent, F.; Camins, A.; Pallàs, M.; Bartolini, M.; Mancini, F.; Andrisano, V.; Arce, M.P.; Rodríguez-Franco, M.I.; Bidon-Chanal, A.; Luque, F.J.; Camps, P.; Muñoz-Torrero, D. Novel huprine derivatives with inhibitory activity toward-amyloid aggregation and formation as diseasemodifying anti-Alzheimer drug candidates. ChemMedChem, 2010, 5, 1855-1870.
80. Zheng, X.; Zhang, Z.; Chou, G.; Wu, T.; Cheng, X.; Wang, C.; Wang, Z. Acetylcholinesterase inhibitive activity-guided isolation of two new alkaloids from seed of peganum nigellastrum Bunge by an in vitro TLC-bioautographic assay. Arch. Pharm. Res., 2009, 32, 1245-1251.
81. Herraiz, T.; González, D.; Ancín-Azpilicueta, C.; Arán, V.J.; Guillén, H. βCarboline alkaloids in Peganum harmala and inhibition of human monoamine oxidase (MAO). Food Chem. Toxicol., 2010, 48, 839-845.
82. Reniers, J.; Robert, S.; Frederick, R.; Masereel, B.; Vincent, S.; Wouters, J. Synthesis and evaluation of βcarboline derivatives as potential monoamine oxidase inhibitors. Bioorg. Med. Chem., 2011, 19, 134-144.
83. Rook, Y.; Schmidtke, K.-U.; Gaube, F.; Schepmann, D.; Wünsch, B.; Heilmann, J.; Lehmann, J.; Winckler, T. Bivalent βcarbolines as potential multitarget anti-Alzheimer agents. J. Med. Chem., 2010, 53, 3611-3617.
84. Mensch, J.; Jaroskova L, L.; Sanderson, W.; Melis, A.; Mackie, C.; Verreck, G.; Brewster, M.E.; Augustijins, P. Application of PAMPA-models to predict BBB permeability including efflux ration, plasma protein binding and physicochemical parameters. Int. J. Pharm., 2010, 395, 182-197.
85. Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliver. Rev., 2001, 46, 3-26.
86. Mensch, J.; Melis, A.; Mackie, C.; Verreck, G.; Brewster, M.E.; Augustijins, P. Evaluation of various PAMPA models to identify the most discriminating method for the prediction of BBB permeability. Eur. J. Pharm. Biopharm., 2010, 74, 495-502.
87. Di, L.; Kerns, E.H.; Fan, K.; McConell, O.J.; Carter, G.T. High throughput artificial membrane permeability assay for blood-brain barrier. Eur. J. Med. Chem., 2003, 38, 223-232.
88. Nakagawa-Goto, K.; Yamada, K.; Nakamura, S.; Chen, T.-H.; Chiang, P.-C.; Bastow, K.F.; Wang, S.-C.; Spohn, B.; Hung, M.-C.; Lee, F.-Y.; Lee, F.-C.; Lee, K.-H. Antitumor agents. 258. Syntheses and evaluation of dietary antioxidant-taxoid conjugates as novel cytotoxic agents. Bioorg. Med. Chem. Lett., 2007, 17, 5204-5209.