Derivatives and Analogues of Resveratrol: Recent Advances in Structural Modification

Author(s): Qing-Shan Li, Yao Li, Girdhar Singh Deora*, Ban-Feng Ruan*

Journal Name: Mini-Reviews in Medicinal Chemistry

Volume 19 , Issue 10 , 2019

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Graphical Abstract:


Resveratrol is a non-flavonoid polyphenol containing a terpenoid backbone. It has been intensively studied because of its various promising biological properties, such as anticancer, antioxidant, antibacterial, neuroprotective and anti-inflammatory activities. However, the medicinal application of resveratrol is constrained by its poor bioavailability and stability. In the past decade, more attention has been focused on making resveratrol derivatives to improve its pharmacological activities and pharmacokinetics. This review covers the literature published over the past 15 years on synthetic analogues of resveratrol. The emphasis is on the chemistry of new compounds and relevant biological activities along with structure-activity relationship. This review aims to provide a scientific and reliable basis for the development of resveratrol-based clinical drugs.

Keywords: Resveratrol, antioxidants, anticancer, anti-inflammatory, structure-activity relationship, roots of white hellebore.

Huang, X-F.; Ruan, B-F.; Wang, X-T.; Xu, C.; Ge, H-M.; Zhu, H-L.; Tan, R-X. Synthesis and cytotoxic evaluation of a series of resveratrol derivatives modified in C2 position. Eur. J. Med. Chem., 2007, 42(2), 263-267.
Ruan, B-F.; Huang, X-F.; Ding, H.; Xu, C.; Ge, H-M.; Zhu, H-L.; Tan, R-X. Synthesis and cytotoxic evaluation of a series of resveratrol derivatives. Chem. Biodivers., 2006, 3(9), 975-981.
Biasutto, L.; Mattarei, A.; Azzolini, M.; La Spina, M.; Sassi, N.; Romio, M.; Paradisi, C.; Zoratti, M. Resveratrol derivatives as a pharmacological tool. Ann. N. Y. Acad. Sci., 2017, 1403(1), 27-37.
Kurgvietiene, L.; Staneviciene, I.; Mongirdiene, A.; Bernatoniene, J. Multiplicity of effects and health benefits of resveratrol. Medicina- Lithuania., 2016, 52(3), 148-155.
Gulcin, I. Antioxidant properties of resveratrol: A structure-activity insight. Innov. Food Sci. Emerg. Technol., 2010, 11(1), 210-218.
Bishayee, A.; Barnes, K.F.; Bhatia, D.; Darvesh, A.S.; Carroll, R.T. Resveratrol Suppresses Oxidative Stress and Inflammatory Response in Diethylnitrosamine-Initiated Rat Hepatocarcinogenesis. Cancer Prev. Res., 2010, 3(6), 753-763.
Ma, D.S.L.; Tan, L.T-H.; Chan, K-G.; Yap, W.H.; Pusparajah, P.; Chuah, L-H.; Ming, L.C.; Khan, T.M.; Lee, L-H.; Goh, B-H. Resveratrol-Potential Antibacterial Agent against Foodborne Pathogens. Front. Pharmacol., 2018, 9, 102.
Rauf, A.; Imran, M.; Butt, M.S.; Nadeem, M.; Peters, D.G.; Mubarak, M.S. Resveratrol as an anti-cancer agent: A review. Crit. Rev. Food Sci. Nutr., 2018, 58(9), 1428-1447.
Shi, D-D.; Dong, C.M.; Ho, L.C.; Lam, C.T.W.; Zhou, X-D.; Wu, E.X.; Zhou, Z-J.; Wang, X-M.; Zhang, Z-J. Resveratrol, a natural polyphenol, prevents chemotherapy-induced cognitive impairment: Involvement of cytokine modulation and neuroprotection. Neurobiol. Dis., 2018, 114, 164-173.
Hansen, H.C.; Chiacchia, F.S.; Patel, R.; Wong, N.C.W.; Khlebnikov, V.; Jankowska, R.; Patel, K.; Reddy, M.M. Stilbene analogs as inducers of apolipoprotein-I transcription. Eur. J. Med. Chem., 2010, 45(5), 2018-2023.
Sebai, H.; Sani, M.; Yacoubi, M.T.; Aouani, E.; Ghanem-Boughanmi, N.; Ben-Attia, M. Resveratrol, a red wine polyphenol, attenuates lipopolysaccharide-induced oxidative stress in rat liver. Ecotoxicol. Environ. Saf., 2010, 73(5), 1078-1083.
Pervaiz, S.; Holme, A.L. Resveratrol: Its biologic targets and functional activity. Antioxid. Redox Signal., 2009, 11(11), 2851-2897.
Fan, Y.; Liu, Y.; Gao, L.; Zhang, Y.; Yi, J. Improved chemical stability and cellular antioxidant activity of resveratrol in zein nanoparticle with bovine serum albumin-caffeic acid conjugate. Food Chem., 2018, 261, 283-291.
Fan, E.; Zhang, K.; Zhu, M.; Wang, Q. Obtaining resveratrol: From chemical synthesis to biotechnological production. Mini Rev. Org. Chem., 2010, 7(4), 272-281.
Ravera, S.; Capanni, C.; Tognotti, D.; Bottega, R.; Columbaro, M.; Dufour, C.; Cappelli, E.; Degan, P. Inhibition of metalloproteinase activity in FANCA is linked to altered oxygen metabolism. J. Cell. Physiol., 2015, 230(3), 603-609.
Mayhoub, A.S.; Marler, L.; Kondratyuk, T.P.; Park, E-J.; Pezzuto, J.M.; Cushman, M. Optimization of thiazole analogues of resveratrol for induction of NAD(P)H: Quinone reductase 1 (QR1). Bioorg. Med. Chem., 2012, 20(24), 7030-7039.
Mayhoub, A.S.; Marler, L.; Kondratyuk, T.P.; Park, E-J.; Pezzuto, J.M.; Cushman, M. Optimizing thiadiazole analogues of resveratrol versus three chemopreventive targets. Bioorg. Med. Chem., 2012, 20(1), 510-520.
He, S.; Yan, X. From resveratrol to its derivatives: New sources of natural antioxidant. Curr. Med. Chem., 2013, 20(8), 1005-1017.
Csuk, R.; Albert, S.; Siewert, B. Synthesis and radical scavenging activities of resveratrol analogs. Archiv der Pharmazie, 2013, 346(7), 504-510.
Lee, S.K.; Nam, K.A.; Hoe, Y.H.; Min, H.Y.; Kim, E.Y.; Ko, H.; Song, S.; Lee, T.; Kim, S. Synthesis and evaluation of cytotoxicity of stilbene analogues. Arch. Pharm. Res., 2003, 26(4), 253-257.
Stivala, L.A.; Savio, M.; Carafoli, F.; Perucca, P.; Bianchi, L.; Maga, G.; Forti, L.; Pagnoni, U.M.; Albini, A.; Prosperi, E.; Vannini, V. Specific structural determinants are responsible for the antioxidant activity and the cell cycle effects of resveratrol. J. Biol. Chem., 2001, 276(25), 22586-22594.
Ferrero-Miliani, L.; Nielsen, O.H.; Andersen, P.S.; Girardin, S.E. Chronic inflammation: Importance of NOD2 and NALP3 in interleukin-1 beta generation. Clin. Experiment. Immunol., 2007, 147(2), 227-235.
Park, J.; Min, J-S.; Kim, B.; Chae, U-B.; Yun, J.W.; Choi, M-S.; Kong, I-K.; Chang, K-T.; Lee, D-S. Mitochondrial ROS govern the LPS-induced pro-inflammatory response in microglia cells by regulating MAPK and NF-kappa B pathways. Neurosci. Lett., 2015, 584, 191-196.
Miguel, R.N.; Wong, J.; Westoll, J.F.; Brooks, H.J.; O’Neill, L.A.J.; Gay, N.J.; Bryant, C.E.; Monie, T.P. A dimer of the toll-like receptor 4 cytoplasmic domain provides a specific scaffold for the recruitment of signalling adaptor proteins. PLoS One, 2007, 2(8)
Feroze, U.; Kalantar-Zadeh, K.; Sterling, K.A.; Molnar, M.Z.; Noori, N.; Benner, D.; Shah, V.; Dwivedi, R.; Becker, K.; Kovesdy, C.P.; Raj, D.S. Examining associations of circulating endotoxin with nutritional status, inflammation, and mortality in hemodialysis patients. J. Ren. Nutr., 2012, 22(3), 317-326.
Simmons, D.L. What makes a good anti-inflammatory drug target? Drug Discov. Today, 2006, 11(5-6), 210-219.
Zordok, W.A. Synthesis, spectroscopic, structural characterization, thermal analysis, kinetics, biological evaluation of non-steroidal anti-inflammatory drug diclofenac zirconium (IV) solvates (L) (L = H2O, DMF, Py and Et3N). J. Mol. Struct., 2018, 1166, 270-285.
Buttner, A.; Thieme, D. Side effects of anabolic androgenic steroids: Pathological findings and structure-activity relationships. Handb. Exp. Pharmacol., 2010, 195, 459-484.
Rainsford, K.D. Cardiovascular adverse reactions from NSAIDs are more than COX-2 inhibition alone ‘The gun must be loaded for COX-2 inhibitors to pull the trigger and cause cardiovascular toxicity’. Rheumatology, 2010, 49(5), 834-836.
Minamiyama, Y.; Takemura, S.; Nishino, Y.; Okada, S. Organic nitrate tolerance is induced by degradation of some cytochrome P450 isoforms. Redox Report: Communicat. Free Radical Res., 2002, 7(5), 339-342.
Basudhar, D.; Bharadwaj, G.; Cheng, R.Y.; Jain, S.; Shi, S.; Heinecke, J.L.; Holland, R.J.; Ridnour, L.A.; Caceres, V.M.; Spadari-Bratfisch, R.C.; Paolocci, N.; Velazquez-Martinez, C.A.; Wink, D.A.; Miranda, K.M. Synthesis and chemical and biological comparison of nitroxyl- and nitric oxide-releasing diazeniumdiolate-based aspirin derivatives. J. Med. Chem., 2013, 56(20), 7804-7820.
Ruan, B.F.; Ge, W.W.; Cheng, H.J.; Xu, H.J.; Li, Q.S.; Liu, X.H. Resveratrol-based cinnamic ester hybrids: synthesis, characterization, and anti-inflammatory activity. J. Enzyme Inhib. Med. Chem., 2017, 32(1), 1282-1290.
Pan, J.; Xu, T.; Xu, F.; Zhang, Y.; Liu, Z.; Chen, W.; Fu, W.; Dai, Y.; Zhao, Y.; Feng, J.; Liang, G. Development of resveratrol-curcumin hybrids as potential therapeutic agents for inflammatory lung diseases. Eur. J. Med. Chem., 2017, 125, 478-491.
Lanzilli, G.; Cottarelli, A.; Nicotera, G.; Guida, S.; Ravagnan, G.; Fuggetta, M.P. Anti-inflammatory effect of resveratrol and polydatin by in vitro IL-17 modulation. Inflammation, 2012, 35(1), 240-248.
Trombetta, D.; Giofre, S.V.; Tomaino, A.; Raciti, R.; Saija, A.; Cristani, M.; Romeo, R.; Siracusa, L.; Ruberto, G. Selective COX-2 Inhibitory Properties of Dihydrostilbenes from Liquorice Leaves-In Vitro Assays and Structure/Activity Relationship Study. Nat. Prod. Commun., 2014, 9(12), 1761-1764.
Choo, Q-Y.; Yeo, S.C.M.; Ho, P.C.; Tanaka, Y.; Lin, H-S. Pterostilbene surpassed resveratrol for anti-inflammatory application: Potency consideration and pharmacokinetics perspective. J. Funct. Foods, 2014, 11, 352-362.
Lin, Y.J.; Ding, Y.; Wu, J.; Ning, B.T. Pterostilbene as treatment for severe acute pancreatitis. Genet. Mol. Res., 2016, 15(3)
Ma, P.; Ding, Y.S.; Xuan, L.L.; Wang, L.; Shi, J.; Bai, J.Y.; Lin, M.B.; Zheng, W.S.; Hou, Q. Anti-inflammatory effect of a resveratrol derivative 3,4,5-trimethoxy-4′,5′-dihydroxy-trans-stilbene (WL-09-5) via ROS-mediated NF-kappaB pathway. J. Asian Nat. Prod. Res., 2016, 18(10), 1004-1013.
Feddal, S.; Bouakouk, Z.; Meyar, M.; Kellou-Tairi, S. Atomic 3D-QSAR study based on pharmacophore modeling of resveratrol derivatives as selective COX-2 inhibitors. Med. Chem. Res., 2017, 26(6), 1259-1267.
Peng, W.; Ma, Y-Y.; Zhang, K.; Zhou, A-Y.; Zhang, Y.; Wang, H.; Du, Z.; Zhao, D-G. Synthesis and Biological Evaluation of Novel Resveratrol-NSAID Derivatives as Anti-inflammatory Agents. Chem. Pharm. Bull., 2016, 64(6), 609-615.
Choi, R.J.; Chun, J.; Khan, S.; Kim, Y.S. Desoxyrhapontigenin, a potent anti-inflammatory phytochemical, inhibits LPS-induced inflammatory responses via suppressing NF-kappaB and MAPK pathways in RAW 264.7 cells. Int. Immunopharmacol., 2014, 18, 182-190.
Park, E-J.; Min, H-Y.; Chung, H-J.; Ahn, Y-H.; Pyee, J-H.; Lee, S.K. Pinosylvin Suppresses LPS-stimulated inducible nitric oxide synthase expression via the MyD88-independent, but TRIF-dependent downregulation of IRF-3 signaling pathway in mouse macrophage cells. Cell. Physiol. Biochem., 2011, 27(3-4), 353-362.
Wang, W.; Sun, L.; Zhang, P.; Song, J.; Liu, W. An anti-inflammatory cell-free collagen/resveratrol scaffold for repairing osteochondral defects in rabbits. Acta Biomater., 2014, 10(12), 4983-4995.
Antus, C.; Radnai, B.; Dombovari, P.; Fonai, F.; Avar, P.; Matyus, P.; Racz, B.; Sumegi, B.; Veres, B. Anti-inflammatory effects of a triple-bond resveratrol analog: structure and function relationship. Eur. J. Pharmacol., 2015, 748, 61-67.
Kim, M.H.; Son, Y.J.; Lee, S.Y.; Yang, W.S.; Yi, Y.S.; Yoon, D.H.; Yang, Y.; Kim, S.H.; Lee, D.; Rhee, M.H.; Kang, H.; Kim, T.W.; Sung, G.H.; Cho, J.Y. JAK2-targeted anti-inflammatory effect of a resveratrol derivative 2,4-dihydroxy-N-(4-hydroxyphenyl)-benzamide. Biochem. Pharmacol., 2013, 86(12), 1747-1761.
Lin, S.J.; Tsai, W.J.; Chiou, W.F.; Yang, T.H.; Yang, L.M. Selective COX-2 inhibitors. Part 2: Synthesis and biological evaluation of 4-benzylideneamino- and 4-phenyliminomethyl-benzenesulfonamides. Bioorg. Med. Chem., 2008, 16(5), 2697-2706.
Chen, W.; Ge, X.; Xu, F.; Zhang, Y.; Liu, Z.; Pan, J.; Song, J.; Dai, Y.; Zhou, J.; Feng, J.; Liang, G. Design, synthesis and biological evaluation of paralleled Aza resveratrol-chalcone compounds as potential anti-inflammatory agents for the treatment of acute lung injury. Bioorg. Med. Chem. Lett., 2015, 25(15), 2998-3004.
Chen, L.Q.; Shen, X.F.; Hu, B.Y.; Lin, Y.; Igbe, I.; Zhang, C.G.; Zhang, G.L.; Yuan, X.H.; Wang, F. Nitric oxide production inhibition and mechanism of phenanthrene analogs in lipopolysaccharide-stimulated RAW264.7 macrophages. Bioorg. Med. Chem. Lett., 2016, 26(10), 2521-2525.
Chang, C.I.; Chien, W.C.; Huang, K.X.; Hsu, J.L. Anti-Inflammatory effects of vitisinol a and four other oligostilbenes from ampelopsis brevipedunculata var. hancei. Molecules, 2017, 22(7)
Zhong, C.; Liu, X.H.; Chang, J.; Yu, J.M.; Sun, X. Inhibitory effect of resveratrol dimerized derivatives on nitric oxide production in lipopolysaccharide-induced RAW 264.7 cells. Bioorg. Med. Chem. Lett., 2013, 23(15), 4413-4418.
Chen, G.; Shan, W.; Wu, Y.L.; Ren, L.X.; Dong, I.H.; Ji, Z.Z. Synthesis and anti-inflammatory activity of resveratrol analogs. Chem. Pharm. Bull., 2005, 53(12), 1587-1590.
Jadhav, S.B.; Fatema, S.; Patil, R.B.; Sangshetti, J.N.; Farooqui, M. Pyrido [1,2-a]pyrimidin-4-ones: Ligand-based Design, Synthesis, and Evaluation as an Anti-inflammatory Agent. J. Heterocycl. Chem., 2017, 54(6), 3299-3313.
Kim, M-H.; Shin, J-S.; Lee, K-T.; Lee, Y-S. Synthesis of Pyronyl Derivatives as Resveratrol Analogues and Their Inhibitory Effects on Nitric Oxide and PGE2Productions. Bull. Korean Chem. Soc., 2011, 32(1), 299-302.
Huang, C-C.; Tung, Y-T.; Cheng, K-C.; Wu, J-H. Phytocompounds from Vitis kelungensis stem prevent carbon tetrachloride-induced acute liver injury in mice. Food Chem., 2011, 125(2), 726-731.
Ha, D.T.; Long, P.T.; Hien, T.T.; Tuan, D.T.; An, N.T.T.; Khoi, N.M.; Van Oanh, H.; Hung, T.M. Anti-inflammatory effect of oligostilbenoids from Vitis heyneana in LPS-stimulated RAW 264.7 macrophages via suppressing the NF-kappaB activation. Chem. Cent. J., 2018, 12(1), 14.
Holohan, C.; Van Schaeybroeck, S.; Longley, D.B.; Johnston, P.G. Cancer drug resistance: An evolving paradigm. Nat. Rev. Cancer, 2013, 13(10), 714-726.
Jemal, A.; Bray, F.; Center, M.M.; Ferlay, J.; Ward, E.; Forman, D. Global Cancer Statistics. CA Cancer J. Clin., 2011, 61(2), 69-90.
Wu, W.; Liu, F.; Su, A.; Gong, Y.; Zhao, W.; Liu, Y.; Ye, H.; Zhu, J. The effect and mechanism of millepachine-disrupted spindle assembly in tumor cells. Anticancer Drugs, 2018, 29(5), 449-456.
Fresco, P.; Borges, F.; Diniz, C.; Marques, M.P.M. New insights on the anticancer properties of dietary polyphenols. Med. Res. Rev., 2006, 26(6), 747-766.
Khan, M.A.; Chen, H-c.; Wan, X-x.; Tania, M.; Xu, A-h.; Chen, F-z.; Zhang, D-z. Regulatory effects of resveratrol on antioxidant enzymes: A mechanism of growth inhibition and apoptosis induction in cancer cells (vol 35, pg 219, 2013). Mol. Cells, 2013, 35(4), 355-355.
Shi, Y.; Yang, S.; Troup, S.; Lu, X.; Callaghan, S.; Park, D.S.; Xing, Y.; Yang, X. Resveratrol induces apoptosis in breast cancer cells by E2F1-mediated up-regulation of ASPP1. Oncol. Rep., 2011, 25(6), 1713-1719.
Trung, L.Q.; Espinoza, J.L.; Takami, A.; Nakao, S. Resveratrol induces cell cycle arrest and apoptosis in malignant NK cells via JAK2/STAT3 pathway inhibition. PLoS One, 2013, 8(1)
Ko, A.; Han, S.Y.; Song, J. Regulatory network of ARF in cancer development. Mol. Cells, 2018, 41(5), 381-389.
Delmas, D.; Passilly-Degrace, P.; Jannin, B.; Cherkaoui Malki, M.; Latruffe, N. Resveratrol, a chemopreventive agent, disrupts the cell cycle control of human SW480 colorectal tumor cells. Int. J. Mol. Med., 2002, 10(2), 193-199.
Delmas, D.; Rebe, C.; Lacour, S.; Filomenko, R.; Athias, A.; Gambert, P.; Cherkaoui-Malki, M.; Jannin, B.; Dubrez-Daloz, L.; Latruffe, N.; Solary, E. Resveratrol-induced apoptosis is associated with Fas redistribution in the rafts and the formation of a death-inducing signaling complex in colon cancer cells. J. Biol. Chem., 2003, 278(42), 41482-41490.
Schneider, Y.; Vincent, F.; Duranton, B.; Badolo, L.; Gosse, F.; Bergmann, C.; Seiler, N.; Raul, F. Anti-proliferative effect of resveratrol, a natural component of grapes and wine, on human colonic cancer cells. Cancer Lett., 2000, 158, 85-91.
Athar, M.; Back, J.H.; Tang, X.; Kim, K.H.; Kopelovich, L.; Bickers, D.R.; Kim, A.L. Resveratrol: A review of preclinical studies for human cancer prevention. Toxicol. Appl. Pharmacol., 2007, 224(3), 274-283.
Bernhard, D.; Tinhofer, I.; Tonko, M.; Hubl, H.; Ausserlechner, M.J.; Greil, R.; Kofler, R.; Csordas, A. Resveratrol causes arrest in the S-phase prior to Fas-independent apoptosis in CEM-C7H2 acute leukemia cells. Cell Death Differ., 2000, 7(9), 834-842.
Helfinger, V.; Schroder, K. Redox control in cancer development and progression. Mol. Aspects Med., 2018.
Platella, C.; Guida, S.; Bonmassar, L.; Aquino, A.; Bonmassar, E.; Ravagnan, G.; Montesarchio, D.; Roviello, G.N.; Musumeci, D.; Fuggetta, M.P. Antitumour activity of resveratrol on human melanoma cells: A possible mechanism related to its interaction with malignant cell telomerase. Biochimica et biophysica acta, 2017, 1861(11 Pt A), 2843-2851.
Shankar, S.; Singh, G.; Srivastava, R.K. Chemoprevention by resveratrol: Molecular mechanisms and therapeutic potential. Front. Bioscience-Landmark, 2007, 12, 4839-4854.
Mikula-Pietrasik, J.; Sosinska, P.; Murias, M.; Wierzchowski, M.; Brewinska-Olchowik, M.; Piwocka, K.; Szpurek, D.; Ksiazek, K. High potency of a novel resveratrol derivative, 3,3′,4,4′-Tetrahydroxy-trans-stilbene, against ovarian cancer is associated with an oxidative stress-mediated imbalance between DNA damage accumulation and repair. Oxid. Med. Cell. Longev., 2015, 2015135691
Marel, A.K.; Lizard, G.; Izard, J.C.; Latruffe, N.; Delmas, D. Inhibitory effects of trans-resveratrol analogs molecules on the proliferation and the cell cycle progression of human colon tumoral cells. Mol. Nutr. Food Res., 2008, 52(5), 538-548.
Nivelle, L.; Hubert, J.; Courot, E.; Jeandet, P.; Aziz, A.; Nuzillard, J.M.; Renault, J.H.; Clement, C.; Martiny, L.; Delmas, D.; Tarpin, M. Anti-Cancer activity of resveratrol and derivatives produced by grapevine cell suspensions in a 14 L stirred bioreactor. Molecules, 2017, 22(3)
Zhu, Y.; Fu, J.; Shurlknight, K.L.; Soroka, D.N.; Hu, Y.; Chen, X.; Sang, S. Novel resveratrol-based aspirin prodrugs: Synthesis, metabolism, and anticancer activity. J. Med. Chem., 2015, 58(16), 6494-6506.
Kumar, D.; Raj, K.K.; Malhotra, S.V.; Rawat, D.S. Synthesis and anticancer activity evaluation of resveratrol–chalcone conjugates. MedChemComm, 2014, 5(4), 528.
Szekeres, T.; Saiko, P.; Fritzer-Szekeres, M.; Djavan, B.; Jager, W. Chemopreventive effects of resveratrol and resveratrol derivatives. Ann. N. Y. Acad. Sci., 2011, 1215, 89-95.
Chillemi, R.; Cardullo, N.; Greco, V.; Malfa, G.; Tomasello, B.; Sciuto, S. Synthesis of amphiphilic resveratrol lipoconjugates and evaluation of their anticancer activity towards neuroblastoma SH-SY5Y cell line. Eur. J. Med. Chem., 2015, 96, 467-481.
Madlener, S.; Saiko, P.; Vonach, C.; Viola, K.; Huttary, N.; Stark, N.; Popescu, R.; Gridling, M.; Vo, N.T.; Herbacek, I.; Davidovits, A.; Giessrigl, B.; Venkateswarlu, S.; Geleff, S.; Jager, W.; Grusch, M.; Kerjaschki, D.; Mikulits, W.; Golakoti, T.; Fritzer-Szekeres, M.; Szekeres, T.; Krupitza, G. Multifactorial anticancer effects of digalloyl-resveratrol encompass apoptosis, cell-cycle arrest, and inhibition of lymphendothelial gap formation in vitro. Br. J. Cancer, 2010, 102(9), 1361-1370.
Saiko, P.; Graser, G.; Giessrigl, B.; Steinmann, M.T.; Schuster, H.; Lackner, A.; Grusch, M.; Krupitza, G.; Jaeger, W.; Somepalli, V.; Golakoti, T.; Fritzer-Szekeres, M.; Szekeres, T. Digalloylresveratrol, a novel resveratrol analog inhibits the growth of human pancreatic cancer cells. Invest. New Drugs, 2013, 31(5), 1115-1124.
Moon, H.I.; Chung, I.M.; Jung, J.C.; Lim, E.; Lee, Y.; Oh, S.; Jung, M. The convenient synthesis and evaluation of the anticancer activities of new resveratrol derivatives. J. Enzyme Inhib. Med. Chem., 2009, 24(2), 328-336.
Yoo, K.M.; Kim, S.; Moon, B.K.; Kim, S.S.; Kim, K.T.; Kim, S.Y.; Choi, S.Y. Potent inhibitory effects of resveratrol derivatives on progression of prostate cancer cells. Archiv der Pharmazie, 2006, 339(5), 238-241.
de Freitas Silva, M.; Coelho, L.F.; Guirelli, I.M.; Pereira, R.M.; Ferreira-Silva, G.A.; Graravelli, G.Y.; Horvath, R.O.; Caixeta, E.S.; Ionta, M.; Viegas, C. Synthetic resveratrol-curcumin hybrid derivative inhibits mitosis progression in estrogen positive MCF-7 breast cancer cells. Toxicol. in vitro: An Intl. J. Pub. Associat. BIBRA, 2018, 50, 75-85.
Bernhaus, A.; Ozsvar-Kozma, M.; Saiko, P.; Jaschke, M.; Lackner, A.; Grusch, M.; Horvath, Z.; Madlener, S.; Krupitza, G.; Handler, N.; Erker, T.; Jaeger, W.; Fritzer-Szekeres, M.; Szekeres, T. Antitumor effects of KITC, a new resveratrol derivative, in AsPC-1 and BxPC-3 human pancreatic carcinoma cells. Invest. New Drugs, 2009, 27(5), 393-401.
Mikstacka, R.; Stefanski, T.; Rozanski, J. Tubulin-interactive stilbene derivatives as anticancer agents. Cell. Mol. Biol. Lett., 2013, 18(3), 368-397.
Simoni, D.; Roberti, M.; Invidiata, F.P.; Aiello, E.; Aiello, S.; Marchetti, P.; Baruchello, R.; Eleopra, M.; Di Cristina, A.; Grimaudo, S.; Gebbia, N.; Crosta, L.; Dieli, F.; Tolomeo, M. Stilbene-based anticancer agents: resveratrol analogues active toward HL60 leukemic cells with a non-specific phase mechanism. Bioorg. Med. Chem. Lett., 2006, 16(12), 3245-3248.
Aldawsari, F.S.; Aguayo-Ortiz, R.; Kapilashrami, K.; Yoo, J.; Luo, M.; Medina-Franco, J.L.; Velazquez-Martinez, C.A. Resveratrol-salicylate derivatives as selective DNMT3 inhibitors and anticancer agents. J. Enzyme Inhib. Med. Chem., 2016, 31(5), 695-703.
Cheah, F.K.; Leong, K.H.; Thomas, N.F.; Chin, H.K.; Ariffin, A.; Awang, K. Resveratrol analogue, (E)-N-(2-(4-methoxystyryl) phenyl) furan-2-carboxamide induces G2/M cell cycle arrest through the activation of p53-p21(CIP1/WAF1) in human colorectal HCT116 cells. Apoptosis: An Intl. J. Prog. Cell Death., 2018.
Okamoto, H.; Matsukawa, T.; Doi, S.; Tsunoda, T.; Sawata, Y.; Naemura, M.; Ohnuki, K.; Shirasawa, S.; Kotake, Y. A novel resveratrol derivative selectively inhibits the proliferation of colorectal cancer cells with KRAS mutation. Mol. Cell. Biochem., 2018, 442(1-2), 39-45.
Duan, Y.C.; Guan, Y.Y.; Zhai, X.Y.; Ding, L.N.; Qin, W.P.; Shen, D.D.; Liu, X.Q.; Sun, X.D.; Zheng, Y.C.; Liu, H.M. Discovery of resveratrol derivatives as novel LSD1 inhibitors: Design, synthesis and their biological evaluation. Eur. J. Med. Chem., 2017, 126, 246-258.
Belluti, F.; Fontana, G.; Dal Bo, L.; Carenini, N.; Giommarelli, C.; Zunino, F. Design, synthesis and anticancer activities of stilbene-coumarin hybrid compounds: Identification of novel proapoptotic agents. Bioorg. Med. Chem., 2010, 18(10), 3543-3550.
Jeong, S.H.; Song, I.S.; Kim, H.K.; Lee, S.R.; Song, S.; Suh, H.; Yoon, Y.G.; Yoo, Y.H.; Kim, N.; Rhee, B.D.; Ko, K.S.; Han, J. An analogue of resveratrol HS-1793 exhibits anticancer activity against MCF-7 cells via inhibition of mitochondrial biogenesis gene expression. Mol. Cells, 2012, 34(4), 357-365.
Jeong, S.H.; Jo, W.S.; Song, S.; Suh, H.; Seol, S.Y.; Leem, S.H.; Kwon, T.K.; Yoo, Y.H. A novel resveratrol derivative, HS1793, overcomes the resistance conferred by Bcl-2 in human leukemic U937 cells. Biochem. Pharmacol., 2009, 77(8), 1337-1347.
Srivastava, V.; Lee, H. Synthesis and bio-evaluation of novel quinolino-stilbene derivatives as potential anticancer agents. Bioorg. Med. Chem., 2015, 23(24), 7629-7640.
Sala, M.; Chimento, A.; Saturnino, C.; Gomez-Monterrey, I.M.; Musella, S.; Bertamino, A.; Milite, C.; Sinicropi, M.S.; Caruso, A.; Sirianni, R.; Tortorella, P.; Novellino, E.; Campiglia, P.; Pezzi, V. Synthesis and cytotoxic activity evaluation of 2,3-thiazolidin-4-one derivatives on human breast cancer cell lines. Bioorg. Med. Chem. Lett., 2013, 23(17), 4990-4995.
Vergara, D.; De Domenico, S.; Tinelli, A.; Stanca, E.; Del Mercato, L.L.; Giudetti, A.M.; Simeone, P.; Guazzelli, N.; Lessi, M.; Manzini, C.; Santino, A.; Bellina, F.; Maffia, M. Anticancer effects of novel resveratrol analogues on human ovarian cancer cells. Mol. Biosyst., 2017, 13(6), 1131-1141.
Bellina, F.; Guazzelli, N.; Lessi, M.; Manzini, C. Imidazole analogues of resveratrol: Synthesis and cancer cell growth evaluation. Tetrahedron, 2015, 71(15), 2298-2305.
Zukowski, P.; Maciejczyk, M.; Waszkiel, D. Sources of free radicals and oxidative stress in the oral cavity. Arch. Oral Biol., 2018, 92, 8-17.
Lagouge, M.; Larsson, N.G. The role of mitochondrial DNA mutations and free radicals in disease and ageing. J. Intern. Med., 2013, 273(6), 529-543.
Finkel, T. Radical medicine: Treating ageing to cure disease. Nat. Rev. Mol. Cell Biol., 2005, 6(12), 971-976.
Valko, M.; Leibfritz, D.; Moncol, J.; Cronin, M.T.D.; Mazur, M.; Telser, J. Free radicals and antioxidants in normal physiological functions and human disease. Int. J. Biochem. Cell Biol., 2007, 39, 44-84.
Yan, L-J. Positive oxidative stress in aging and aging-related disease tolerance. Redox Biol., 2014, 2, 165-169.
Lee, H.J.; Seo, J.W.; Lee, B.H.; Chung, K.H.; Chi, D.Y. Syntheses and radical scavenging activities of resveratrol derivatives. Bioorg. Med. Chem. Lett., 2004, 14(2), 463-466.
Amorati, R.; Lucarini, M.; Mugnaini, V.; Pedulli, G.F.; Roberti, M.; Pizzirani, D. Antioxidant activity of hydroxystilbene derivatives in homogeneous solution. J. Org. Chem., 2004, 69(21), 7101-7107.
Fukuhara, K.; Nakanishi, I.; Matsuoka, A.; Matsumura, T.; Honda, S.; Hayashi, M.; Ozawa, T.; Miyata, N.; Saito, S.; Ikota, N.; Okuda, H. Effect of methyl substitution on the antioxidative property and genotoxicity of resveratrol. Chem. Res. Toxicol., 2008, 21(2), 282-287.
Sueishi, Y.; Nii, R.; Kakizaki, N. Resveratrol analogues like piceatannol are potent antioxidants as quantitatively demonstrated through the high scavenging ability against reactive oxygen species and methyl radical. Bioorg. Med. Chem. Lett., 2017, 27(23), 5203-5206.
Bernini, R.; Barontini, M.; Spatafora, C. New lipophilic piceatannol derivatives exhibiting antioxidant activity prepared by aromatic hydroxylation with 2-iodoxybenzoic acid (IBX). Molecules, 2009, 14(11), 4669-4681.
Vlachogianni, I.C.; Fragopoulou, E.; Kostakis, I.K.; Antonopoulou, S. In vitro assessment of antioxidant activity of tyrosol, resveratrol and their acetylated derivatives. Food Chem., 2015, 177, 165-173.
Torres, P.; Poveda, A.; Jimenez-Barbero, J.; Ballesteros, A.; Plou, F.J. Regioselective lipase-catalyzed synthesis of 3-o-acyl derivatives of resveratrol and study of their antioxidant properties. J. Agric. Food Chem., 2010, 58(2), 807-813.
Kerem, Z.; Regev-Shoshani, G.; Flaishman, M.A.; Sivan, L. Resveratrol and two monomethylated stilbenes from Israeli Rumex bucephalophorus and their antioxidant potential. J. Nat. Prod., 2003, 66(9), 1270-1272.
Kucinska, M.; Piotrowska, H.; Luczak, M.W.; Mikula-Pietrasik, J.; Ksiazek, K.; Wozniak, M.; Wierzchowski, M.; Dudka, J.; Jager, W.; Murias, M. Effects of hydroxylated resveratrol analogs on oxidative stress and cancer cells death in human acute T cell leukemia cell line: Prooxidative potential of hydroxylated resveratrol analogs. Chemico-biol. Interact., 2014, 209, 96-110.
Jung, J.C.; Lim, E.; Lee, Y.; Kang, J.M.; Kim, H.; Jang, S.; Oh, S.; Jung, M. Synthesis of novel trans-stilbene derivatives and evaluation of their potent antioxidant and neuroprotective effects. Eur. J. Med. Chem., 2009, 44(8), 3166-3174.
Kerem, Z.; Bilkis, I.; Flaishman, M.A.; Sivan, U. Antioxidant activity and inhibition of alpha-glucosidase by trans-resveratrol, piceid, and a novel trans-stilbene from the roots of Israeli Rumex bucephalophorus L. J. Agric. Food Chem., 2006, 54(4), 1243-1247.
Kim, M.J.; Jung, S.H.; Moon, I.; Jun, J-G.; Lee, J.T. Syntheses of resveratrol analogues and evaluation of their antioxidant activity. Bull. Korean Chem. Soc., 2014, 35(5), 1549-1552.
Kotora, P.; Sersen, F.; Filo, J.; Loos, D.; Gregan, J.; Gregan, F. The scavenging of DPPH, galvinoxyl and ABTS radicals by imine analogs of resveratrol. Molecules, 2016, 21E127
Lu, J.; Li, C.; Chai, Y.F.; Yang, D.Y.; Sun, C.R. The antioxidant effect of imine resveratrol analogues. Bioorg. Med. Chem. Lett., 2012, 22(17), 5744-5747.
Semenov, A.V.; Balakireva, O.I.; Tarasova, I.V.; Burtasov, A.A.; Semenova, E.V.; Petrov, P.S.; Minaeva, O.V.; Pyataev, N.A. Synthesis, theoretical, and experimental study of radical scavenging activity of 3-pyridinol containing trans-resveratrol analogs. Med. Chem. Res., 2018, 27(4), 1298-1308.
Ficarra, S.; Tellone, E.; Pirolli, D.; Russo, A.; Barreca, D.; Galtieri, A.; Giardina, B.; Gavezzotti, P.; Riva, S.; De Rosa, M.C. Insights into the properties of the two enantiomers of trans-delta-viniferin, a resveratrol derivative: Antioxidant activity, biochemical and molecular modeling studies of its interactions with hemoglobin. Mol. BioSys., 2016, 12(4), 1276-1286.
Domazetovic, V.; Fontani, F.; Tanini, D.; D’Esopo, V.; Viglianisi, C.; Marcucci, G.; Panzella, L.; Napolitano, A.; Brandi, M.L.; Capperucci, A.; Menichetti, S.; Vincenzini, M.T.; Iantomasi, T. Protective role of benzoselenophene derivatives of resveratrol on the induced oxidative stress in intestinal myofibroblasts and osteocytes. Chemico-biol. Interact., 2017, 275, 13-21.
Tanini, D.; Panzella, L.; Amorati, R.; Capperucci, A.; Pizzo, E.; Napolitano, A.; Menichetti, S.; d’Ischia, M. Resveratrol-based benzoselenophenes with an enhanced antioxidant and chain breaking capacity. Org. Biomol. Chem., 2015, 13(20), 5757-5764.
Manikova, D.; Sestakova, Z.; Rendekova, J.; Vlasakova, D.; Lukacova, P.; Paegle, E.; Arsenyan, P.; Chovanec, M. Resveratrol-Inspired Benzo[b]selenophenes act as anti-oxidants in yeast. Molecules, 2018, 23(2)
Matos, M.J.; Mura, F.; Vazquez-Rodriguez, S.; Borges, F.; Santana, L.; Uriarte, E.; Olea-Azar, C. Study of coumarin-resveratrol hybrids as potent antioxidant compounds. Molecules, 2015, 20(2), 3290-3308.
Ding, D.J.; Cao, X.Y.; Dai, F.; Li, X.Z.; Liu, G.Y.; Lin, D.; Fu, X.; Jin, X.L.; Zhou, B. Synthesis and antioxidant activity of hydroxylated phenanthrenes as cis-restricted resveratrol analogues. Food Chem., 2012, 135(3), 1011-1019.
Bao, L.; Ma, X.; Song, X.; Wang, M.; Liu, H. Two new resveratrol tetramers isolated from cayratia japonica (THUNB.) GAGN. with strong inhibitory activity on fatty acid synthase and antioxidant activity. Chem. Biodivers., 2010, 7(12), 2931-2940.
Razavi, S.F.; Khoobi, M.; Nadri, H.; Sakhteman, A.; Moradi, A.; Emami, S.; Foroumadi, A.; Shafiee, A. Synthesis and evaluation of 4-substituted coumarins as novel acetylcholinesterase inhibitors. Eur. J. Med. Chem., 2013, 64, 252-259.
Crews, L.; Masliah, E. Molecular mechanisms of neurodegeneration in Alzheimer’s disease. Hum. Mol. Genet., 2010, 19, R12-R20.
Castro, A.; Martinez, A. Targeting beta-amyloid pathogenesis through acetylcholinesterase inhibitors. Curr. Pharm. Des., 2006, 12(33), 4377-4387.
Tumiatti, V.; Minarini, A.; Bolognesi, M.L.; Milelli, A.; Rosini, M.; Melchiorre, C. Tacrine Derivatives and Alzheimer’s Disease. Curr. Med. Chem., 2010, 17(17), 1825-1838.
Deora, G.S.; Kantham, S.; Chan, S.; Dighe, S.N.; Veliyath, S.K.; McColl, G.; Parat, M.O.; McGeary, R.P.; Ross, B.P. Multifunctional analogs of kynurenic acid for the treatment of Alzheimer’s Disease: Synthesis, pharmacology, and molecular modeling studies. ACS Chem. Neurosci., 2017, 8(12), 2667-2675.
Alzheimer’s Association. 2016 Alzheimer’s disease facts and figures. Alzheimer’s Dementia: J. Alzheimer’s Associat., 2016, 12(4), 459-509.
Okamura, H.; Ishii, S.; Ishii, T.; Eboshida, A. Prevalence of dementia in japan: A systematic review. Dement. Geriatr. Cogn. Disord., 2013, 36(1-2), 111-118.
Terry, A.V.; Buccafusco, J.J. The cholinergic hypothesis of age and Alzheimer’s disease-related cognitive deficits: Recent challenges and their implications for novel drug development. J. Pharmacol. Experiment. Therapeut., 2003, 306(3), 821-827.
Pepeu, G.; Giovannini, M.G. Cholinesterase inhibitors and beyond. Curr. Alzheimer Res., 2009, 6(2), 86-96.
Saiko, P.; Szakmary, A.; Jaeger, W.; Szekeres, T. Resveratrol and its analogs: Defense against cancer, coronary disease and neurodegenerative maladies or just a fad? Mutat. Res. Rev. Mutat. Res., 2008, 658(1-2), 68-94.
Savelieff, M.G.; Lee, S.; Liu, Y.Z.; Lim, M.H. Untangling Amyloid-beta, Tau, and metals in Alzheimer’s disease. ACS Chem. Biol., 2013, 8(5), 856-865.
Jakob-Roetne, R.; Jacobsen, H. Alzheimer’s Disease: From pathology to therapeutic approaches. Angew. Chem. Int. Ed., 2009, 48(17), 3030-3059.
Penalver, P.; Belmonte-Reche, E.; Adan, N.; Caro, M.; Mateos-Martin, M.L.; Delgado, M.; Gonzalez-Rey, E.; Morales, J.C. Alkylated resveratrol prodrugs and metabolites as potential therapeutics for neurodegenerative diseases. Eur. J. Med. Chem., 2018, 146, 123-138.
Vion, E.; Page, G.; Bourdeaud, E.; Paccalin, M.; Guillard, J.; Rioux Bilan, A. Trans epsilon-viniferin is an amyloid-beta disaggregating and anti-inflammatory drug in a mouse primary cellular model of Alzheimer’s disease. Mol. Cell. Neurosci., 2018, 88, 1-6.
Awasthi, M.; Singh, S.; Pandey, V.P.; Dwivedi, U.N. CoMFA and CoMSIA-based designing of resveratrol derivatives as amyloid-beta aggregation inhibitors against Alzheimer’s disease. Med. Chem. Res., 2018, 27(4), 1167-1185.
Yuan, W.; Shang, Z.; Qiang, X.; Tan, Z.; Deng, Y. Synthesis of pterostilbene and resveratrol carbamate derivatives as potential dual cholinesterase inhibitors and neuroprotective agents. Res. Chem. Intermed., 2013, 40(2), 787-800.
Puksasook, T.; Kimura, S.; Tadtong, S.; Jiaranaikulwanitch, J.; Pratuangdejkul, J.; Kitphati, W.; Suwanborirux, K.; Saito, N.; Nukoolkarn, V. Semisynthesis and biological evaluation of prenylated resveratrol derivatives as multi-targeted agents for Alzheimer’s disease. J. Nat. Med., 2017, 71(4), 665-682.
Lu, C.; Guo, Y.; Yan, J.; Luo, Z.; Luo, H.B.; Yan, M.; Huang, L.; Li, X. Design, synthesis, and evaluation of multitarget-directed resveratrol derivatives for the treatment of Alzheimer’s disease. J. Med. Chem., 2013, 56(14), 5843-5859.
Lu, C.; Guo, Y.; Li, J.; Yao, M.; Liao, Q.; Xie, Z.; Li, X. Design, synthesis, and evaluation of resveratrol derivatives as Ass((1)-(4)(2)) aggregation inhibitors, antioxidants, and neuroprotective agents. Bioorg. Med. Chem. Lett., 2012, 22(24), 7683-7687.
Jung, J-C.; Lim, E.; Lee, Y.; Kang, J-M.; Kim, H.; Jang, S.; Oh, S.; Jung, M. Synthesis of novel trans-stilbene derivatives and evaluation of their potent antioxidant and neuroprotective effects. Eur. J. Med. Chem., 2009, 44(8), 3166-3174.
Jerabek, J.; Uliassi, E.; Guidotti, L.; Korabecny, J.; Soukup, O.; Sepsova, V.; Hrabinova, M.; Kuca, K.; Bartolini, M.; Pena-Altamira, L.E.; Petralla, S.; Monti, B.; Roberti, M.; Bolognesi, M.L. Tacrine-resveratrol fused hybrids as multi-target-directed ligands against Alzheimer’s disease. Eur. J. Med. Chem., 2017, 127, 250-262.
Pan, L-F.; Wang, X-B.; Xie, S-S.; Li, S-Y.; Kong, L-Y. Multitarget-directed resveratrol derivatives: anti-cholinesterases, anti-β-amyloid aggregation and monoamine oxidase inhibition properties against Alzheimer’s disease. MedChemComm, 2014, 5(5), 609.
Chen, P.C.; Tsai, W.J.; Ueng, Y.F.; Tzeng, T.T.; Chen, H.L.; Zhu, P.R.; Huang, C.H.; Shiao, Y.J.; Li, W.T. Neuroprotective and antineuroinflammatory effects of Hydroxyl-Functionalized stilbenes and 2-Arylbenzo[b]furans. J. Med. Chem., 2017, 60(9), 4062-4073.
Lan, J.S.; Liu, Y.; Hou, J.W.; Yang, J.; Zhang, X.Y.; Zhao, Y.; Xie, S.S.; Ding, Y.; Zhang, T. Design, synthesis and evaluation of resveratrol-indazole hybrids as novel monoamine oxidases inhibitors with amyloid-beta aggregation inhibition. Bioorg. Chem., 2018, 76, 130-139.
Li, S.Y.; Wang, X.B.; Kong, L.Y. Design, synthesis and biological evaluation of imine resveratrol derivatives as multi-targeted agents against Alzheimer’s disease. Eur. J. Med. Chem., 2014, 71, 36-45.
Koukoulitsa, C.; Villalonga-Barber, C.; Csonka, R.; Alexi, X.; Leonis, G.; Dellis, D.; Hamelink, E.; Belda, O.; Steele, B.R.; Micha-Screttas, M.; Alexis, M.N.; Papadopoulos, M.G.; Mavromoustakos, T. Biological and computational evaluation of resveratrol inhibitors against Alzheimer’s disease. J. Enzyme Inhib. Med. Chem., 2016, 31, 67-77.
Yang, X.; Qiang, X.; Li, Y.; Luo, L.; Xu, R.; Zheng, Y.; Cao, Z.; Tan, Z.; Deng, Y. Pyridoxine-resveratrol hybrids mannich base derivatives as novel dual inhibitors of AChE and MAO-B with antioxidant and metal-chelating properties for the treatment of Alzheimer’s disease. Bioorg. Chem., 2017, 71, 305-314.
Xu, P.; Zhang, M.; Sheng, R.; Ma, Y. Synthesis and biological evaluation of deferiprone-resveratrol hybrids as antioxidants, Abeta1-42 aggregation inhibitors and metal-chelating agents for Alzheimer’s disease. Eur. J. Med. Chem., 2017, 127, 174-186.
Lee, I.; Choe, Y.S.; Choi, J.Y.; Lee, K.H.; Kim, B.T. Synthesis and evaluation of (1)(8)F-labeled styryltriazole and resveratrol derivatives for beta-amyloid plaque imaging. J. Med. Chem., 2012, 55(2), 883-892.

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Year: 2019
Page: [809 - 825]
Pages: 17
DOI: 10.2174/1389557519666190128093840
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