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Semisynthesis and biological evaluation of prenylated resveratrol derivatives as multi-targeted agents for Alzheimer’s disease

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Abstract

A series of prenylated resveratrol derivatives were designed, semisynthesized and biologically evaluated for inhibition of β-secretase (BACE1) and amyloid-β (Aβ) aggregation as well as free radical scavenging and neuroprotective and neuritogenic activities, as potential novel multifunctional agents against Alzheimer’s disease (AD). The results showed that compound 4b exhibited good anti-Aβ aggregation (IC50 = 4.78 µM) and antioxidant activity (IC50 = 41.22 µM) and moderate anti-BACE1 inhibitory activity (23.70% at 50 µM), and could be a lead compound. Moreover, this compound showed no neurotoxicity along with a greater ability to inhibit oxidative stress on P19-derived neuronal cells (50.59% cell viability at 1 nM). The neuritogenic activity presented more branching numbers (9.33) and longer neurites (109.74 µm) than the control, and was comparable to the quercetin positive control. Taken together, these results suggest compound 4b had the greatest multifunctional activities and might be a very promising lead compound for the further development of drugs for AD.

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  • 11 July 2017

    An erratum to this article has been published.

References

  1. Alzheimer’s association (2016) Alzheimer’s disease facts and figures. Alzheimers Dement 12:1–80

    Article  Google Scholar 

  2. Okamura H, Ishii S, Ishii T, Eboshida A (2013) Prevalence of dementia in Japan: a systematic review. Dement Geriatr Cogn Disord 36:111–118

    Article  Google Scholar 

  3. Klafki HW, Staufenbiel M, Kornhuber J, Wiltfang J (2006) Therapeutic approaches to Alzheimer’s disease. Brain 129:2840–2855

    Article  Google Scholar 

  4. Terry JRAV, Buccafusco JJ (2003) The cholinergic hypothesis of age and Alzheimer’s disease-related cognitive deficits: recent challenges and their implications for novel drug development. J Pharm Exp Ther 306:821–827

    Article  CAS  Google Scholar 

  5. Giacobini E (2004) Cholinesterase inhibitors: new roles and therapeutic alternatives. Pharmocol Res 50:433–440

    Article  CAS  Google Scholar 

  6. Selkoe DJ, Hardy J (2016) The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med 8:595–608

    Article  CAS  Google Scholar 

  7. Bihel F, Das C, Bowman MJ, Wolfe MS (2004) Discovery of a subnanomolar helical d-tridecapeptide inhibitor of β-secretase. J Med Chem 47:3931–3933

    Article  CAS  Google Scholar 

  8. Nishiyama Y, Taguchi H, Hara M, Planque SA, Mitsuda Y, Paul S (2014) Metal-dependent amyloid β-degrading catalytic antibody construct. J Biotechnol 180:17–22

    Article  CAS  Google Scholar 

  9. Maccioni RB, Farias G, Morales I, Navarrete L (2010) The revitalized tau hypothesis on Alzheimer’s disease. Arch Med Res 41:226–231

    Article  CAS  Google Scholar 

  10. Boutajangout A, Sigurdsson EM, Krishnamurthy PK (2011) Tau as a therapeutic target for Alzheimer’s Disease. Curr Alzheimer Res 8:666–677

    Article  CAS  Google Scholar 

  11. Anand P, Singh B (2013) A review on cholinesterase inhibitors for Alzheimer’s disease. Arch Pharm Res 36:375–399

    Article  CAS  Google Scholar 

  12. Cavalli A, Bolognesi ML, Minarini A, Rosini M, Tumiatti V, Recanatini M, Melchiorre C (2008) Multi-target-directed ligands to combat Neurodegenerative diseases. J Med Chem 51:347–372

    Article  CAS  Google Scholar 

  13. Leon R, Garcia AG, Contelles JM (2013) Recent advances in the multitarget-directed ligands approach for the treatment of Alzheimer’s disease. Med Res Rev 33:139–189

    Article  CAS  Google Scholar 

  14. Li RS, Wang XB, Hu XJ, Kong LY (2013) Design, synthesis and evaluation of flavonoid derivatives as potential multifunctional acetylcholinesterase inhibitors against Alzheimer’s disease. Bioorg Med Chem Lett 23:2636–2641

    Article  CAS  Google Scholar 

  15. Xu ZC, Wang XB, Yu WY, Xie SS, Li SY, Kong LL (2014) Design, synthesis and biological evaluation of benzylisoquinoline derivatives as multifunctional agents against Alzheimer’s disease. Bioorg Med Chem Lett 24:2368–2373

    Article  CAS  Google Scholar 

  16. Lu C, Guo Y, Yan J, Luo Z, Luo HB, Yan M, Huang L, Li X (2013) Design, synthesis, and evaluation of multitarget-directed resveratrol derivatives for the treatment of Alzheimer’s disease. J Med Chem 56:5843–5859

    Article  CAS  Google Scholar 

  17. Li SY, Wang XB, Kong LY (2014) Design, synthesis and biological evaluation of imine resveratrol derivatives as multi-targeted agents against Alzheimer’s disease. Eur J Med Chem 71:36–45

    Article  CAS  Google Scholar 

  18. Baur JA, Sinclair DA (2006) Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov 5:493–506

    Article  CAS  Google Scholar 

  19. Galli RL, Bielinski DF, Szprengiel A, Shukitt-Hale B, Joseph JA (2006) Blueberry supplemented diet reverses age-related decline in hippocampal HSP70 neuroprotection. Neurobiol Aging 27:344–350

    Article  CAS  Google Scholar 

  20. Smoliga JM, Baur JA, Hausenblas HA (2011) Resveratrol and health—a comprehensive review of human clinical trials. Mol Nutr Food Res 55:1129–1141

    Article  CAS  Google Scholar 

  21. Choi B, Kim S, Jang BG, Kim MJ (2016) Piceatannol, a natural analogue of resveratrol, effectively reduces beta-amyloid levels via activation of alpha-secretase and matrix metalloproteinase-9. J Funct Foods 23:124–134

    Article  CAS  Google Scholar 

  22. Yazir Y, Utkan T, Gacar N, Aricioglu F (2015) Resveratrol exerts anti-inflammatory and neuroprotective effects to prevent memory deficits in rats exposed to chronic unpredictable mild stress. Physiol Behav 138:297–304

    Article  CAS  Google Scholar 

  23. Turner RS, Thomas RG, Craft S, Van Dyck CH, Mintzer J, Reynolds BA, Aisen PS (2015) A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease. Neurology 85:1383–1391

    Article  CAS  Google Scholar 

  24. Tellone E, Galtieri A, Russo A, Giardina B, Ficarra S (2015) Resveratrol: a focus on several neurodegenerative diseases. Oxid Med Cell Longev doi:10.1155/2015/392169

    Article  PubMed  PubMed Central  Google Scholar 

  25. Ohno M, Sametsky EA, Younkin LH, Oakley H, Younkin SG, Citron M, Disterhoft JF (2004) BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer’s disease. Neuron 41:27–33

    Article  CAS  Google Scholar 

  26. DaSilva KA, Shaw JE, McLaurin J (2010) Amyloid-β fibrillogenesis: structural insight and therapeutic intervention. Exp Neurol 223:311–321

    Article  CAS  Google Scholar 

  27. Nunomura A, Castellani RJ, Zhu X, Moreira PI, Perry G, Smith MA (2006) Involvement of oxidative stress in Alzheimer disease. J Neuropathol Exp Neurol 65:631–641

    Article  CAS  Google Scholar 

  28. Mandel S, Youdim MB (2004) Catechin polyphenols: neurodegeneration and neuroprotection in neurodegenerative diseases. Free Radic Biol Med 37:304–317

    Article  CAS  Google Scholar 

  29. Singh NA, Mandal AKA, Khan ZA (2016) Potential neuroprotective properties of epigallocatechin-3-gallate (EGCG). Nutr J 15:60

    Article  Google Scholar 

  30. More SV, Koppula S, Kim IS, Kumar H, Kim BW, Choi DK (2012) The role of bioactive compounds on the promotion of neurite outgrowth. Molecules 17:6728–6753

    Article  CAS  Google Scholar 

  31. Zhao HF, Li N, Wang Q, Cheng XJ, Li XM, Liu TT (2015) Resveratrol decreases the insoluble Aβ-42 Level in hippocamous and protects the integrity of the blood-brain barrier in AD rats. Neuroscience 310:641–649

    Article  CAS  Google Scholar 

  32. Bastianetto S, Zheng WH, Quirion RJ (2000) Neuroprotective abilities of resveratrol and other red wine constituents against nitric oxide-related toxicity in cultured hippocampal neurons. Br J Pharmacol 131:711–720

    Article  CAS  Google Scholar 

  33. Vella F, Ferry G, Delagrange P, Boutin JA (2005) NRH:quinone reductase 2: an enzyme of surprises and mysteries. Biochem Pharmacol 71:1–12

    Article  CAS  Google Scholar 

  34. Bastianetto S, Menard C, Quirion R (2015) Neuroprotective action of resveratrol. Biochim Biophys Acta 1852:1195–1201

    Article  CAS  Google Scholar 

  35. Cho JK, Ryu YB, Curtis-Long MJ, Kim JY, Kim D, Lee WS, Park KH (2011) Inhibition and structural reliability of prenylated flavones from the stem bark of Morus lhou on β-secretase (BACE-1). Bioorg Med Chem Lett 21:2945–2948

    Article  CAS  Google Scholar 

  36. Marumoto S, Miyazawa M (2012) Structure–activity relationships for naturally occurring coumarins as β-secretase inhibitor. Bioorg Med Chem 20:784–788

    Article  CAS  Google Scholar 

  37. Chanmahasathien W, Li Y, Satake M, Oshima Y, Ruangrungsi N, Ohizumi Y (2003) Prenylated xanthones with NGF-potentiating activity from Garcinia xanthochymus. Phytochemistry 64:981–986

    Article  CAS  Google Scholar 

  38. Kano Y, Horie N, Doi S, Aramaki F, Maeda H, Hiragami F, Kawamura K, Motoda H, Koike Y, Akiyama J, Eguchi S, Hashimoto K (2008) Artepillin C derived from propolis induces neurite outgrowth in PC12m3 cells via ERK and p38 MAPK pathways. Neurochem Res 33:1795–1803

    Article  CAS  Google Scholar 

  39. Chao J, Li H, Cheng KW, Yu MS, Chang RC, Wang M (2010) Protective effects of pinostilbene, a resveratrol methylated derivative, against 6-hydroxydopamine-induced neurotoxicity in SH-SY5Y cells. J Nutr Biochem 21:482–489

    Article  CAS  Google Scholar 

  40. Orsini F, Verotta L, Lecchi M, Restano R, Curia G, Redaelli E, Wanke E (2004) Resveratrol derivatives and their role as potassium channels modulators. J Nat Prod 67:421–426

    Article  CAS  Google Scholar 

  41. Ruan BF, Huang XF, Ding H, Xu C, Ge HM, Zhu HL, Tan RX (2006) Synthesis and cytotoxic evaluation of a series of resveratrol derivatives. Chem Biodivers 3:975–981

    Article  CAS  Google Scholar 

  42. Kumano T, Richard SB, Noel JP, Nishiyama M, Kuzuyama T (2008) Chemoenzymatic syntheses of prenylated aromatic small molecules using Streptomyces prenyltransferases with relaxed substrate specificities. Bioorg Med Chem 16:8117–8126

    Article  CAS  Google Scholar 

  43. Park BH, Lee HJ, Lee YR (2011) Total synthesis of chiricanine A, arahypin-1, trans-arachidin-2, trans-arachidin-3, and arahypin-5 from peanut seeds. J Nat Prod 74:644–649

    Article  CAS  Google Scholar 

  44. Verotta L, Orsini F, Gerhauser C, Klimo K (2009) Biologically-activity stilbene derivatives and compositions thereof. PCT Int Appl WO 2009012910 A1 (patent number)

  45. Kumano T, Tomita T, Nishiyama M, Kuzuyama T (2010) Functional characterization of the promiscuous prenyltransferase responsible for furaquinocin biosynthesis identification of a physiological polyketide substrate and its prenylated reaction products. J Biol Chem 285:39663–39671

    Article  CAS  Google Scholar 

  46. Rodríguez RA, Lahoz IR, Faza ON, Cid MM, Lopez CS (2012) Theoretical and experimental exploration of the photochemistry of resveratrol: beyond the simple double bond isomerization. Org Biomol Chem 10:9175–9182

    Article  Google Scholar 

  47. Mattarei A, Azzolini M, Carraro M, Sassi N, Zoratti M, Paradisi C, Biasutto L (2013) Acetal derivatives as prodrugs of resveratrol. Mol Pharm 10:2781–2792

    Article  CAS  Google Scholar 

  48. Hartung AM, Beutler JA, Navarro HA, Wiemer DF, Neighbors JD (2014) Stilbenes as K-selective, non-nitrogenous opioid receptor antagonists. J Nat Prod 77:311–319

    Article  CAS  Google Scholar 

  49. Jiaranaikulwanitch J, Boonyarat C, Fokin VV, Vajragupta O (2010) Triazolyl tryptoline derivatives as β-secretase inhibitors. Bioorg Med Chem Lett 20:6572–6576

    Article  CAS  Google Scholar 

  50. Jiaranaikulwanitch J, Govitrapong P, Fokin VV, Vajragupta O (2012) From BACE1 inhibitor to multifunctionality of tryptoline and tryptamine triazole derivatives for Alzheimer’s disease. Molecules 17:8312–8333

    Article  CAS  Google Scholar 

  51. Brand-Williams W, Cuvelier ME, Berset C (1995) Use of a free radical method to evaluate antioxidant activity. Lebensm Wiss Technol 28:25–30

    Article  CAS  Google Scholar 

  52. McBurney MW (1993) P19 embryonal carcinoma cells. Intl J Dev Biol 37:135–140

    CAS  Google Scholar 

  53. MacPherson PA, McBurney MW (1995) P19 embryonal carcinoma cells: a source of cultured neurons amenable to genetic manipulation. Methods 7:238–252

    Article  CAS  Google Scholar 

  54. Tadtong S, Athikomkulchai S, Sareedenchai V (2012) Neuritogenic activity of Thai plant extracts. J Health Res 26:293–296

    Google Scholar 

  55. Tangsaengvit N, Kitphati W, Tadtong S, Bunyapraphatsara N, Nukoolkarn V (2013) Neurite outgrowth and neuroprotective effects of quercetin from Caesalpinia mimosoides Lamk. on oultured P19-derived neurons. Evid Based Complement Alternat Med doi:10.1155/2013/838051

    Article  PubMed  PubMed Central  Google Scholar 

  56. Tadtong S, Kanlayavattanakul M, Lourith N (2013) Neuritogenic and neuroprotective activities of fruit residues. Nat Prod Commun 8:1583–1586

    CAS  PubMed  Google Scholar 

  57. Hamada Y, Miyamoto N, Kiso Y (2015) Novel β-amyloid aggregation inhibitors possessing a turn mimic. Bioorg Med Chem Lett 25:1572–1576

    Article  CAS  Google Scholar 

  58. Ahmed M, Davis J, Aucoin D, Sato T, Ahuja S, Aimoto S, Elliott JI, Nostrand WV, Smith SO (2010) Structural conversion of neurotoxic amyloid-beta(1–42) oligomers to fibrils. Nat Struct Mol Biol 17:561–567

    Article  CAS  Google Scholar 

  59. Shimizu H, Tosaki A, Kaneko K, Hisano T, Sakurai T, Nukina N (2008) Crystal structure of an active form of BACE1, an enzyme responsible for amyloid β protein production. Mol Cell Biol 28:3663–3671

    Article  CAS  Google Scholar 

  60. Kim SH, Kumar CN, Kim HJ, Kim DH, Cho J, Jin C, Lee YS (2009) Glucose-containing flavones—their synthesis and antioxidant and neuroprotective activities. Bioorg Med Chem Lett 19:6009–6013

    Article  CAS  Google Scholar 

  61. Hossain SU, Bhattacharya S (2007) Synthesis of O-prenylated and O geranylated derivatives of 5-benzylidene2,4-thiazolidinediones and evaluation of their free radical scavenging activity as well as effect on some phase II antioxidant/detoxifying enzymes. Bioorg Med Chem Lett 17:1149–1154

    Article  CAS  Google Scholar 

  62. Tadtong S, Meksuriyen D, Tanasupawat S, Isobe M, Suwanborirux K (2007) Geldanamycin derivatives and neuroprotective effect on cultured P19-derived neurons. Bioorg Med Chem Lett 17:2939–2943

    Article  CAS  Google Scholar 

  63. More SV, Koppula S, Kim IS, Kumar H, Kim BW, Choi DK (2012) The role of bioactive compounds on the promotion of neurite outgrowth. Molecules 7:6728–6753

    Article  Google Scholar 

  64. Li P, Matsunaga K, Yumakuni T, Ohizumi Y (2002) Picrosides I and II, selective enhancers of the mitogen-activated protein kinase-dependent signaling pathway in the action of neuritogenic substances on PC12D cells. Life Sci 71:1821–1835

    Article  CAS  Google Scholar 

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Acknowledgements

This project was supported by Mahidol University and the National Research Council of Thailand (NRCT). This work was supported in part by a grant from the Dementia Drug Resource Development Center Project (DRC), the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan (S1511016). We also express their gratitude for research funding from the Meiji Pharmaceutical University Asia/Africa Center for Drug Discovery (MPU-AACDD).

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Authors and Affiliations

  1. Department of Pharmacognosy, Faculty of Pharmacy, Mahidol University, Bangkok, 10400, Thailand

    Thanchanok Puksasook & Veena Nukoolkarn

  2. Graduate School of Pharmaceutical Sciences, Meiji Pharmaceutical University, Tokyo, 204-8588, Japan

    Shinya Kimura & Naoki Saito

  3. Department of Pharmacognosy, Faculty of Pharmacy, Srinakharinwirot University, Nakhon Nayok, 26120, Thailand

    Sarin Tadtong

  4. Department of Pharmaceutical Sciences, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, 50200, Thailand

    Jutamas Jiaranaikulwanitch

  5. Department of Microbiology, Faculty of Pharmacy, Mahidol University, Bangkok, 10400, Thailand

    Jaturong Pratuangdejkul

  6. Department of Physiology, Faculty of Pharmacy, Mahidol University, Bangkok, 10400, Thailand

    Worawan Kitphati

  7. Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Center for Bioactive Natural Products from Marine Organisms and Endophytic Fungi (BNPME), Chulalongkorn University, Bangkok, 10330, Thailand

    Khanit Suwanborirux

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  1. Thanchanok Puksasook
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Correspondence to Veena Nukoolkarn.

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The original version of this article was revised: The chemical structures of compounds 3a-d, 4a-c, and 5a-c were incorrect and it has been updated in this article.

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Puksasook, T., Kimura, S., Tadtong, S. et al. Semisynthesis and biological evaluation of prenylated resveratrol derivatives as multi-targeted agents for Alzheimer’s disease. J Nat Med 71, 665–682 (2017). https://doi.org/10.1007/s11418-017-1097-2

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