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Synthesis and structure–activity relationship of nuciferine derivatives as potential acetylcholinesterase inhibitors

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Abstract

Acetylcholinesterase inhibitors (AChEIs) are currently the best available pharmacotherapy for Alzheimer patients, but because of bioavailability issues, there is still great interest in discovering better AChEIs. The aporphine alkaloid is an important class of natural products, which shows diverse biological activity, such as acetylcholinesterase inhibitory activity. To find new lead AChEIs compounds, eight aporphine alkaloids were synthesized by O-dealkylation, N-dealkylation, and ring aromatization reactions using nuciferine as raw material. The anti-acetylcholinesterase activity of synthesized compounds was measured using modified Ellman’s method. The results showed that some synthesized compounds exhibited higher affinity to AChE than the parent compound nuciferine. Among these compounds, 1,2-dihydroxyaporphine (2) and dehydronuciferine (5) were the most active compounds (IC50 = 28 and 25 μg/mL, respectively). Preliminary analysis of structure–activity relationships suggested that aromatization of the C ring, the presence of the alkoxyl group at C1 and the hydroxy group at C2 position as well as the alkyl substituent at the N atom were favorable to the acetylcholinesterase inhibition. Molecular docking was also applied to predict the binding modes of compounds 1, 2, and 9 into the huperzine A binding site of AChE.

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References

  • Acosta K, Cessac JW, Rao PN, Kim HK (1994) Oxidative demethylation of 4-substituted N,N-dimethylanilines with iodine and calcium-oxide in the presence of methanol. J Chem Soc 17:1985–1986

    Google Scholar 

  • Ahmad R, Saa JM, Cava MP (1977) Regioselective O-demethylation in aporphine alkaloid series. J Org Chem 42:1228–1230

    Article  CAS  PubMed  Google Scholar 

  • Barolo SM, Teng X, Cuny GD, Rossi RA (2006) Syntheses of aporphine and homoaporphine alkaloids by intramolecular ortho-arylation of phenols with aryl halides via S(RN)1 reactions in liquid ammonia. J Org Chem 71:8493–8499

    Article  CAS  PubMed  Google Scholar 

  • Boustie J, Stigliani JL, Montanha J, Amoros M, Payard P, Girre L (1998) Antipoliovirus structure–activity relationships of some aporphine alkaloids. J Nat Prod 61:480–484

    Article  CAS  PubMed  Google Scholar 

  • Cava MP, Veznkatfswarlu A, Srinivasa M, Edie DL (1972) Oxidative tranformations in the aporphine alkaloid series. Tetrahedron 28:4299–4307

    Article  CAS  Google Scholar 

  • Couture A, Deniau E, Woisel P, Grandclaudon P, Carpentier JF (1996) Base-induced cyclization of trimethoxy-O-aroyldiphenylphosphoryl methylbenz-amide: A formal synthesis of (+/−) cherylline and (+/−) cherylline dimethylether. Tetrahedron Lett 37:3697–3700

    Article  Google Scholar 

  • Guinaudeau H, Leboeuf M, Cave A (1979) Aporphine alkaloids. II. J Nat Prod 42:325–360

    Article  CAS  Google Scholar 

  • Guinaudeau H, Leboeuf M, Cave A (1983) Aporphinoid alkaloids III. J Nat Prod 46:761–835

    Article  CAS  Google Scholar 

  • Han BH, Park MH, Han YN (1989) Aporphine and tetrahydrobenzylisoquin-oline alkaloids from the seeds of Zizyphus vulgaris var. spinosus. Arch Pharm Res 12:263–268

    Article  CAS  Google Scholar 

  • Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356

    Article  CAS  PubMed  Google Scholar 

  • Horie T, Tominaga H, Kawamura Y, Yamada T (1992) Studies of the selective O-Alkylation and dealkylation of flavonoids. 13. An improved method for synthesizing 5,6,7-trihydroxyflavones from 6-hydroxy-5,7-dimet-hoxyflavones. J Org Chem 57:3343–3347

    Article  CAS  Google Scholar 

  • Horie T, Kobayashi T, Kawamura Y, Yoshida I, Tominaga H, Yamashita K (1995) Studies of the selective O-alkylation and dealkylation of flavonoids.XVIII. A convenient method for synthesizing 3,5,6,7-tetradroxyflavones. Bull Chem Soc Jpn 68:2033–2041

    Article  CAS  Google Scholar 

  • Huang WJ, Chen CH, Singh OV, Lee SL, Lee SS (2002) A facile method for the synthesis of glaucine and norglaucine from boldine. Syn Commun 32:3681–3686

    Article  CAS  Google Scholar 

  • Kelly PH, Miller RJ, Neumeyer JL (1976) Aporphines. 16. Action of aporphine alkaloids on locomotor activity in rats with 6-hydroxydopamine lesions of the nucleus accumbens. Eur J Pharm 35:85–92

    Article  CAS  Google Scholar 

  • Kuo RY, Chang FR, Chen CY, Teng CM, Yen HF, Wu YC (2001) Antiplatelet activity of N-methoxycarbonyl aporphines from Rollinia mucosa. Phytochemistry 57:421–425

    Article  CAS  PubMed  Google Scholar 

  • Lahiri DK, Farlow MR, Greig NH, Sambamurti K (2002) Current drug targets for Alzheimer’s disease treatment. Drug Dev Res 56:267–281

    Article  CAS  Google Scholar 

  • Lu ST, Wu YC, Leou SP (1987) The oxidation of isoquinoline alkaloids with m-chloroperbenzoic acid. J Chin Chem Soc (Taipei, Taiwan) 34:33–42

    Article  CAS  Google Scholar 

  • Markmee S, Ruchirawat S, Prachyawarakorn V, Ingkaninan K, Khorana N (2006) Isoquinoline derivatives as potential acetylcholinesterase inhibitors. Bioorg Med Chem Lett 16:2170–2172

    Article  CAS  PubMed  Google Scholar 

  • Munoz TD, Camps P (2006) Dimeric and hybrid anti-Alzheimer drug candidates. Curr Med Chem 13:399–422

    Article  Google Scholar 

  • Racchi M, Mazzucchelli M, Porrello E, Lanni C, Govoni S (2004) Acetylcholinesterase inhibitors: novel activities of old molecules. Pharmacol Res 50:441–451

    Article  CAS  PubMed  Google Scholar 

  • Rollinger JM, Schuster D, Baier E, Ellmerer EP, Langer T, Stuppner H (2006) Taspine: bioactivity-guided isolation and molecular ligand-target insight of a potent acetylcholinesterase inhibitor from Magnolia soulangiana. J Nat Prod 69:1341–1346

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Scarpini E, Scheltens P, Feldman H (2003) Treatment of Alzheimer’s disease: current status and new perspectives. Lancet Neurol 2:539–547

    Article  CAS  PubMed  Google Scholar 

  • Wafo P, Nyasse B, Fontaine C, Sondengam BL (1999) Aporphine alkaloids from Enantia chlorantha. Fitoterapia 70:157–160

    Article  CAS  Google Scholar 

  • Wang LL, Liu B, Shi RB (2009) Study on chemical constituents of Folium Nelumbinis. Nat Prod Res Dev 21:416–419

    Google Scholar 

  • Yang ZD, Zhang X, Du J, Ma ZJ, Guo F, Li S, Yao XJ (2012) An aporphine alkaloid from Nelumbo nucifera as an acetylcholinesterase inhibitor and the primary investigation for structure–activity correlations. Nat Prod Res 26:387–392

    Article  CAS  PubMed  Google Scholar 

  • Zou CL, Ji H, Xie GB, Chen DL, Wang FP (2008) An effective O-demethylation of some C19-diterpenoid alkaloids with HBr–glacial acetic acid. J Asian Nat Prod Res 10:1063–1067

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors are grateful to the National Natural Science Foundation of China (No. 21262022), the Elitist Program of Lanzhou University of Technology (No. J201303) and Zhejiang Provincial Natural Science Foundation of China (No. LY12B02005). The authors also thank Miss Karen Tenney, a researcher of University of California, Santa Cruz, for revising the grammar errors

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The authors declare that there are no conflicts of interest.

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Authors and Affiliations

  1. School of Life Science and Engineering, Lanzhou University of Technology, Lanzhou, 730050, Gansu, People’s Republic of China

    Zhongduo Yang, Zhuwen Song, Jie Sheng, Zongmei Shu & Jibei Liang

  2. Department of Chemistry, Lanzhou University, Lanzhou, 730000, People’s Republic of China

    Weiwei Xue & Xiaojun Yao

  3. Key Lab of New Animal Drug Project, Gansu Province, Key Lab of Veterinary Pharmaceutical Development, Ministry of Agriculture, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, Lanzhou, 730050, People’s Republic of China

    Yin Shi

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  1. Zhongduo Yang
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Correspondence to Zhongduo Yang.

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Yang, Z., Song, Z., Xue, W. et al. Synthesis and structure–activity relationship of nuciferine derivatives as potential acetylcholinesterase inhibitors. Med Chem Res 23, 3178–3186 (2014). https://doi.org/10.1007/s00044-013-0905-9

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  • DOI: https://doi.org/10.1007/s00044-013-0905-9

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