A unified strategy for the synthesis of amorfrutins A and B and evaluation of their cytotoxicity

A unified strategy for the synthesis of amorfrutins A and B and evaluation of their cytotoxicity

Authors

  • Benjamin Brandes Martin-Luther Universität Halle-Wittenberg
  • Sophie Hoenke Martin-Luther Universität Halle-Wittenberg
  • Michael Türk Martin-Luther Universität Halle-Wittenberg
  • Björn Weber Martin-Luther Universität Halle-Wittenberg
  • Hans-Peter Deigner Furtwangen University
  • Ahmed Al-Harrasi University of Nizwa
  • René Csuk Martin-Luther Universität Halle-Wittenberg http://orcid.org/0000-0001-7911-290X

DOI:

https://doi.org/10.13171/mjc10902011171546rc

Abstract

3,5-Dimethoxy-benzaldehyde was used as a starting material to synthesize a central intermediate, 2-hydroxy-4-methoxy-6-phenethylbenzoic acid that was converted very quickly and with good yields into amorfrutins A and B. Furthermore, this compound was also used as a starting material to synthesize a piperazinyl-rhodamine B conjugate. The latter compound showed good cytotoxicity (EC50 = 2.3–5.1 mM) and promising selective cytotoxicity (S = 2.1–4.6) for human tumor cell lines as compared to non-malignant fibroblasts (NIH 3T3).

Author Biography

René Csuk, Martin-Luther Universität Halle-Wittenberg

Organic Chemistry

Head of Department

References

- D.J. Newman, Developing natural product drugs: Supply problems and how they have been overcome, Pharmacol. Therapeut., 2016, 162,

-9.

- D.J. Newman, G.M. Cragg, Natural Products as Sources of New Drugs from 1981 to 2014, J. Nat. Prod., 2016, 79, 629-661.

- D.J. Newman, G.M. Cragg, Natural Product Scaffolds of Value in Medicinal Chemistry, RSC Drug Discov., 2016, 50, 348-378.

- H. von Bingen, Komplette Werkausgabe, Abtei St. Hildegard, Eibingen, Germany, 2017.

- M. Treben, Health through God's pharmacy, Ennsthaler Verlag, Steyr, Austria, 2007.

- https://www.who.int/new-room/fact-sheets/detail/the-top-10-causes-of-death;last accessed 2020-11-17.

- D. Yach, D. Stuckler, K.D. Brownell, Epidemiologic and economic consequences of the global epidemics of obesity and diabetes, Nat. Med., 2006, 12, 62-66.

- S. Sauer, Amorfrutins: A Promising Class of Natural Products that Are Beneficial to Health, ChemBioChem., 2014, 15, 1231-1238.

- D. Raederstorff, Novel nutraceutical, and pharmaceutical compositions comprising methoxylated aromatic compounds for the treatment, co-treatment or prevention of inflammatory disorders, 2007, WO2007093387A2.

- J.L. Rios, F. Francini, G.R. Schinella, Natural Products for the Treatment of Type 2 Diabetes Mellitus, Planta Med., 2015, 81, 975-994.

- L.A. Mitscher, Y.H. Park, A. Al-Shamma, P.B. Hudson, T. Haas, Amorfrutin A and B, bibenzyl antimicrobial agents from Amorpha fruticosa, Phytochemistry, 1981, 20, 781-785.

- R. Muharini, A. Diaz, W. Ebrahim, A. Mandi, T. Kurtan, N. Rehberg, R. Kalscheuer, R. Hartmann, R.S. Orfali, W. Lin, Z. Liu, P. Proksch, Antibacterial and Cytotoxic Phenolic Metabolites from the Fruits of Amorpha fruticosa, J. Nat. Prod., 2017, 80, 169-180.

- C. Weidner, J.C. de Groot, A. Prasad, A. Freiwald, C. Quedenau, M. Kliem, A. Witzke, V. Kodelja, C.T. Han, S. Giegold, M. Baumann, B. Klebl, K. Siems, L. Muller-Kuhrt, A. Schurmann, R. Schuler, A.F.H. Pfeiffer, F.C. Schroeder, K. Bussow, S. Sauer, Amorfrutins are potent antidiabetic dietary natural products, P. Natl. Acad. Sci., 2012, 109, 7257-7262.

- L. Fuhr, M. Rousseau, A. Plauth, F.C. Schroeder, S. Sauer, Amorfrutins Are Natural PPAR gamma Agonists with Potent Anti-inflammatory Properties, J. Nat. Prod., 2015, 78, 1160-1164.

- C. Chen, Y. Wu, L.L. Du, Qualitative and quantitative analysis of amorfrutins, novel antidiabetic dietary natural products, by HPLC, Pharm. Biol., 2016, 54, 488-493.

- C. Weidner, M. Rousseau, R.J. Micikas, C. Fischer, A. Plauth, S.J. Wowro, K. Siems, G. Hetterling, M. Kliem, F.C. Schroeder, S. Sauer, Amorfrutin C Induces Apoptosis and Inhibits Proliferation in Colon Cancer Cells through Targeting Mitochondria, J. Nat. Prod., 2016, 79, 2-12.

- J.C. de Groot, C. Weidner, J. Krausze, K. Kawamoto, F.C. Schroeder, S. Sauer, K. Buessow, Structural Characterization of Amorfrutins Bound to the Peroxisome Proliferator-Activated Receptor γ, J. Med. Chem., 2013, 56, 1535-1543.

- C. Weidner, S.J. Wowro, A. Freiwald, K. Kawamoto, A. Witzke, M. Kliem, K. Siems, L. Mueller-Kuhrt, F.C. Schroeder, S. Sauer, Amorfrutin B is an efficient natural peroxisome proliferator-activated receptor gamma (PPARγ) agonist with potent glucose-lowering properties, Diabetologia, 2013, 56, 1802-1812.

- L. Wang, B. Waltenberger, E.M. Pferschy-Wenzig, M. Blunder, X. Liu, C. Malainer, T. Blazevic, S. Schwaiger, J.M. Rollinger, E.H. Heiss, D. Schuster, B. Kopp, R. Bauer, H. Stuppner, V.M. Dirsch, A.G. Atanasov, Natural product agonists of peroxisome proliferator-activated receptor-gamma (PPARγ): a review, Biochem. Pharmacol., 2014, 92, 73-89.

- S. Garcia-Vallve, L. Guasch, S. Tomas-Hernandez, J.M. del Bas, V. Ollendorff, L. Arola, G. Pujadas, M. Mulero, Peroxisome Proliferator-Activated Receptor γ (PPARγ) and Ligand Choreography: Newcomers Take the Stage, J. Med. Chem., 2015, 58, 5381-5394.

- A. Lavecchia, C. Di Giovanni, Amorfrutins are efficient modulators of peroxisome proliferator-activated receptor-gamma (PPARγ) with potent antidiabetic and anticancer properties: a patent evaluation of WO2014177593 A1, Expert Opin. Ther. Pat., 2015, 25, 1341-1347.

- S. Yousefnia, S. Momenzadeh, F. Seyed Forootan, K. Ghaedi, M.H. Nasr Esfahani, The influence of peroxisome proliferator-activated receptor γ (PPARγ) ligands on cancer cell tumorigenicity, Gene, 2018, 649, 14-22.

- D. Raederstorff, J. Schwager, K. Wertz, Composition comprising rosehip for treatment of the inflammatory disorder, 2008, WO2008006589A2.

- S. Liu, M. Su, S.J. Song, J. Hong, H.Y. Chung, J.H. Jung, An Anti-Inflammatory PPAR-γ Agonist from the Jellyfish-Derived Fungus Penicillium chrysogenum J08NF-4, J. Nat. Prod., 2018, 81, 356-363.

- P. Lefebvre, B. Staels, Naturally improving insulin resistance with amorfrutins, Proc. Natl. Acad. Sci., 2012, 109, 7136-7137.

- D. Raederstorff, J. Schwager, G. Schueler, Nutraceutical and pharmaceutical compositions and use thereof for the treatment, co-treatment or prevention of inflammatory disorders, 2012, WO2007093387A1.

- C. Chen, Y. Xue, Q.M. Li, Y. Wu, J. Liang, L.S. Qing, Neutral Loss Scan - Based Strategy for Integrated Identification of Amorfrutin Derivatives, New Peroxisome Proliferator-Activated Receptor Gamma Agonists, from Amorpha Fruticosa by UPLC-QqQ-MS/M.S. and UPLCQ-TOF-MS, J. Am. Soc. Mass Spectrom., 2018, 29, 685-693.

- S. Laclef, K. Anderson, A.J.P. White, A.G.M. Barrett, Total synthesis of amorfrutin A via a palladium-catalyzed migratory prenylation-aromatization sequence, Tetrahedron Lett., 2012, 53, 225-227.

- C. Weidner, J.C. de Groot, A. Prasad, A. Freiwald, C. Quedenau, M. Kliem, A. Witzke, V. Kodelja, C.T. Han, S. Giegold, M. Baumann, B. Klebl, K. Siems, L. Muller-Kuhrt, A. Schurmann, R. Schuler, A.F.H. Pfeiffer, F.C. Schroeder, K. Bussow, S. Sauer, Amorfrutins are potent antidiabetic dietary natural products, Proc. Natl. Acad. Sci., 2012, 109, 7257-7262.

- Y.Y. Song, H.G. He, Y. Li, Y. Deng, A facile total synthesis of amorfrutin A, Tetrahedron Lett., 2013, 54, 2658-2660.

- I.S. Aidhen, R. Mukkamala, C. Weidner, S. Sauer, A Common Building Block for the Syntheses of Amorfrutin and Cajaninstilbene Acid Libraries Toward Efficient Binding with Peroxisome Proliferator-Activated Receptors, Org. Lett., 2015, 17, 194-197.

- X.Y. Ji, J.H. Chen, G.H. Zheng, M.H. Huang, L. Zhang, H. Yi, J. Jin, J.-D. Jiang, Z.G. Peng, Z.R. Li, Design, and Synthesis of Cajanine Analogues against Hepatitis C Virus through Down-Regulating Host Chondroitin Sulfate N-Acetylgalactosaminyltransferase 1, J. Med. Chem., 2016, 59, 10268-10284.

- T. Fujita, S. Kuwahara, Y. Ogura, Unified total synthesis of amorfrutins A and C via the Claisen rearrangement, Biosci. Biotechnol. Biochem., 2019, 83, 1635-1641.

- B. Weber, B. Brandes, D. Powroznik, R. Kluge, R. Csuk, An efficient and robust synthesis of amorfrutin A, Tetrahedron Lett., 2019, 60,

-1381.

- T. Fujita, S. Kuwahara, Y. Ogura, Synthesis of amorfrutins B and D from amorfrutin A ethyl ester, Tetrahedron Lett., 2020, 61, 151477.

- G.S. Grandhi, J. Selvakumar, S. Dana, M. Baidya, Directed C-H Bond Functionalization: A Unified Approach to Formal Syntheses of Amorfrutin A, Cajaninstilbene Acid, Hydrangenol, and Macrophyllol, J. Org. Chem., 2018, 83, 12327-12333.

- E.L. Ghisalberti, P.R. Jefferies, D. McAdam, Isoprenylated resorcinol derivatives from Glycyrrhiza acanthocarpa, Phytochemistry, 1981, 20, 1959-1961.

- M. Kozubek, I. Serbian, S. Hoenke, O. Kraft, R. Csuk, Synthesis and cytotoxic evaluation of hydroxycinnamic acid rhodamine B conjugates, Results Chem., 2020, 2, 100057.

- S. Sommerwerk, L. Heller, C. Kerzig, A.E. Kramell, R. Csuk, Rhodamine B conjugates of triterpenoic acids are cytotoxic mitocans even at nanomolar concentrations, Eur. J. Med. Chem., 2017, 127, 1-9.

- M. Kahnt, J. Wiemann, L. Fischer, S. Sommerwerk, R. Csuk, Transformation of asiatic acid into a mitocanic, bimodal-acting rhodamine B conjugate of nanomolar cytotoxicity, Eur. J. Med. Chem., 2018, 159,

-148.

- J. Wiemann, L. Fischer, J. Kessler, D. Ströhl, R. Csuk, Ugi multicomponent-reaction: Syntheses of cytotoxic dehydroabietylamine derivatives, Bioorg Chem., 2018, 81, 567-576.

- R.K. Wolfram, L. Fischer, R. Kluge, D. Ströhl, A. Al-Harrasi, R. Csuk, Homopiperazine-rhodamine B adducts of triterpenoic acids are strong mitocans, Eur. J. Med. Chem., 2018, 155, 869-879.

- R.K. Wolfram, L. Heller, R. Csuk, Targeting mitochondria: Esters of rhodamine B with triterpenoids are mitocanic triggers of apoptosis, Eur. J. Med. Chem., 2018, 152, 21-30.

- R. Csuk, H.P. Deigner, The potential of click reactions for the synthesis of bioactive triterpenes, Bioorg. Med. Chem. Lett., 2019, 29, 949-958.

- B. Brandes, S. Hoenke, L. Fischer, R. Csuk, Design, synthesis, and cytotoxicity of BODIPY FL labelled triterpenoids, Eur. J. Med. Chem., 2020, 185, 111858.

- S. Friedrich, I. Serbian, S. Hoenke, R.K. Wolfram, R. Csuk, Synthesis and cytotoxic evaluation of malachite green derived oleanolic and ursolic acid piperazineamides, Med. Chem. Res., 2020, 29, 926-933.

- B. Del Secco, G. Malachin, L. Milli, N. Zanna, E. Papini, A. Cornia, R. Tavano, C. Tomasini, Form matters: Stable helical foldamers preferentially target human monocytes and granulocytes, ChemMedChem, 2017, 12,

-345.

- A.N. Preston, J.D. Farr, B.K. O'Neill, K.K. Thompson, S.E. Tsirka, S.T. Laughlin, Visualizing the Brain's Astrocytes with Diverse Chemical Scaffolds, ACS Chem. Biol., 2018, 13, 1493-1498.

- I. Serbian, S. Hoenke, R. Csuk, Synthesis of some steroidal mitocans of nanomolar cytotoxicity acting by apoptosis, Eur. J. Med. Chem., 2020, 199, 112425.

- X.-J. Xu, T. Zeng, Z.X. Huang, X.F. Xu, J. Lin, W.M. Chen, Synthesis, and Biological Evaluation of Cajaninstilbene Acid and Amorfrutins A and B as Inhibitors of the Pseudomonas aeruginosa Quorum Sensing System, J. Nat. Prod., 2018, 81, 2621-2629.

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Published

17-11-2020

Issue

Vol. 11 No. 1 (2021)

Section

Bioorganic Chemistry

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