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Synthesis of amide-spacered dimers of ursolic and oleanolic acid

Sophie Hoenke, Isabell Wiengarn, Immo Serbian, Ahmed Al-Harrasi, René Csuk

Abstract


Transdermal therapeutic systems can release drug substances slowly and in a controlled manner from a drug depot. To provide a slow-release form of ursolic and oleanolic acid amide-spacered dimers were synthesized from the parent acids and diamines of variable chain lengths. These dimers were assayed in sulforhodamine B (SRB) assays for their cytotoxicity since as a pre-requisite for their use in slow-release forms these substances must not exert any unfavorable side-effects such as cytotoxicity. As a result of long term incubation up to 96 hours, none of these compounds showed any significant cytotoxicity in sulforhodamine B assays.


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- M. Vrettou, A.A. Gray, A.R.E. Brewer, A.G.M. Barrett, Strategies for the synthesis of C-2 symmetric natural products- a review, Tetrahedron 2007, 63, 1487-1536.

- G. Berube, Natural and synthetic biologically active dimeric molecules: Anticancer agents, anti-HIV agents, steroid derivatives and opioid antagonists, Curr. Med. Chem. 2006, 13, 131-154.

- G. Berube, D. Rabouina, V. Perron,

B. N'Zemba, R.C. Gaudreault, S. Parenta, E.E. Asselin, Synthesis of unique 17 beta-estradiol homo-dimers, estrogen receptors binding affinity evaluation and cytocidal activity on breast, intestinal and skin cancer cell lines, Steroids 2006, 71, 911-921.

- T. Wezeman, K.S. Masters, S. Bräse, Double Trouble-The Art of Synthesis of Chiral Dimeric Natural Products, Angew. Chem. Int. Ed. 2014, 53, 4524-4526.

- J. L. Jeffrey, R. Sarpong, An approach to the synthesis of dimeric resveratrol natural products via a palladium-catalysed domino reaction, Tetrahedron Lett. 2009, 50, 1969-1972.

- N. J. Marianayagam, M. Sunde, J.M. Matthews, The power of two: protein dimerization in biology, Trends Biochem. Sci. 2004, 29, 618-625.

- B. Bednarczyk-Cwynar, A. Gunther, Advances in Chemistry and Pharmacology of Triterpenoid Synthetic Dimers, Curr. Med. Chem. 2017, 24, 2205-2240.

- O. B. Kazakova, G.V. Giniyatullina, G.A. Tolstikov, V.E. Kataev, R.Z. Musin, Synthesis and modification of triterpenoids with two lupan backbones, Russ. J. Bioorg. Chem. 2009, 35, 645-650.

- G. R. Pettit, N. Melody, F. Hempenstall, J.C. Chapuis, T.L. Groy, L. Williams, Antineoplastic Agents. 595. Structural Modifications of Betulin and the X-ray Crystal Structure of an Unusual Betulin Amine Dimer, J. Nat. Prod. 2014, 77, 863-872.

- J. Hu, R.F. Li, J.R. Lu, Y. Ju, Synthesis and anion recognition of a novel oleanolic acid-based cyclic dimer, Tetrahedron Lett. 2011, 52, 4211-4214.

- L. J. Dolby, M. Debono, Studies of Terpene Chemistry .1. Acid-Catalyzed Dimerization of Citronellal, J. Org. Chem. 1964, 29, 2306-2310.

- C. M. Ma, N. Nakamura, M. Hattori, Chemical modification of oleanene type triterpenes and their inhibitory activity against HIV-1 protease dimerization, Chem. Pharm. Bull. 2000, 48, 1681-1688.

- K. G. Cheng, J. Liu, H.B. Sun, J. Xie, Synthesis of Oleanolic Acid Dimers as Inhibitors of Glycogen Phosphorylase, Chem. Biodivers. 2010, 7, 690-697.

- K. G. Cheng, C.H. Su, L.D. Yang, J. Liu, Z.F. Chen, Synthesis of oleanolic acid dimers linked at C-28 and evaluation of anti-tumor activity, Eur. J. Med. Chem. 2015, 89, 480-489.

- J. R. Lu, J.D. Wu, Y. Ju, Tuning the aggregation mode to induce different chiralities in organogels of mono- and bis-triterpenoid derivatives and the preparation of gold nanoparticles for use as a template, New. J. Chem. 2014, 38, 6050-6056.

- T. Honda, E.M. Padegimas, E. David, C. Sundararajan, K.T. Liby, C. Williams, M.B. Sporn, M. Visnick, 2-Cyano-3,10-dioxooleana-1,9(11)-dien-28-oic acid anhydride. A novel and highly potent anti-inflammatory and cytoprotective agent, Bioorg. Med. Chem. Lett. 2010, 20, 2275-2278.

- M. R. Prausnitz, R. Langer, Transdermal drug delivery, Nat. Biotechnol. 2008, 26, 1261-1268.

- M. Kahnt, L. Fischer, A. Al-Harrasi, R. Csuk, Ethylenediamine Derived Carboxamides of Betulinic and Ursolic Acid as Potential Cytotoxic Agents, Molecules 2018, 23, 2558; doi:10.3390/molecules23102558.

- M. Kahnt, L. Heller, P. Grabandt, A. Al-Harrasi, R. Csuk, Platanic acid: A new scaffold for the synthesis of cytotoxic agents, Eur. J. Med. Chem. 2018, 143, 259-265.

- 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, 143-148.

- L. Heller, A. Knorrscheidt, F. Flemming,

J. Wiemann, S. Sommerwerk, I.Z. Pavel, A. Al-Harrasi, R. Csuk, Synthesis and proapoptotic activity of oleanolic acid derived amides, Bioorg. Chem. 2016, 68, 137-151.

- 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.

- S. Sommerwerk, L. Heller, J. Kuhfs, R. Csuk, Selective killing of cancer cells with triterpenoic acid amides - The substantial role of an aromatic moiety alignment, Eur. J. Med. Chem. 2016, 122, 452-464.

- A. Loesche, M. Kahnt, I. Serbian, W. Brandt, R. Csuk, Triterpene-based carboxamides act as good inhibitors of butyrylcholinesterase, Molecules 2019, 24, 948/941-948/916.

- R. K. Wolfram, L. Fischer, R. Kluge,

D. Stroehl, 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.

- W. Jiang, R.-Z. Huang, J. Zhang, T. Guo, M.-T. Zhang, X.-C. Huang, B. Zhang, Z.-X. Liao, J. Sun, H.-S. Wang, Discovery of antitumor ursolic acid long-chain diamine derivatives as potent inhibitors of NF-κB, Bioorg. Chem. 2018, 79, 265-276.

- L.-H. Zhang, Z.-H. Zhang, M.-Y. Li, Z.-Y. Wei, X.-J. Jin, H.-R. Piao, Synthesis and evaluation of the HIF-1α inhibitory activities of novel ursolic acid tetrazole derivatives, Bioorg. Med. Chem. Lett. 2019, 29, 1440-1445.

- L. Ruzicka, K. Hofmann, Polyterpenes and polyterpenoids. C. Transpositions in the rings A and E of oleanolic acid. Carbon skeleton of pentacyclic triterpenes, Helv. Chim. Acta 1936, 19, 114-128.

- S. C. B. Gnoatto, L. Dalla Vechia, C.L. Lencina, A. Dassonville-Klimpt, S. Da Nascimento, D. Mossalayi, J. Guillon,

G. Gosmann, P. Sonnet, Synthesis and preliminary evaluation of new ursolic and oleanolic acids derivatives as antileishmanial agents, J. Enzyme Inhib. Med. Chem. 2008, 23, 604-610.

- M. Miyazawa, Y. Okuno, K. Imanishi, Suppression of the SOS-Inducing Activity of Mutagenic Heterocyclic Amine, Trp-P-1, by Triterpenoid from Uncaria sinensis in the Salmonella typhimurium TA1535/pSK1002 Umu Test, J. Agric. Food Chem. 2005, 53, 2312-2315.


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