Synthesis of amide-spacered dimers of ursolic and oleanolic acid
AbstractTransdermal 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.
- 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. BrÃ¤se, 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-ÎºB, 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-1Î± 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.
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (SeeÂ The Effect of Open Access).