Synthesis and cytotoxicity of 3-amino-glycyrrhetinic acid derivatives
AbstractThe aim of this study was to prepare 3-hydroximino- and 3-amino derivatives of glycyrrhetinic acid and derivatives to evaluate their in vitro cytotoxicity for a panel of human tumor cell lines. Thus, commercially available glycyrrhetinic acid (1) was acetylated or oxidized at position C-3 and transformed into a variety of different esters and amides followed by their conversion to 3-oximes and amines. While the parent compound was not cytotoxic at all, the 3-amino esters are highly cytotoxic. Interestingly, 3-amino amides were significantly less cytotoxic than 3-amino esters. The (3b, 18b, 20b) Benzyl 3-amino-11-oxoolean-12-en-30-oate was the most cytotoxic compound of this series showing an EC50 = 1.3 mM for 518A2 melanoma cells.
- R. Csuk, Recent Developments in the Synthesis of Antitumor-active Glycyrrhetinic Acid Derivatives, Mini- Rev. Org. Chem., 2014, 11, 253-261.
- T.-C. Kao, C.-H. Wu, G.-C. Yen, Bioactivity and Potential Health Benefits of Licorice, J. Agric. Food Chem., 2014, 62, 542-553.
- A. Roohbakhsh, M. Iranshahy, M. Iranshahi, Glycyrrhetinic Acid and Its Derivatives: Anti-Cancer and Cancer Chemopreventive Properties, Mechanisms of Action and Structure- Cytotoxic Activity Relationship, Curr. Med. Chem., 2016, 23, 498-517.
- Z.-H. Tang, T. Li, Y.-G. Tong, X.-J. Chen, X.-P. Chen, Y.-T. Wang, J.-J. Lu, A Systematic Review of the Anticancer Properties of Compounds Isolated from Licorice (Gancao), Planta Med., 2015, 81, 1670-1687.
- R. Yang, L.-q. Wang, B.-c. Yuan, Y. Liu, The Pharmacological Activities of Licorice, Planta Med., 2015, 81, 1654-1669.
- R. Csuk, S. Schwarz, R. Kluge, D. Ströhl, Synthesis and biological activity of some antitumor active derivatives from glycyrrhetinic acid, Eur. J. Med. Chem., 2010, 45, 5718-5723.
- R. Csuk, S. Schwarz, B. Siewert, R. Kluge, D. Ströhl, Synthesis and antitumor activity of ring A modified glycyrrhetinic acid derivatives, Eur. J. Med. Chem., 2011, 46, 5356-5369.
- S. Schwarz, R. Csuk, Synthesis and antitumour activity of glycyrrhetinic acid derivatives, Bioorg. Med. Chem., 2010, 18, 7458-7474.
- 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.
- J. Wiemann, L. Heller, R. Csuk, An access to a library of novel triterpene derivatives with a promising pharmacological potential by Ugi and Passerini multicomponent reactions, Eur. J. Med. Chem., 2018, 150, 176-194.
- B. Bednarczyk-Cwynar, A. GÃ¼nther, Advances in Chemistry and Pharmacology of Triterpenoid Synthetic Dimers, Curr. Med. Chem., 2017, 24, 2205-2240.
- R. Csuk, A. Barthel-Niesen, A. Barthel, R. SchÃ¤fer, A. Al-Harrasi, 11-Keto-boswellic acid derived amides and monodesmosidic saponins induce apoptosis in breast and cervical cancers cells, Eur. J. Med. Chem., 2015, 100, 98-105.
- 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.
- B. Siewert, E. Pianowski, R. Csuk, Esters and amides of maslinic acid trigger apoptosis in human tumor cells and alter their mode of action with respect to the substitution pattern at C-28, Eur. J. Med. Chem., 2013, 70, 259-272.
- 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.
- I. Beseda, L. Czollner, P.S. Shah, R. Khunt, R. Gaware, P. Kosma, C. Stanetty, M.C. del Ruiz-Ruiz, H. Amer, K. Mereiter, T. Da Cunha, A. Odermatt, D. Classen-Houben, U. Jordis, Synthesis of glycyrrhetinic acid derivatives for the treatment of metabolic diseases, Bioorgan Med Chem, 2010, 18, 433-454.
- R. Csuk, S. Schwarz, B. Siewert, R. Kluge, D. Ströhl, Conversions at C-30 of Glycyrrhetinic Acid and Their Impact on Antitumor Activity, Arch Pharm, 2012, 345, 223-230.
- L. Heller, S. Schwarz, V. Perl, A. Köwitsch, B. Siewert, R. Csuk, Incorporation of a Michael acceptor enhances the antitumor activity of triterpenoic acids, Eur. J. Med. Chem., 2015, 101, 391-399.
- B.P. Pradhan, P. Ghosh, On the study of the action of N-bromosuccinimide on triterpenoids and steroids. Part VI. Studies on the action of N-bromosuccinimide on 3-oximinolupanes in chloroform-dimethyl sulfoxide, Indian J. Chem., Sect. B, 1993, 32B, 491-493.
- T. Sundararamaiah, S.K. Ramraj, K.L. Rao, V.V. Bai, Synthesis of A-aza triterpenes. I: A-Aza triterpenes from methyl oleanonate, methyl betulonate and lupenone, J. Indian Chem. Soc., 1976, 53, 664-665.
- B. Bednarczyk-Cwynar, P. Ruszkowski, T. Bobkiewicz-Kozlowska, L. Zaprutko, Oleanolic Acid A-lactams Inhibit the Growth of HeLa, KB, MCF-7 and Hep-G2 Cancer Cell Lines at Micromolar Concentrations, Anti-Cancer Agents Med. Chem., 2016, 16, 579-592.
- B. Bednarczyk-Cwynar, N. Wachowiak, M. Szulc, E. Kaminska, A. Bogacz, J. Bartkowiak-Wieczorek, L. Zaprutko, P.L. Mikolajczak, Strong and long-lasting antinociceptive and anti-inflammatory conjugate of naturally occurring oleanolic acid and aspirin, Front. Pharmacol., 2016, 7, 201-218.
- B. Bednarczyk-Cwynar, L. Zaprutko, A. Froelich, Beckmann rearrangement of oxime obtained from oleanolic acid. Structure elucidation of the initial oxime, J. Mol. Struct., 2013, 1053, 115-121.
- B. Bednarczyk-Cwynar, L. Zaprutko, J. Marciniak, G. Lewandowski, M. Szulc, E. Kaminska, N. Wachowiak, P.L. Mikolajczak, The analgesic and anti-inflammatory effect of new oleanolic acid acyloxyimino derivative, Eur. J. Pharm. Sci., 2012, 47, 549-555.
- S. Babar, Synthesis and characterization of new imine and pthalic acid derivatives of ursolic acid, Int. J. Pharm. Pharm. Sci., 2014, 6, 560-564.
- F. Chu, W. Zhang, W. Guo, Z. Wang, Y. Yang, X. Zhang, K. Fang, M. Yan, P. Wang, H. Lei, Oleanolic Acid-amino Acids Derivatives: Design, Synthesis, and Hepatoprotective Evaluation In Vitro and In Vivo, Molecules, 2018, 23, ahead of print, doi:10.3390/molecules23020322.
- J. Wang, X. Hu, W. Wen, L. Yang, Y. Zhu, Synthesis and activity of 3-amino acid derivatives of glycyrrhetinic acid, Yingyong Huaxue, 2012, 29, 873-877.
- R. Csuk, S. Schwarz, R. Kluge, D. Ströhl, Improvement of the Cytotoxicity and Tumor Selectivity of Glycyrrhetinic Acid by Derivatization with Bifunctional Aminoacids, Arch. Pharm. 2011, 344, 505-513.
- S. Schwarz, S.D. Lucas, S. Sommerwerk, R. Csuk, Amino derivatives of glycyrrhetinic acid as potential inhibitors of cholinesterases, Bioorg. Med. Chem., 2014, 22, 3370-3378.
- C.H. Brieskorn, H. Eschelbach, Glycamines from ursolic and 18β-glycyrrhetinic acids, Arch. Pharm. 1979, 312, 752-762.
- S. Ijichi, S. Tamagaki, Molecular design of sweet tasting compounds based on 3β-amino-
Î²-deoxy-18β-glycyrrhetinic acid: amido functionality eliciting tremendous sweetness, Chem. Lett., 2005, 34, 356-357.
- H.-O. Kim, M.I. Goryaev, M.P. Irismetov, K.A. Alibaeva, Triterpenoids. XXVIII. Leuckart reaction with glycyrrhetic acid derivatives, Izv. Akad. Nauk Kaz. SSR, Ser. Khim., 1972, 22, 86-87.
- D.V. Krätschmar, A. Vuorinen, T. Da Cunha, G. Wolber, D. Classen-Houben, O. Doblhoff, D. Schuster, A. Odermatt, Characterization of activity and binding mode of glycyrrhetinic acid derivatives inhibiting 11β-hydroxysteroid dehydrogenase type 2, J. Steroid Biochem. Mol. Biol., 2011, 125, 129-142.
- C. Stanetty, L. Czollner, I. Koller, P. Shah, R. Gaware, T. Da Cunha, A. Odermatt, U. Jordis, P. Kosma, D. Classen-Houben, Synthesis of novel 3-amino and 29-hydroxamic acid derivatives of glycyrrhetinic acid as selective 11β-hydroxysteroid dehydrogenase 2 inhibitors, Bioorg. Med. Chem., 2010, 18, 7522-7541.
- R. Csuk, S. Schwarz, B. Siewert, R. Kluge, D. Ströhl, Synthesis and Antitumor Activity of Ring A-modified Glycyrrhetinic Acid Derivatives, Z Naturforsch B, 2011, 66, 521-532.
- X.D. Su, H. Lawrence, D. Ganeshapillai, A. Cruttenden, A. Purohit, M.J. Reed, N. Vicker, B.V.L. Potter, Novel 18 beta-glycyrrhetinic acid analogues as potent and selective inhibitors of 11 beta-hydroxysteroid dehydrogenases, Bioorgan Med Chem, 2004, 12, 4439-4457.
- 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).