β-11-Keto-boswellic acid derived amides: synthesis and cytotoxicity
AbstractThe aim of this study was to prepare 11-keto-β-boswellic acid derivatives modified at C-24 and to evaluate their in vitro cytotoxicity. Acetyl-11-keto-β-boswellic acid (AKBA) was isolated from frankincense and transformed into 11-keto-β-boswellic acid (KBA). Both compounds served as starting materials for the synthesis of several amides or hydrazides. The derivatives were fully characterized, and their cytotoxicity was evaluated in vitro using sulforhodamine B (SRB) assays employing two human tumor cell lines (A2780 and MCF7) as well as nonmalignant mouse fibroblasts (NIH 3T3). Nearly all of the compounds were more cytotoxic than their parent compounds. The highest cytotoxicity was observed for (3 α, 4 β) 3-acetyloxy-N-(3- aminopropyl)-11-oxo-urs-12-en-24-amide (15) and (3 α, 4 β) 3-acetyloxy-N-[4-(3-aminopropyl)piperazin-1-yl]- propyl-11-oxo-urs-12-en-24-amide (16) and the ovarian carcinoma cell line A2780. These compounds showed EC50 = 1.0-1.7 µM while being significantly less toxic for the mouse fibroblasts NIH 3T3 (EC50 = 9.3-16.3µM). Thus, compounds 15 and 16 have good antitumor effects and may serve as starting points for developing potential and selective antitumor agents
- E. M. Al-Mathal, Commiphora molmol in human welfare, J. Egypt. Soc. Parasitol., 2007, 37, 449-468.
- A. M. D. Tonkal, T. A. Morsy, An update review on Commiphora molmol and related species, J. Egypt. Soc. Parasitol., 2008, 38, 763-796.
- S. Ahmed, A. Alam, M. Shahabuddin, I. Khan, H. Ali, Versatile pharmacological action and compound formulation of Kundur in Unani medicine: a review, Int. J. Pharmacogn., 2014, 1, 627-631.
- F. Iram, S. A. Khan, A. Husain, Phytochemistry and potential therapeutic actions of Boswellic acids: A mini-review, Asian Pacif. J. Trop. Biomed., 2017, 7, 513-523.
- H. Hussain, A. Al-Harrasi, R. Csuk, U. Shamraiz, I. R. Green, I. Ahmed, I. A. Khan, Z. Ali, Therapeutic potential of boswellic acids: a patent review (1990-2015), Expert Opin. Ther. Pat., 2017, 27, 81-90.
- N. Bansal, S. Mehan, S. Kalra, D. Khanna, Boswellia serrata-frankincense (a jesus gifted herb); an updated pharmacological profile, Pharmacologia, 2013, 4, 457-463.
- Z. Du, Z. Liu, Z. Ning, Y. Liu, Z. Song, C. Wang, A. Lu, Prospects of Boswellic Acids as Potential Pharmaceutics, Planta Med., 2015, 81, 259-271.
- A. Moussaieff, R. Mechoulam, Boswellia resin: from religious ceremonies to medical uses; a review of in-vitro, in-vivo and clinical trials, J. Pharm. Pharmacol., 2009, 61, 1281-1293.
- M. Zviely, M. Li, Sesquiterpenoids: the holy fragrance ingredients, Perfum. Flavor., 2013, 38, 52-55.
- T. Eichhorn, H. J. Greten, T. Efferth, Molecular determinants of the response of tumor cells to boswellic acids, Pharmaceuticals, 2011, 4, 1171-1182.
- P. Fan, T. Li, Y. Ye, Q. Luo, H. Yuan, H. Lou, Synthesis and cytotoxic activity of boswellic acid analogues, Phytochem. Lett., 2016, 18, 99-104.
- Y.S. Park, J. H. Lee, J. A. Harwalkar, J. Bondar, H. Safayhi, M. Golubic, Acetyl-11-keto-Î²-boswellic acid (AKBA) is cytotoxic for meningioma cells and inhibits phosphorylation of the extracellular-signal regulated kinase 1 and 2, Adv. Exp. Med. Biol., 2002, 507, 387-393.
- S. A. Ali, S. A. Zaitone, Y. M. Moustafa, Boswellic acids synergize antitumor activity and protect against the cardiotoxicity of doxorubicin in mice bearing Ehrlich's carcinoma, Can. J. Physiol. Pharmacol., 2015, 93, 695-708
- R. Csuk, A. Barthel-Niesen, A. Barthel, R. Schäfer, 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.
- R. Csuk, A. Barthel-Niesen, D. Ströhl, R. Kluge, C. Wagner, A. Al-Harrasi, Oxidative and reductive transformations of 11-keto-β-boswellic acid, Tetrahedron, 2015, 71, 2025-2034.
- R. Csuk, A. Niesen-Barthel, R. Schäfer, A. Barthel, A. Al-Harrasi, Synthesis and antitumor activity of ring A modified 11-keto-β-boswellic
acid derivatives, Eur. J. Med. Chem., 2015, 92, 700-711.
- S. Kapoor, Boswellic acid and its inhibitory effect on tumor growth in systemic malignancies: an emerging concept in oncology, Future Oncol., 2013, 9, 627-628.
- T. Li, P. Fan, Y. Ye, Q. Luo, H. Lou, Ring A-modified Derivatives from the Natural Triterpene 3-O-acetyl-11-keto-β-Boswellic Acid and their Cytotoxic Activity, Anti-Cancer Agents Med. Chem., 2017, 17, 1153-1167.
- N. K. Roy, A. Deka, D. Bordoloi, S. Mishra, A. P. Kumar, G. Sethi, A.B. Kunnumakkara, The potential role of boswellic acids in cancer prevention and treatment, Cancer Lett., 2016, 377, 74-86.
- R. K. Wolfram, A. Barthel-Niesen, R. Schäfer, L. Heller, A. Al-Harrasi, R. Csuk, Synthesis and cytotoxic screening of β-boswellic acid derivatives, Medit. J. Chem., 2017, 6, 142-164.
- J. Jauch, J. Bergmann, An efficient method for the large-scale preparation of 3-O-acetyl-11-oxo-beta-boswellic acid and other boswellic acids, Eur. J. Org. Chem., 2003, 4752-4756.
- O. B. Flekhter, E. I. Boreko, L. R. Nigmatullina, N. I. Pavlova, S. N. Nikolaeva, O. V. Savinova, V. F. Eremin, L. A. Baltina, F. Z. Galin, G. A. Tolstikov, Synthesis and antiviral activity of hydrazides and substituted benzalhydrazides of betulinic acid and its derivatives, Bioorg. Khim., 2003, 29, 326-332.
- N. V. Galaiko, I. A. Tolmacheva, L. V. Volkova, V. V. Grishko, Synthesis of 2,3-seco-triterpene hydrazonohydrazides of the lupane and 19β,28-epoxy-18α-oleanane types, Chem. Nat. Compd., 2012, 48, 72-74
- V. V. Grishko, I. A. Tolmacheva, N. V. Galaiko, A. V. Pereslavceva, L. V. Anikina, L. V. Volkova, B. A. Bachmetyev, P. A. Slepukhin, Synthesis, transformation and biological evaluation of 2,3-secotriterpene acetylhydrazones and their derivatives, Eur. J. Med. Chem., 2013, 68, 203-211.
- S. Huneck, Triterpenes. VIII. Rearrangement of 1-substituted triterpenes into A-nor-B-homotriterpenes, Tetrahedron Lett., 1963, 1977-1980.
- O. O. Oyedeji, F. O. Shode, A. O. Oyedeji, S. P. Songca, E. T. Gwebu, G. M. Hill, W. N. Setzer, Semi-synthesis of nitrogen derivatives of oleanolic acid and effect on breast carcinoma MCF-7 cells, Anticancer Res., 2014, 34, 4135-4139.
- S. Shen, X. Xu, Z. Liu, J. Liu, L. Hu, Synthesis and structure-activity relationships of boswellic acid derivatives as potent VEGFR-2 inhibitors, Bioorg. Med. Chem., 2015, 23, 1982-1993.
LicenseAuthors who publish with this journal agree to the following terms:
- 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).