In search of cytotoxic abietyl amides
Abstract
Based on prior research findings with pentacyclic triterpenoids, it was hypothesized that (un)-substituted benzylamides would exhibit enhanced cytotoxic activity compared to parent abietic acid. Conversely, none of these compounds was cytotoxic, but (homo)-piperazinyl amides demonstrated significant cytotoxic activity across multiple cell lines, even at concentrations as low single-digit micromolar levels. Additional staining experiments revealed that the most potent compound (with an EC50 value of 2.8 mM for HT29 colon carcinoma cells) primarily induced apoptosis rather than necrosis.
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- G. Bonsignore, M. Patrone, F. Grosso, S. Martinotti, E. Ranzato, Cancer Therapy Challenge: It Is Time to Look in the "St. Patrick's Well" of the Nature, Int. J. Mol. Sci., 2021, 22, 10380.
- S. Coseri, Natural products and their analogues as efficient anticancer drugs, Mini-Rev. Med. Chem., 2009, 9, 560-571.
- M. Erkisa, M. Sariman, O.G. Geyik, C. Geyik, T. Stanojkovic, E. Ulukaya, Natural products as a promising therapeutic strategy to target cancer stem cells, Curr. Med. Chem., 2022, 29, 741-783.
- M. He, L. Xia, J. Li, Potential Mechanisms of Plant-Derived Natural Products in the Treatment of Cervical Cancer, Biomolecules, 2021, 11, 1539.
- 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 Products as Sources of New Drugs over the Nearly Four Decades from 01/1981 to 09/2019, J. Nat. Prod., 2020, 83, 770-803.
- C. Fedele, R.W. Tothill, G.A. McArthur, Navigating the challenge of tumor heterogeneity in cancer therapy, Cancer Discovery, 2014, 4, 146-148.
- I.I. Wistuba, J.G. Gelovani, J.J. Jacoby, S.E. Davis, R.S. Herbst, Methodological and practical challenges for personalized cancer therapies, Nat. Rev. Clin. Oncol., 2011, 8, 135-141.
- S. Arı, M. Kargıoğlu, M. Temel, M. Konuk, Traditional Tar Production from the Anatolian Black Pine [Pinus nigra Arn. subsp. pallasiana (Lamb.) Holmboe var. pallasiana.- and its usages in Afyonkarahisar, Central Western Turkey,
J Ethnobiol Ethnomed, 2014, 10, 29.
- N. El Omari, F. Ezzahrae Guaouguaou, N. El Menyiy, T. Benali, T. Aanniz, I. Chamkhi,
A. Balahbib, D. Taha, M.A. Shariati, G. Zengin, M. El-Shazly, A. Bouyahya, Phytochemical and biological activities of Pinus halepensis mill., and their ethnomedicinal use, J. Ethnopharmacol., 2021, 268, 113661.
- I. Tumen, E.K. Akkol, H. Tastan, I. Suntar,
M. Kurtca, Research on the antioxidant, wound healing, and anti-inflammatory activities and the phytochemical composition of maritime pine (Pinus pinaster Ait), J. Ethnopharmacol., 2018, 211, 235-246.
- J.R. Hanson, Diterpenoids of terrestrial origin, Nat. Prod. Rep., 2011, 28, 1755-1772.
- P. Reveglia, A. Cimmino, M. Masi, P. Nocera,
N. Berova, G. Ellestad, A. Evidente, Pimarane diterpenes: Natural source, stereochemical configuration, and biological activity, Chirality, 2018, 30, 1115-1134.
- R. Acquaviva, G.A. Malfa, M.R. Loizzo, J. Xiao, S. Bianchi, R. Tundis, Advances on Natural Abietane, Labdane and Clerodane Diterpenes as Anticancer Agents: Sources and Mechanisms of Action, Molecules, 2022, 27, 4791.
- A.H. Conner, B.A. Nagasampagi, J.W. Rowe, Terpenoid and other extractives of western white pine bark, Phytochemistry, 1980, 19, 1121.
- I.I. Bardyshev, Purification of l-abietic acid (low-melting form), Zh. Obshch. Khim., 1941, 11, 996-1000.
- A.T. Karlberg, E. Bergstedt, A. Boman,
K. Bohlinder, C. Liden, J. Lars, G. Nilsson, J.E. Wahlberg, Is abietic acid the allergenic component of colophony?, Contact Dermatitis, 1985, 13, 209.
- A.T. Karlberg, K. Bohlinder, A. Boman,
U. Hacksell, J. Hermansson, S. Jacobsson, J.L.G. Nilsson, Identification of 15-hydroperoxyabietic acid as a contact allergen in Portuguese colophony, J. Pharm. Pharmacol., 1988, 40, 42.
- M.A. Fernandez, M.P. Tornos, M.D. Garcia,
B. De las Heras, A.M. Villar, M.T. Saenz, Anti-inflammatory activity of abietic acid, a diterpene isolated from Pimenta racemosa var. grissea,
J. Pharm. Pharmacol., 2001, 53, 867-872.
- N. Takahashi, T. Kawada, T. Goto, C.-S. Kim,
A. Taimatsu, K. Egawa, T. Yamamoto,
M. Jisaka, K. Nishimura, K. Yokota, R. Yu,
T. Fushiki, Abietic acid activates peroxisome proliferator-activated receptor-γ (PPARγ) in RAW264.7 macrophages and 3T3-L1 adipocytes to regulate gene expression involved in inflammation and lipid metabolism, FEBS Lett., 2003, 550, 190-194.
- M.A. Gonzalez, J. Correa-Royero, L. Agudelo, A. Mesa, L. Betancur-Galvis, Synthesis and biological evaluation of abietic acid derivatives, Eur. J. Med. Chem., 2009, 44, 2468-2472.
- H. Haffez, S. Osman, H.Y. Ebrahim, Z.A. Hassan, Growth Inhibition and Apoptotic Effect of Pine Extract and Abietic Acid on MCF-7 Breast Cancer Cells via Alteration of Multiple Gene Expressions Using In Vitro Approach, Molecules, 2022, 27, 293.
- Y. Ito, T. Ito, K. Yamashiro, F. Mineshiba,
K. Hirai, K. Omori, T. Yamamoto, S. Takashiba, Antimicrobial and antibiofilm effects of abietic acid on cariogenic Streptococcus mutans, Odontology, 2020, 108, 57-65.
- N. Yoshida, T. Takada, Y. Yamamura, I. Adachi, H. Suzuki, J. Kawakami, Inhibitory effects of terpenoids on multidrug resistance-associated protein 2- and breast cancer resistance protein-mediated transport, Drug Metab. Dispos., 2008, 36, 1206-1211.
- B. Brandes, S. Hoenke, N. Starke, I. Serbian,
H.-P. Deigner, A. Al-Harrasi, R. Csuk, Synthesis and cytotoxicity of apoptosis-inducing
N-heterocyclic triterpene amides, Eur. J. Med. Chem. Rep., 2022, 6, 100085.
- N.V. Heise, J. Heisig, L. Hoehlich, S. Hoenke,
R. Csuk, Synthesis and cytotoxicity of diastereomeric benzylamides derived from maslinic acid, augustic acid and bredemolic acid, Results Chem., 2023, 5, 100805.
- S. Hoenke, N.V. Heise, M. Kahnt, H.-P. Deigner, R. Csuk, Betulinic acid-derived amides are highly cytotoxic, apoptotic and selective, Eur. J. Med. Chem., 2020, 207, 112815.
- M. Kozubek, L. Hoehlich, S. Hoenke, H.-P. Deigner, A. Al-Harrasi, R. Csuk, Apoptotic activity of substituted 3-O-acetyl-betulinic acid benzylamides, Eur. J. Med. Chem. Rep., 2021, 3, 100016.
- 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.
- O. Kraft, A.-K. Hartmann, S. Hoenke, I. Serbian,
R. Csuk, Madecassic Acid-A New Scaffold for Highly Cytotoxic Agents, Int. J. Mol. Sci., 2022, 23, 4362.
- J. Wiemann, A. Al-Harrasi, R. Csuk, Cytotoxic
Dehydroabietylamine Derived Compounds, Anticancer Agents Med. Chem., 2020, 20,
-1767.
DOI: http://dx.doi.org/10.13171/mjc02307191709csuk
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