{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,29]],"date-time":"2026-03-29T11:14:13Z","timestamp":1774782853841,"version":"3.50.1"},"reference-count":55,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2019,2,20]],"date-time":"2019-02-20T00:00:00Z","timestamp":1550620800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"PT2020 (Programa Operacional do Centro 2020),  and the financial support by FEDER (European Regional Development Fund) through the COMPETE 2020 Programme (Operational Programme for Competitiveness and Internationalisation)","award":["Grant n\u00ba 3269, drugs2CAD"],"award-info":[{"award-number":["Grant n\u00ba 3269, drugs2CAD"]}]},{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia (FCT)","award":["SFRH\/BD\/66020\/2009"],"award-info":[{"award-number":["SFRH\/BD\/66020\/2009"]}]},{"name":"MINECO-European Commission FEDER","award":["SAF2014-56059-R"],"award-info":[{"award-number":["SAF2014-56059-R"]}]},{"name":"Ag\u00e8ncia de Gesti\u00f3 d\u2019Ajuts Universitaris i de Recerca (AGAUR) \u2013 Generalitat de Catalunya","award":["2014SGR1017"],"award-info":[{"award-number":["2014SGR1017"]}]},{"name":"FEDER and FCT","award":["REEQ\/481\/QUI\/2006, RECI\/QEQ-FI\/0168\/2012 and CENTRO-07-CT62-FEDER-002012"],"award-info":[{"award-number":["REEQ\/481\/QUI\/2006, RECI\/QEQ-FI\/0168\/2012 and CENTRO-07-CT62-FEDER-002012"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>A new series of glycyrrhetinic acid derivatives has been synthesized via the introduction of different heterocyclic rings conjugated with an \u03b1,\u03b2-unsaturated ketone in its ring A. These new compounds were screened for their antiproliferative activity in a panel of nine human cancer cell lines. Compound 10 was the most active derivative, with an IC50 of 1.1 \u00b5M on Jurkat cells, which is 96-fold more potent than that of glycyrrhetinic acid, and was 4-fold more selective toward that cancer cell line. Further biological studies performed in Jurkat cells showed that compound 10 is a potent inducer of apoptosis that activates both the intrinsic and extrinsic pathways.<\/jats:p>","DOI":"10.3390\/molecules24040766","type":"journal-article","created":{"date-parts":[[2019,2,20]],"date-time":"2019-02-20T11:45:39Z","timestamp":1550663139000},"page":"766","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Synthesis and Antiproliferative Activity of Novel Heterocyclic Glycyrrhetinic Acid Derivatives"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1564-6528","authenticated-orcid":false,"given":"Daniela P. S.","family":"Alho","sequence":"first","affiliation":[{"name":"Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Centre for Neuroscience and Cell Biology, 3004-504 Coimbra, Portugal"}]},{"given":"Jorge A. R.","family":"Salvador","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Centre for Neuroscience and Cell Biology, 3004-504 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2062-4633","authenticated-orcid":false,"given":"Marta","family":"Cascante","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Diagonal 643, 08028 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0693-2207","authenticated-orcid":false,"given":"Silvia","family":"Marin","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Diagonal 643, 08028 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain"}]}],"member":"1968","published-online":{"date-parts":[[2019,2,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1039\/b515312n","article-title":"Pharmacological activities of natural triterpenoids and their therapeutic implications","volume":"23","author":"Dzubak","year":"2006","journal-title":"Nat. Prod. Rep."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1039\/c2np20060k","article-title":"Ursane-type pentacyclic triterpenoids as useful platforms to discover anticancer drugs","volume":"29","author":"Salvador","year":"2012","journal-title":"Nat. Prod. Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/B978-0-444-63294-4.00002-4","article-title":"Highlights of pentacyclic triterpenoids in the cancer settings","volume":"Volume 41","author":"AttaUrRahman","year":"2014","journal-title":"Studies in Natural Products Chemistry"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1610","DOI":"10.3390\/molecules20011610","article-title":"Triterpenes as potentially cytotoxic compounds","volume":"20","author":"Chudzik","year":"2015","journal-title":"Molecules"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.ejmech.2017.07.013","article-title":"Oleanane-, ursane-, and quinone methide friedelane-type triterpenoid derivatives: Recent advances in cancer treatment","volume":"142","author":"Salvador","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/j.ejmech.2015.07.004","article-title":"Incorporation of a michael acceptor enhances the antitumor activity of triterpenoic acids","volume":"101","author":"Heller","year":"2015","journal-title":"Eur. J. Med. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.ejmech.2016.02.057","article-title":"Synthesis and anticancer activity of novel fluorinated asiatic acid derivatives","volume":"114","author":"Goncalves","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.ejmech.2016.07.045","article-title":"Synthesis and cytotoxic activity of novel a-ring cleaved ursolic acid derivatives in human non-small cell lung cancer cells","volume":"123","author":"Mendes","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ejmech.2016.04.051","article-title":"Urea derivates of ursolic, oleanolic and maslinic acid induce apoptosis and are selective cytotoxic for several human tumor cell lines","volume":"119","author":"Sommerwerk","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ejmech.2016.12.040","article-title":"Rhodamine b conjugates of triterpenoic acids are cytotoxic mitocans even at nanomolar concentrations","volume":"127","author":"Sommerwerk","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Spivak, A., Khalitova, R., Nedopekina, D., Dzhemileva, L., Yunusbaeva, M., Odinokov, V., D\u2019Yakonov, V., and Dzhemilev, U. (2018). Synthesis and evaluation of anticancer activities of novel c-28 guanidine-functionalized triterpene acid derivatives. Molecules, 23.","DOI":"10.3390\/molecules23113000"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1002\/ptr.2362","article-title":"Review of pharmacological effects of glycyrrhiza sp and its bioactive compounds","volume":"22","author":"Asl","year":"2008","journal-title":"Phytother. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.canlet.2012.02.037","article-title":"Targeted inhibition of tumor proliferation, survival, and metastasis by pentacyclic triterpenoids: Potential role in prevention and therapy of cancer","volume":"320","author":"Shanmugam","year":"2012","journal-title":"Cancer Lett."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1831","DOI":"10.1002\/ijc.27852","article-title":"18 beta-glycyrrhetinic acid inhibits hepatocellular carcinoma development by reversing hepatic stellate cell-mediated immunosuppression in mice","volume":"132","author":"Kuang","year":"2013","journal-title":"Int. J. Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1177\/0960327114554045","article-title":"18-glycyrrhetinic acid alleviates 2-acetylaminofluorene-induced hepatotoxicity in wistar rats: Role in hyperproliferation, inflammation and oxidative stress","volume":"34","author":"Hasan","year":"2015","journal-title":"Hum. Exp. Toxicol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"615","DOI":"10.3892\/ijo.2017.4059","article-title":"18 beta-glycyrrhetinic acid exhibits potent antitumor effects against colorectal cancer via inhibition of cell proliferation and migration","volume":"51","author":"Wang","year":"2017","journal-title":"Int. J. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/j.lfs.2008.07.014","article-title":"18 beta-glycyrrhetinic acid induces apoptotic cell death in siha cells and exhibits a synergistic effect against antibiotic anti-cancer drug toxicity","volume":"83","author":"Lee","year":"2008","journal-title":"Life Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1923","DOI":"10.1002\/jcp.22920","article-title":"18 beta-glycyrrhetinic acid (concur) induces apoptosis through modulation of akt\/foxo3a\/bim pathway in human breast cancer mcf-7 cells","volume":"227","author":"Sharma","year":"2012","journal-title":"J. Cell. Physiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/s11060-013-1292-2","article-title":"18beta-glycyrrhetinic acid induces apoptosis in pituitary adenoma cells via ros\/mapks-mediated pathway","volume":"116","author":"Wang","year":"2014","journal-title":"J. Neuro-Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1007\/s11010-016-2705-2","article-title":"Chemopreventive effect of 18 beta-glycyrrhetinic acid via modulation of inflammatory markers and induction of apoptosis in human hepatoma cell line (hepg2)","volume":"416","author":"Hasan","year":"2016","journal-title":"Mol. Cell. Biochem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.ejphar.2017.05.026","article-title":"The selective effect of glycyrrhizin and glycyrrhetinic acid on topoisomerase ii alpha and apoptosis in combination with etoposide on triple negative breast cancer mda-mb-231 cells","volume":"809","author":"Cai","year":"2017","journal-title":"Eur. J. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"155","DOI":"10.2174\/0929867033368538","article-title":"Chemical modification of glycyrrhizic acid as a route to new bioactive compounds for medicine","volume":"10","author":"Baltina","year":"2003","journal-title":"Curr. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s13065-016-0222-8","article-title":"Design, synthesis, and biological evaluation of the novel glycyrrhetinic acid-cinnamoyl hybrids as anti-tumor agents","volume":"10","author":"Guo","year":"2016","journal-title":"Chem. Cent. J."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Li, Y., Feng, L., Song, Z.F., Li, H.B., and Huai, Q.Y. (2016). Synthesis and anticancer activities of glycyrrhetinic acid derivatives. Molecules, 21.","DOI":"10.3390\/molecules21020199"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1002\/cmdc.201700271","article-title":"Synthesis and biological evaluation of glycyrrhetic acid derivatives as potential vegfr2 inhibitors","volume":"12","author":"Yan","year":"2017","journal-title":"ChemMedChem"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Xu, B., Wu, G.R., Zhang, X.Y., Yan, M.M., Zhao, R., Xue, N.N., Fang, K., Wang, H., Chen, M., and Guo, W.B. (2017). An overview of structurally modified glycyrrhetinic acid derivatives as antitumor agents. Molecules, 22.","DOI":"10.3390\/molecules22060924"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.2147\/DDDT.S166051","article-title":"Design and preparation of derivatives of oleanolic and glycyrrhetinic acids with cytotoxic properties","volume":"12","author":"Wang","year":"2018","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4385","DOI":"10.1016\/j.bmc.2010.04.085","article-title":"Synthesis and structure-activity relationship study of novel cytotoxic carbamate and n-acylheterocyclic bearing derivatives of betulin and betulinic acid","volume":"18","author":"Santos","year":"2010","journal-title":"Bioorg. Med. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5774","DOI":"10.1016\/j.bmc.2012.08.010","article-title":"Synthesis of novel ursolic acid heterocyclic derivatives with improved abilities of antiproliferation and induction of p53, p21(waf1) and noxa in pancreatic cancer cells","volume":"20","author":"Leal","year":"2012","journal-title":"Bioorg. Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4905","DOI":"10.1021\/cr200409f","article-title":"Click chemistry for drug development and diverse chemical-biology applications","volume":"113","author":"Thirumurugan","year":"2013","journal-title":"Chem. Rev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2022","DOI":"10.2174\/0929867322666150421110819","article-title":"Click chemistry, a potent tool in medicinal sciences","volume":"22","author":"Musumeci","year":"2015","journal-title":"Curr. Med. Chem."},{"key":"ref_32","first-page":"1585","article-title":"The application of click chemistry in the synthesis of agents with anticancer activity","volume":"9","author":"Ma","year":"2015","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1604","DOI":"10.1016\/j.drudis.2017.07.007","article-title":"Mechanistic applications of click chemistry for pharmaceutical drug discovery and drug delivery","volume":"22","author":"Meghani","year":"2017","journal-title":"Drug Discov. Today"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"7661","DOI":"10.3390\/molecules18077661","article-title":"1,2,3-triazole-substituted oleanolic acid derivatives: Synthesis and antiproliferative activity","volume":"18","author":"Pertino","year":"2013","journal-title":"Molecules"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.steroids.2017.04.002","article-title":"A convergent synthesis of novel alkyne-azide cycloaddition congeners of betulinic acid as potent cytotoxic agent","volume":"123","author":"Dangroo","year":"2017","journal-title":"Steroids"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"636","DOI":"10.2174\/0929867324666171009122612","article-title":"Click reactions in chemistry of triterpenes - advances towards development of potential therapeutics","volume":"25","author":"Pokorny","year":"2018","journal-title":"Curr. Med. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Pertino, M.W., Petrera, E., Alche, L.E., and Schmeda-Hirschmann, G. (2018). Synthesis, antiviral and cytotoxic activity of novel terpenyl hybrid molecules prepared by click chemistry. Molecules, 23.","DOI":"10.3390\/molecules23061343"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"6706","DOI":"10.1039\/C4OB00703D","article-title":"Synthesis of methyl 2-cyano-3,12-dioxo-18 beta-olean-1,9(11)-dien-30-oate analogues to determine the active groups for inhibiting cell growth and inducing apoptosis in leukemia cells","volume":"12","author":"Li","year":"2014","journal-title":"Org. Biomol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"7458","DOI":"10.1016\/j.bmc.2010.08.054","article-title":"Synthesis and antitumour activity of glycyrrhetinic acid derivatives","volume":"18","author":"Schwarz","year":"2010","journal-title":"Bioorg. Med. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"11541","DOI":"10.1016\/j.tet.2008.10.035","article-title":"Chemical modifications of natural triterpenes-glycyrrhetinic and boswellic acids: Evaluation of their biological activity","volume":"64","author":"Rao","year":"2008","journal-title":"Tetrahedron"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"18215","DOI":"10.3390\/molecules191118215","article-title":"Amino acid derivatives of ligustrazine-oleanolic acid as new cytotoxic agents","volume":"19","author":"Chu","year":"2014","journal-title":"Molecules"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.ejmech.2012.11.022","article-title":"Neutral and charged phosphine\/scorpionate copper(i) complexes: Effects of ligand assembly on their antiproliferative activity","volume":"59","author":"Porchia","year":"2013","journal-title":"Eur. J. Med. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3967","DOI":"10.1039\/C5RA19120C","article-title":"Synthesis and biological evaluation of novel asiatic acid derivatives with anticancer activity","volume":"6","author":"Goncalves","year":"2016","journal-title":"RSC Advances"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1038\/bjc.2014.325","article-title":"Structurally diverse mdm2-p53 antagonists act as modulators of mdr-1 function in neuroblastoma","volume":"111","author":"Chen","year":"2014","journal-title":"Br. J. Cancer"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1097\/CAD.0000000000000174","article-title":"Cytotoxic activity of novel palladium-based compounds on leukemia cell lines","volume":"26","author":"Antunovic","year":"2015","journal-title":"Anti-Cancer Drugs"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"837","DOI":"10.3390\/11110837","article-title":"Hydantoin derivatives of l- and d-amino acids: Synthesis and evaluation of their antiviral and antitumoral activity","volume":"11","author":"Rajic","year":"2006","journal-title":"Molecules"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/1756-9966-30-87","article-title":"Apoptosis in cancer: From pathogenesis to treatment","volume":"30","author":"Wong","year":"2011","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_48","first-page":"215","article-title":"Glycyrrhetic acid (a metabolic substance and aglycon of glycyrrhizin) induces apoptosis in human hepatoma, promyelotic leukemia and stomach cancer cells","volume":"17","author":"Hibasami","year":"2006","journal-title":"Int. J. Mol. Med."},{"key":"ref_49","first-page":"4043","article-title":"Glycyrrhetinic acid and related compounds induce g1 arrest and apoptosis in human hepatocellular carcinoma hepg2","volume":"25","author":"Satomi","year":"2005","journal-title":"Anticancer Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1016\/j.ejphar.2010.09.047","article-title":"18 beta-glycyrrhetinic acid potentiates apoptotic effect of trichostatin a on human epithelial ovarian carcinoma cell lines","volume":"649","author":"Lee","year":"2010","journal-title":"Eur. J. Pharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1007\/s11010-012-1412-x","article-title":"18 beta-glycyrrhetinic acid potentiates hsp90 inhibition-induced apoptosis in human epithelial ovarian carcinoma cells via activation of death receptor and mitochondrial pathway","volume":"370","author":"Yang","year":"2012","journal-title":"Mol. Cell Biochem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1038\/35042675","article-title":"Surfing the p53 network","volume":"408","author":"Vogelstein","year":"2000","journal-title":"Nature"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2527","DOI":"10.1242\/jcs.064501","article-title":"P53 at a glance","volume":"123","author":"Brady","year":"2010","journal-title":"J. Cell Sci."},{"key":"ref_55","first-page":"5502","article-title":"Frequent mutations in the p53 tumor suppressor gene in human leukemia t-cell lines","volume":"10","author":"Cheng","year":"1990","journal-title":"Mol. Cell Biol."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/4\/766\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:33:29Z","timestamp":1760186009000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/4\/766"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,2,20]]},"references-count":55,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2019,2]]}},"alternative-id":["molecules24040766"],"URL":"https:\/\/doi.org\/10.3390\/molecules24040766","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,2,20]]}}}