{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T16:56:44Z","timestamp":1775235404509,"version":"3.50.1"},"reference-count":52,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2019,8,14]],"date-time":"2019-08-14T00:00:00Z","timestamp":1565740800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"(Programa Operacional do Centro 2020) PT2020","award":["project n\u00ba 3269"],"award-info":[{"award-number":["project n\u00ba 3269"]}]},{"name":"FEDER (Programa Operacional Factores de Competitividade\u2014COMPETE 2020)","award":["Projecto Estrat\u00e9gico: UID\/NEU\/04539\/2013"],"award-info":[{"award-number":["Projecto Estrat\u00e9gico: UID\/NEU\/04539\/2013"]}]},{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia (FCT)","award":["PhD grant SFRH\/BD\/66020\/2009"],"award-info":[{"award-number":["PhD grant SFRH\/BD\/66020\/2009"]}]},{"name":"MINECO-European Commission FEDER\u2014Una manera de hacer Europa","award":["SAF2017-89673-R"],"award-info":[{"award-number":["SAF2017-89673-R"]}]},{"name":"Ag\u00e8ncia de Gesti\u00f3 d\u2019Ajuts Universitaris i de Recerca (AGAUR)\u2014Generalitat de Catalunya","award":["2017SGR1033"],"award-info":[{"award-number":["2017SGR1033"]}]},{"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 series of new glycyrrhetinic acid derivatives was synthesized via the opening of its ring A along with the coupling of an amino acid. The antiproliferative activity of the derivatives was evaluated against a panel of nine human cancer cell lines. Compound 17 was the most active compound, with an IC50 of 6.1 \u00b5M on Jurkat cells, which is 17-fold more potent than that of glycyrrhetinic acid, and was up to 10 times more selective toward that cancer cell line. Further biological investigation in Jurkat cells showed that the antiproliferative activity of compound 17 was due to cell cycle arrest at the S phase and induction of apoptosis.<\/jats:p>","DOI":"10.3390\/molecules24162938","type":"journal-article","created":{"date-parts":[[2019,8,14]],"date-time":"2019-08-14T03:59:26Z","timestamp":1565755166000},"page":"2938","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Synthesis and Antiproliferative Activity of Novel A-Ring Cleaved 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, 3000-504 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, 3000-504 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":[[2019,8,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: Globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA-Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.jep.2005.05.011","article-title":"Plants as a source of anti-cancer agents","volume":"100","author":"Cragg","year":"2005","journal-title":"J. Ethnopharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1021\/acs.jnatprod.5b01055","article-title":"Natural products as sources of new drugs from 1981 to 2014","volume":"79","author":"Newman","year":"2016","journal-title":"J. Nat. Prod."},{"key":"ref_4","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_5","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_6","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_7","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_8","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_9","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1016\/j.bmcl.2015.12.064","article-title":"Targeting cancer cells with oleanolic and ursolic acid derived hydroxamates","volume":"26","author":"Wiemann","year":"2016","journal-title":"Bio Org. Med. Chem. Lett."},{"key":"ref_10","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_11","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_12","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_13","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_14","doi-asserted-by":"crossref","first-page":"20","DOI":"10.3389\/fchem.2018.00434","article-title":"Synthesis and biological evaluation of new madecassic acid derivatives targeting erk cascade signaling","volume":"6","author":"Valdeira","year":"2018","journal-title":"Front. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1007\/s00044-019-02366-w","article-title":"Synthesis of oleanolic acid\/ursolic acid\/glycyrrhetinic acid-hydrogen sulfide donor hybrids and their antitumor activity","volume":"28","author":"Sheng","year":"2019","journal-title":"Med. Chem. Res."},{"key":"ref_16","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_17","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_18","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1179\/135100005X57346","article-title":"Inhibitory effect of 18 beta-glycyrrhetinic acid on 12-o-tetradecanoyl phorbol-13-acetate-induced cutaneous oxidative stress and tumor promotion in mice","volume":"10","author":"Agarwal","year":"2005","journal-title":"Redox Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"619","DOI":"10.3923\/pjbs.2011.619.626","article-title":"Chemopreventive potential of 18beta-glycyrrhetinic acid: An active constituent of liquorice, in 7,12-dimethylbenz(a)anthracene induced hamster buccal pouch carcinogenesis","volume":"14","author":"Kowsalya","year":"2011","journal-title":"Pak. J. Biol. Sci."},{"key":"ref_20","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_21","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_22","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1177\/2058739218762993","article-title":"The protective effects of 18 beta-glycyrrhetinic acid against inflammation microenvironment in gastric tumorigenesis targeting pge2-ep2 receptor-mediated arachidonic acid pathway","volume":"16","author":"Cao","year":"2018","journal-title":"Eur. J. Inflamm."},{"key":"ref_23","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_24","doi-asserted-by":"crossref","first-page":"981","DOI":"10.3892\/ijo.2015.2819","article-title":"Glycyrrhetinic acid induces g1-phase cell cycle arrest in human non-small cell lung cancer cells through endoplasmic reticulum stress pathway","volume":"46","author":"Zhu","year":"2015","journal-title":"Int. J. Oncol."},{"key":"ref_25","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_26","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_27","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_28","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_29","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_30","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_31","doi-asserted-by":"crossref","first-page":"6416","DOI":"10.1016\/j.bmcl.2010.09.070","article-title":"Synthesis and biological evaluation of furoxan-based nitric oxide-releasing derivatives of glycyrrhetinic acid as anti-hepatocellular carcinoma agents","volume":"20","author":"Lai","year":"2010","journal-title":"Bio Org. Med. Chem. Lett."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/j.bmc.2013.10.049","article-title":"Synthesis of novel 2-cyano substituted glycyrrhetinic acid derivatives as inhibitors of cancer cells growth and no production in lps-activated j-774 cells","volume":"22","author":"Salomatina","year":"2014","journal-title":"Bio Org. Med. Chem."},{"key":"ref_33","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_34","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_35","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_36","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_37","doi-asserted-by":"crossref","first-page":"4274","DOI":"10.1016\/j.bmc.2011.05.054","article-title":"Beta 18b-glycyrrhetinic acid derivatives induced mitochondrial-mediated apoptosis through reactive oxygen species-mediated p53 activation in ntub1 cells","volume":"19","author":"Lin","year":"2011","journal-title":"Bio Org. Med. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"4814","DOI":"10.1016\/j.bmcl.2009.06.046","article-title":"Esters of betulin and betulinic acid with amino acids have improved water solubility and are selectively cytotoxic toward cancer cells","volume":"19","author":"Kulbacka","year":"2009","journal-title":"Bio Org. Med. Chem. Lett."},{"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":"Bio Org. Med. Chem."},{"key":"ref_40","first-page":"731","article-title":"Synthesis and cytotoxic activity of methyl glycyrrhetinate esterified with amino acids","volume":"67","author":"Csuk","year":"2012","journal-title":"Z. Fur Nat. Sect. B J. Chem. Sci."},{"key":"ref_41","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_42","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1016\/j.bmc.2009.02.025","article-title":"Synthesis, anti-inflammatory, and antioxidant activities of 18 beta-glycyrrhetinic acid derivatives as chemical mediators and xanthine oxidase inhibitors","volume":"17","author":"Maitraie","year":"2009","journal-title":"Bio Org. Med. Chem."},{"key":"ref_43","first-page":"1239","article-title":"Microbial conversion of glycyrrhetinic acids .2. Microbial conversion of 18beta-glycyrrhetinic acid and 22-alpha-hydroxy-18beta-glycyrrhetinic acid by chainia-antibiotica","volume":"50","author":"Sakano","year":"1986","journal-title":"Agric. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"7048","DOI":"10.1021\/jo990566+","article-title":"Bis(2-methoxyethyl)aminosulfur trifluoride: A new broad-spectrum deoxofluorinating agent with enhanced thermal stability","volume":"64","author":"Lal","year":"1999","journal-title":"J. Org. Chem"},{"key":"ref_45","unstructured":"(1984). High yield 11-de:Oxo:Glycyrrhetic Acid Prepn\u2013by Reducing Glycyrrhetic Acid in Solvent Using Zinc and Hydrochloric Acid, JP59070638-A.; JP90024264-B, JP59070638-A."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"5356","DOI":"10.1016\/j.ejmech.2011.08.038","article-title":"Synthesis and antitumor activity of ring a modified glycyrrhetinic acid derivatives","volume":"46","author":"Csuk","year":"2011","journal-title":"Eur. J. Med. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"5432","DOI":"10.1016\/j.bmc.2007.05.057","article-title":"The synthesis of 18 beta-glycyrrhetinic acid derivatives which have increased antiproliferative and apoptotic effects in leukemia cells","volume":"15","author":"Liu","year":"2007","journal-title":"Bio Org. Med. Chem"},{"key":"ref_48","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_49","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_50","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_51","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_52","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 Adv."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/16\/2938\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:10:53Z","timestamp":1760188253000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/16\/2938"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,8,14]]},"references-count":52,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2019,8]]}},"alternative-id":["molecules24162938"],"URL":"https:\/\/doi.org\/10.3390\/molecules24162938","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,8,14]]}}}