{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T08:27:20Z","timestamp":1769761640386,"version":"3.49.0"},"reference-count":43,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2019,12,26]],"date-time":"2019-12-26T00:00:00Z","timestamp":1577318400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Szeged Open Access Fund","award":["4059"],"award-info":[{"award-number":["4059"]}]},{"name":"EFOP","award":["3.6.3-VEKOP-16-2017-00009"],"award-info":[{"award-number":["3.6.3-VEKOP-16-2017-00009"]}]},{"name":"EU-funded Hungarian grant","award":["GINOP-2.3.2-15-2016-00012"],"award-info":[{"award-number":["GINOP-2.3.2-15-2016-00012"]}]},{"name":"EU-funded Hungarian grant","award":["UNKP-19-3-SZTE-222"],"award-info":[{"award-number":["UNKP-19-3-SZTE-222"]}]},{"DOI":"10.13039\/501100005881","name":"Emberi Eroforr\u00e1sok Miniszt\u00e9riuma","doi-asserted-by":"publisher","award":["20391-3\/2018\/FEKUSTRAT"],"award-info":[{"award-number":["20391-3\/2018\/FEKUSTRAT"]}],"id":[{"id":"10.13039\/501100005881","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>A library of steviol-based trifunctional chiral ligands was developed from commercially available natural stevisoide and applied as chiral catalysts in the addition of diethylzinc to benzaldehyde. The key intermediate steviol methyl ester was prepared according to literature procedure. Depending on the epoxidation process, both cis- and trans-epoxyalcohols were obtained. Subsequent oxirane ring opening with primary and secondary amines afforded 3-amino-1,2-diols. The ring opening with sodium azide followed by a \u201cclick\u201d reaction with alkynes resulted in dihydroxytriazoles. The regioselective ring closure of N-substituted aminodiols with formaldehyde was also investigated. The resulting steviol-type aminodiols were tested against a panel of human adherent cancer cell lines (A2780, SiHa, HeLa, and MDA-MB-231). It was consistently found that the N-benzyl substituent is an essential part within the molecule and the ring closure towards N-benzyl substituted oxazolidine ring system increased the antiproliferative activity to a level comparable with that of cisplatine. In addition, structure\u2013activity relationships were examined by assessing substituent effects on the aminodiol systems.<\/jats:p>","DOI":"10.3390\/ijms21010184","type":"journal-article","created":{"date-parts":[[2019,12,27]],"date-time":"2019-12-27T05:37:08Z","timestamp":1577425028000},"page":"184","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Stereoselective Synthesis and Antiproliferative Activity of Steviol-Based Diterpen Aminodiols"],"prefix":"10.3390","volume":"21","author":[{"given":"D\u00e1niel","family":"Ozsv\u00e1r","sequence":"first","affiliation":[{"name":"Institute of Pharmaceutical Chemistry, University of Szeged, Interdisciplinary Excellent Center, H-6720 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vikt\u00f3ria","family":"Nagy","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics and Biopharmacy, University of Szeged, H-6720 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3243-5300","authenticated-orcid":false,"given":"Istv\u00e1n","family":"Zupk\u00f3","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics and Biopharmacy, University of Szeged, H-6720 Szeged, Hungary"},{"name":"Interdisciplinary Centre of Natural Products, University of Szeged, H-6720 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2432-8409","authenticated-orcid":false,"given":"Zsolt","family":"Szakonyi","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Chemistry, University of Szeged, Interdisciplinary Excellent Center, H-6720 Szeged, Hungary"},{"name":"Interdisciplinary Centre of Natural Products, University of Szeged, H-6720 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,12,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1398","DOI":"10.1002\/chem.201404303","article-title":"Chiral Ligands Derived from Monoterpenes: Application in the Synthesis of Optically Pure Secondary Alcohols via Asymmetric Catalysis","volume":"21","author":"Suisse","year":"2015","journal-title":"Chem. Eur. J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1016\/j.tetasy.2007.03.027","article-title":"Stereoselective synthesis of cytoxazone and its analogues","volume":"18","author":"Grajewska","year":"2007","journal-title":"Tetrahedron Asymmetry"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1782","DOI":"10.1016\/j.drudis.2017.07.013","article-title":"Polypharmacology of conformationally locked methanocarba nucleosides","volume":"22","author":"Jacobson","year":"2017","journal-title":"Drug Discov. Today"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"5520","DOI":"10.1016\/j.bmc.2009.06.039","article-title":"Synthetic strategies toward carbocyclic purine\u2013pyrimidine hybrid nucleosides","volume":"17","author":"Sadler","year":"2009","journal-title":"Bioorg. Med. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.ejmech.2016.04.034","article-title":"1\u2032-Homonucleosides and their structural analogues: A review","volume":"118","author":"Piotrowska","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1940","DOI":"10.1126\/science.1411510","article-title":"Discovery of a peptide-based renin inhibitor with oral bioavailability and efficacy","volume":"257","author":"Kleinert","year":"1992","journal-title":"Science"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4763","DOI":"10.1016\/S0040-4020(99)00148-9","article-title":"Practical synthesis of Abbott amino-diol: A core unit of the potent renin inhibitor Zankiren","volume":"55","author":"Chandrasekhar","year":"1999","journal-title":"Tetrahedron"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3203","DOI":"10.1016\/j.tet.2015.04.011","article-title":"Asymmetric synthesis of optically active 3-amino-1,2-diols from N-acyl-protected allylamines via catalytic diboration with Rh[bis(oxazolinyl)phenyl] catalysts","volume":"71","author":"Toribatake","year":"2015","journal-title":"Tetrahedron"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"5756","DOI":"10.1016\/j.tet.2006.03.079","article-title":"Enantioselective synthesis of (\u2212)-cytoxazone and (+)-epi-cytoxazone, novel cytokine modulators via Sharpless asymmetric epoxidation and l-proline catalyzed Mannich reaction","volume":"62","author":"Paraskar","year":"2006","journal-title":"Tetrahedron"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"7091","DOI":"10.1021\/jo060964u","article-title":"New Chiral Schiff Base as a Tridentate Ligand for Catalytic Enantioselective Addition of Diethylzinc to Aldehydes","volume":"71","author":"Tanaka","year":"2006","journal-title":"J. Org. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1134\/S1070428010080014","article-title":"New chiral ligands based on (+)-\u03b1-pinene","volume":"46","author":"Koneva","year":"2010","journal-title":"Russ. J. Org. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.1016\/j.tetasy.2014.06.017","article-title":"Stereoselective syntheses and transformations of chiral 1,3-aminoalcohols and 1,3-diols derived from nopinone","volume":"25","author":"Szakonyi","year":"2014","journal-title":"Tetrahedron Asymmetry"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"7163","DOI":"10.1002\/chem.201600749","article-title":"Stereoselective Synthesis and Modelling-Driven Optimisation of Carane-Based Aminodiols and 1,3-Oxazines as Catalysts for the Enantioselective Addition of Diethylzinc to Benzaldehyde","volume":"22","author":"Szakonyi","year":"2016","journal-title":"Chem. Eur. J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1016\/j.tetasy.2011.06.013","article-title":"Stereoselective synthesis of carane-based aminodiols as chiral ligands for the catalytic addition of diethylzinc to aldehydes","volume":"22","author":"Szakonyi","year":"2011","journal-title":"Tetrahedron Asymmetry"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Tashenov, Y., Daniels, M., Robeyns, K., Van Meervelt, L., Dehaen, W., Suleimen, Y., and Szakonyi, Z. (2018). Stereoselective Syntheses and Application of Chiral Bi- and Tridentate Ligands Derived from (+)-Sabinol. Molecules, 23.","DOI":"10.3390\/molecules23040771"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1016\/j.tetasy.2016.04.009","article-title":"Stereoselective synthesis and application of tridentate aminodiols derived from (+)-pulegone","volume":"27","author":"Gonda","year":"2016","journal-title":"Tetrahedron Asymmetry"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1016\/S0957-4166(01)00206-3","article-title":"Chiral aminoalcohols with a menthane skeleton as catalysts for the enantioselective addition of diethylzinc to benzaldehyde","volume":"12","author":"Panev","year":"2001","journal-title":"Tetrahedron Asymmetry"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1055\/s-1990-21244","article-title":"Diastereoselective Ring Opening of 2-Substituted N -Benzyl-4,4, 7\u03b1-trimethyl- trans -octahydro-1,3-benzoxazines by Grignard Reagents. Highly Enantioselective Synthesis of Primary Amines","volume":"1990","author":"Alberola","year":"1990","journal-title":"Synlett"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4130","DOI":"10.1021\/jo960047w","article-title":"Synthesis of Enantiopure Primary Amines by Stereoselective Ring Opening of Chiral Octahydro-1,3-benzoxazines by Grignard and Organoaluminum Reagents","volume":"61","author":"Nieto","year":"1996","journal-title":"J. Org. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4923","DOI":"10.1021\/jo034251c","article-title":"Synthesis of Enantiopure 3-Azabicyclo[3.2.0]heptanes by Diastereoselective Intramolecular [2+2] Photocycloaddition Reactions on Chiral Perhydro-1,3-benzoxazines","volume":"68","author":"Pedrosa","year":"2003","journal-title":"J. Org. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2809","DOI":"10.1016\/S0957-4166(00)00230-5","article-title":"Regio- and stereoselective 6-exo-trig radical cyclisations onto chiral perhydro-1,3-benzoxazines: Synthesis of enantiopure 3-alkylpiperidines","volume":"11","author":"Pedrosa","year":"2000","journal-title":"Tetrahedron Asymmetry"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1055\/s-0034-1368550","article-title":"Simultaneous Determination of Thirteen Aminoalcohol-Diterpenoid Alkaloids in the Lateral Roots of Aconitum carmichaeli by Solid-Phase Extraction-Liquid Chromatography\u2013Tandem Mass Spectrometry","volume":"80","author":"Ding","year":"2014","journal-title":"Planta Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3915","DOI":"10.1055\/s-0037-1611897","article-title":"Recent Advances Towards Syntheses of Diterpenoid Alkaloids","volume":"51","author":"Dank","year":"2019","journal-title":"Synthesis"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1021\/np400203b","article-title":"Steviol Glycosides: Chemical Diversity, Metabolism, and Function","volume":"76","author":"Ceunen","year":"2013","journal-title":"J. Nat. Prod."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1986","DOI":"10.2174\/138527212803251703","article-title":"Stevioside and Steviol as Starting Materials in Organic Synthesis","volume":"16","author":"Moons","year":"2012","journal-title":"Curr. Org. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1002\/cbdv.201200406","article-title":"Cytotoxic and Apoptosis-Inducing Activities of Steviol and Isosteviol Derivatives against Human Cancer Cell Lines","volume":"10","author":"Ukiya","year":"2013","journal-title":"Chem. Biodivers."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.bmcl.2010.11.055","article-title":"Synthesis and biological evaluation of novel exo-methylene cyclopentanone tetracyclic diterpenoids as antitumor agents","volume":"21","author":"Li","year":"2011","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3944","DOI":"10.1021\/acs.jmedchem.5b00208","article-title":"ent-Kaurane Diterpenoids from Chinese Liverworts and Their Antitumor Activities through Michael Addition As Detected in Situ by a Fluorescence Probe","volume":"58","author":"Lin","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"289","DOI":"10.3724\/SP.J.1009.2013.00289","article-title":"Glycosylation of ent-kaurene derivatives and an evaluation of their cytotoxic activities","volume":"11","author":"Zou","year":"2013","journal-title":"Chin. J. Nat. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/0165-1218(86)90088-1","article-title":"Characterization of bacterial mutagenicity mediated by 13-hydroxy-ent-kaurenoic acid (steviol) and several structurally-related derivatives and evaluation of potential to induce glutathione S-transferase in mice","volume":"169","author":"Pezzuto","year":"1986","journal-title":"Mutat. Res. Toxicol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3057","DOI":"10.1021\/acs.jnatprod.6b00671","article-title":"Synthesis of C-4-Substituted Steviol Derivatives and Their Inhibitory Effects against Hepatitis B Virus","volume":"79","author":"Lin","year":"2016","journal-title":"J. Nat. Prod."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Avent, A.G., Hanson, J.R., Hitchcock, P.B., and De Oliveira, B.H. (1990). The influence of a 15-hydroxy group on the rearrangement reactions of steviol and its 16,17-epoxide. J. Chem. Soc. Perkin Trans. 1, 2661\u20132665.","DOI":"10.1039\/p19900002661"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"BeMiller, J.N. (2019). Carbohydrate and Noncarbohydrate Sweeteners. Carbohydrate Chemistry for Food Scientists, Elsevier.","DOI":"10.1016\/B978-0-12-812069-9.05001-9"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1016\/j.ejmech.2018.07.052","article-title":"Diterpenoid lead stevioside and its hydrolysis products steviol and isosteviol: Biological activity and structural modification","volume":"156","author":"Wang","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3807","DOI":"10.1055\/s-0031-1289293","article-title":"Efficient Synthesis of Novel Jolkinolides and Related Derivatives Starting from Stevioside","volume":"2011","author":"Shi","year":"2011","journal-title":"Synthesis"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3217","DOI":"10.1016\/S0040-4020(01)93662-2","article-title":"Diterpenoid total synthesis\u2014XIX","volume":"28","author":"Mori","year":"1972","journal-title":"Tetrahedron"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Aggarwal, V.K., and Yu Fang, G. (2005). Highly regioselective and diastereoselective epoxidation of allylic amines with Oxone. Chem. Commun., 3448.","DOI":"10.1039\/b503516c"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"8786","DOI":"10.1021\/jo701332v","article-title":"Diastereo- and Enantioselective Synthesis of Orthogonally Protected 2,4-Diaminocyclopentanecarboxylates: A Flip from \u03b2-Amino- to \u03b2,\u03b3-Diaminocarboxylates","volume":"72","author":"Kiss","year":"2007","journal-title":"J. Org. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1016\/j.tetasy.2010.04.054","article-title":"Carbocyclic nucleosides from enantiomeric, \u03b1-pinane-based aminodiols","volume":"21","author":"Szakonyi","year":"2010","journal-title":"Tetrahedron Asymmetry"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"13607","DOI":"10.1002\/chem.201802484","article-title":"Regio- and Stereoselective Synthesis of Bicyclic Limonene-Based Chiral Aminodiols and Spirooxazolidines","volume":"24","author":"Le","year":"2018","journal-title":"Chem. Eur. J."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Le, T.M., Szilasi, T., Volford, B., Szekeres, A., F\u00fcl\u00f6p, F., and Szakonyi, Z. (2019). Stereoselective Synthesis and Investigation of Isopulegol-Based Chiral Ligands. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20164050"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3130","DOI":"10.1021\/jo034007l","article-title":"Modular Amino Alcohol Ligands Containing Bulky Alkyl Groups as Chiral Controllers for Et 2 Zn Addition to Aldehydes: Illustration of a Design Principle","volume":"68","author":"Jimeno","year":"2003","journal-title":"J. Org. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0022-1759(83)90303-4","article-title":"Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays","volume":"65","author":"Mosmann","year":"1983","journal-title":"J. Immunol. Methods"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/1\/184\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:45:54Z","timestamp":1760190354000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/1\/184"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,26]]},"references-count":43,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,1]]}},"alternative-id":["ijms21010184"],"URL":"https:\/\/doi.org\/10.3390\/ijms21010184","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,26]]}}}