{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T09:06:00Z","timestamp":1791450360437,"version":"4.3.3"},"reference-count":49,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2020,11,27]],"date-time":"2020-11-27T00:00:00Z","timestamp":1606435200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100012352","name":"Universit\u00e0 degli Studi di Milano","doi-asserted-by":"publisher","award":["Piano di sostegno alla Ricerca 2019-LINEA 2."],"award-info":[{"award-number":["Piano di sostegno alla Ricerca 2019-LINEA 2."]}],"id":[{"id":"10.13039\/100012352","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The synthesis of a small library of 8-substituted 2-methyl-5,6,7,8-tetrahydroquinoline derivatives is presented. All the compounds were tested for their antiproliferative activity in non-cancer human dermal microvascular endothelial cells (HMEC-1) and cancer cells: human T-lymphocyte cells (CEM), human cervix carcinoma cells (HeLa), human dermal microvascular endothelial cells (HMEC-1), colorectal adenocarcinoma (HT-29), ovarian carcinoma (A2780), and biphasic mesothelioma (MSTO-211H). Compounds 3a, 5a, and 2b, showing significant IC50 values against the whole panel of the selected cells, were further synthesized and tested as pure enantiomers in order to shed light on how their stereochemistry might impact on the related biological effect. The most active compound (R)-5a was able to affect cell cycle phases and to induce mitochondrial membrane depolarization and cellular ROS production in A2780 cells.<\/jats:p>","DOI":"10.3390\/molecules25235561","type":"journal-article","created":{"date-parts":[[2020,11,27]],"date-time":"2020-11-27T09:16:49Z","timestamp":1606468609000},"page":"5561","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Biological Properties of New Chiral 2-Methyl-5,6,7,8-tetrahydroquinolin-8-amine-based Compounds"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1260-1335","authenticated-orcid":false,"given":"Giorgio","family":"Facchetti","sequence":"first","affiliation":[{"name":"DISFARM, Sezione di Chimica Generale e Organica \u201cA. Marchesini\u201d, Universit\u00e0 degli Studi di Milano via Venezian, 21, 20133 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5098-3143","authenticated-orcid":false,"given":"Michael S.","family":"Christodoulou","sequence":"additional","affiliation":[{"name":"DISFARM, Sezione di Chimica Generale e Organica \u201cA. Marchesini\u201d, Universit\u00e0 degli Studi di Milano via Venezian, 21, 20133 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0404-2139","authenticated-orcid":false,"given":"Lina Barrag\u00e1n","family":"Mendoza","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze del Farmaco, Universit\u00e0 degli Studi di Padova, via F. Marzolo, 5, 35131 Padova, Italy"},{"name":"Facultad de Ciencias Qu\u00edmicas, Universidad de Colima, Carr. Colima-Coquimatl\u00e1n km 9, Coquimatl\u00e1n  28400, Colima, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Cusinato","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze del Farmaco, Universit\u00e0 degli Studi di Padova, via F. Marzolo, 5, 35131 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2820-4035","authenticated-orcid":false,"given":"Lisa","family":"Dalla Via","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze del Farmaco, Universit\u00e0 degli Studi di Padova, via F. Marzolo, 5, 35131 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6210-0264","authenticated-orcid":false,"given":"Isabella","family":"Rimoldi","sequence":"additional","affiliation":[{"name":"DISFARM, Sezione di Chimica Generale e Organica \u201cA. Marchesini\u201d, Universit\u00e0 degli Studi di Milano via Venezian, 21, 20133 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,27]]},"reference":[{"key":"ref_1","first-page":"10","article-title":"Exploiting the power of stereochemistry in drugs: An overview of racemic and enantiopure drugs","volume":"1","author":"Sekhon","year":"2013","journal-title":"J. Mod. Med. Chem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1021\/acs.jmedchem.9b00640","article-title":"The exploration of chirality for improved druggability within the human kinome","volume":"63","author":"Saha","year":"2019","journal-title":"J. Med. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Uwai, Y. (2018). Enantioselective drug recognition by drug transporters. Molecules, 23.","DOI":"10.3390\/molecules23123062"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.jpba.2017.07.008","article-title":"The market of chiral drugs: Chiral switches versus de novo enantiomerically pure compounds","volume":"147","author":"Calcaterra","year":"2018","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1016\/0731-7085(93)80100-F","article-title":"Chiral drugs: The FDA perspective on manufacturing and control","volume":"11","year":"1993","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1039\/B509523A","article-title":"\u03b2-Phenylethylamines and the isoquinoline alkaloids","volume":"23","author":"Bentley","year":"2006","journal-title":"Nat. Prod. Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"7100","DOI":"10.1016\/j.tetlet.2008.09.098","article-title":"PIFA-mediated synthesis of novel pyrazoloquinolin-4-ones as potential ligands for the estrogen receptor","volume":"49","author":"Christodoulou","year":"2008","journal-title":"Tetrahedron Lett."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4338","DOI":"10.1016\/j.bmc.2010.04.076","article-title":"Novel pyrazole derivatives: Synthesis and evaluation of anti-angiogenic activity","volume":"18","author":"Christodoulou","year":"2010","journal-title":"Bioorganic Med. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4521","DOI":"10.1021\/ol061693c","article-title":"New 4-spiroannulated tetrahydroisoquinolines by a one-pot sequential procedure. Isolation and characterization of \u03c3-alkylpalladium Heck intermediates","volume":"8","author":"Beccalli","year":"2006","journal-title":"Org. Lett."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1080\/14756366.2016.1190711","article-title":"Hybrid imidazole (benzimidazole)\/pyridine (quinoline) derivatives and evaluation of their anticancer and antimycobacterial activity","volume":"31","author":"Mantu","year":"2016","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1016\/j.ejmech.2018.06.033","article-title":"Discovery and development of novel salicylate synthase (MbtI) furanic inhibitors as antitubercular agents","volume":"155","author":"Chiarelli","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4681","DOI":"10.1016\/j.bmc.2015.05.055","article-title":"Modified quaternary ammonium salts as potential antimalarial agents","volume":"23","author":"Basilico","year":"2015","journal-title":"Bioorganic Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1007\/s10822-018-0102-5","article-title":"Structure-based drug design, synthesis and biological assays of P. falciparum Atg3\u2013Atg8 protein\u2013protein interaction inhibitors","volume":"32","author":"Villa","year":"2018","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1080\/14756366.2019.1589462","article-title":"New insight into structure-activity of furan-based salicylate synthase (MbtI) inhibitors as potential antitubercular agents","volume":"34","author":"Chiarelli","year":"2019","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3389","DOI":"10.1002\/ejic.201900644","article-title":"Monofunctional PtII Complexes based on 8-aminoquinoline: Synthesis and pharmacological characterization","volume":"2019","author":"Facchetti","year":"2019","journal-title":"Eur. J. Inorg. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"18773","DOI":"10.1039\/C8NJ04558E","article-title":"8-Amino-5,6,7,8-tetrahydroquinoline in iridium(iii) biotinylated Cp* complex as artificial imine reductase","volume":"42","author":"Facchetti","year":"2018","journal-title":"New J. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"8797","DOI":"10.1002\/slct.201802223","article-title":"Asymmetric hydrogenation vs transfer hydrogenation in the reduction of cyclic imines","volume":"3","author":"Facchetti","year":"2018","journal-title":"ChemistrySelect"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1016\/j.jlumin.2015.08.003","article-title":"Luminescent chiral ionic Ir(III) complexes: Synthesis and photophysical properties","volume":"170","author":"Ricciardi","year":"2016","journal-title":"J. Lumin."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.jorganchem.2014.06.016","article-title":"Diastereoselectivity and catalytic activity in ruthenium complexes chiral at the metal centre","volume":"771","author":"Zerla","year":"2014","journal-title":"J. Organomet. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1016\/j.tetasy.2014.06.003","article-title":"8-Amino-5,6,7,8-tetrahydroquinolines as ligands in iridium(III) catalysts for the reduction of aryl ketones by asymmetric transfer hydrogenation (ATH)","volume":"25","author":"Zerla","year":"2014","journal-title":"Tetrahedron Asymmetry"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2982","DOI":"10.2174\/138527212804546714","article-title":"Enantioselective transfer hydrogenation of aryl ketones: Synthesis and 2D-NMR characterization of new 8-amino-5,6,7,8-tetrahydroquinoline Ru(II)-complexes","volume":"16","author":"Rimoldi","year":"2012","journal-title":"Curr. Org. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"9887","DOI":"10.1016\/j.tet.2003.10.053","article-title":"A valuable heterocyclic ring transformation: From isoxazolin-5(2H)-ones to quinolines","volume":"59","author":"Abbiati","year":"2003","journal-title":"Tetrahedron"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.ejmech.2005.11.003","article-title":"Synthesis and in vitro cytotoxicity of 1,2,3,4-tetrahydroisoquinoline derivatives","volume":"41","author":"Saitoh","year":"2006","journal-title":"Eur. J. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Chung, P.Y.L., Lam, P.L., Zhou, Y., Gasparello, J., Finotti, A., Chilin, A., Marzaro, G., Gambari, R., Bian, Z., and Kwok, W.M. (2018). Targeting DNA binding for NF-\u03baB as an anticancer approach in Hepatocellular Carcinoma. Cells, 7.","DOI":"10.3390\/cells7100177"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1016\/j.bmcl.2019.03.045","article-title":"Anticancer platinum(II) complexes bearing N-heterocycle rings","volume":"29","author":"Facchetti","year":"2019","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/0006-2952(94)90022-1","article-title":"Oxidative activity of primaquine metabolites on rat erythrocytes in vitro and in vivo","volume":"47","author":"Augusto","year":"1994","journal-title":"Biochem. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"111640","DOI":"10.1016\/j.ejmech.2019.111640","article-title":"Primaquine derivatives: Modifications of the terminal amino group","volume":"182","author":"Zorc","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1016\/j.ejmech.2017.11.083","article-title":"Primaquine hybrids as promising antimycobacterial and antimalarial agents","volume":"143","author":"Machado","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1016\/j.ejmech.2018.09.037","article-title":"Synthesis and mechanistic studies of quinolin-chlorobenzothioate derivatives with proteasome inhibitory activity in pancreatic cancer cell lines","volume":"158","author":"Hu","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"6455","DOI":"10.1021\/jm300684u","article-title":"Relating molecular properties and in vitro assay results to in vivo drug disposition and toxicity outcomes","volume":"55","author":"Sutherland","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/j.bcp.2006.04.029","article-title":"NRH: Quinone oxidoreductase 2 (NQO2) catalyzes metabolic activation of quinones and anti-tumor drugs","volume":"72","author":"Celli","year":"2006","journal-title":"Biochem. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1021\/acs.jmedchem.7b01420","article-title":"Discovery of tetrahydroisoquinoline-containing CXCR4 antagonists with improved in vitro ADMET properties","volume":"61","author":"Miller","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1021\/acsmedchemlett.8b00441","article-title":"Tetrahydroisoquinoline CXCR4 antagonists adopt a hybrid binding mode within the peptide subpocket of the CXCR4 receptor","volume":"10","author":"Katzman","year":"2018","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1002\/cbf.1485","article-title":"4-Amino-3-acetylquinoline-induced apoptosis of murine L1210 leukemia cells involves ROS-mitochondrial-mediated death signaling and activation of p38 MAPK","volume":"26","year":"2008","journal-title":"Cell Biochem. Funct."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1039\/C4MD00284A","article-title":"8-Hydroxyquinoline: A privileged structure with a broad-ranging pharmacological potential","volume":"6","author":"Song","year":"2015","journal-title":"MedChemComm"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.ejmech.2018.05.025","article-title":"Development of novel amino-quinoline-5,8-dione derivatives as NAD(P)H:quinone oxidoreductase 1 (NQO1) inhibitors with potent antiproliferative activities","volume":"154","author":"Ling","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1002\/open.201800056","article-title":"Cascade reaction by chemo- and biocatalytic approaches to obtain chiral hydroxy ketones and anti 1,3-diols","volume":"7","author":"Gandolfi","year":"2018","journal-title":"ChemistryOpen"},{"key":"ref_38","unstructured":"(2004). Organisation for Economic Cooperation and Development. OECD Guideline for Testing of Chemicals-Partition Coefficient (n-Octanol\/Water), High Performance Liquid Chromatography (HPLC) Method, 117, Adopted: 30.03.89, Organisation for Economic Cooperation and Development."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0169-409X(96)00423-1","article-title":"Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings","volume":"23","author":"Lipinski","year":"1997","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1021\/ci010315d","article-title":"Novel methods for the prediction of logP, pK(a), and logD","volume":"42","author":"Xing","year":"2008","journal-title":"J. Chem. Inf. Comput. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1016\/j.ejmech.2015.01.038","article-title":"Boehmeriasin A as new lead compound for the inhibition of topoisomerases and SIRT2","volume":"92","author":"Christodoulou","year":"2015","journal-title":"Eur. J. Med. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1021\/acsmedchemlett.9b00557","article-title":"Synthesis, antiproliferative effect, and topoisomerase ii inhibitory activity of 3-methyl-2-phenyl-1H-indoles","volume":"11","author":"Zidar","year":"2020","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_43","first-page":"0625","article-title":"Synthesis of enantiomerically pure 8-substituted 5,6,7,8-tetrahydroquinolines","volume":"2002","author":"Uenishi","year":"2002","journal-title":"Synthesis"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1042\/BCJ20160583","article-title":"Topoisomerases as anticancer targets","volume":"475","author":"Delgado","year":"2018","journal-title":"Biochem. J."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"11960","DOI":"10.1073\/pnas.0904875106","article-title":"A hyperfused mitochondrial state achieved at G1-S regulates cyclin E buildup and entry into S phase","volume":"106","author":"Mitra","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1006\/bbrc.1993.2438","article-title":"A new method for the cytofluorometric analysis of mitochondrial membrane potential using the j-aggregate forming lipophilic cation 5,5\u2032,6,6\u2032-tetrachloro-1,1\u2032,3,3\u2032-tetraethylbenzimidazolcarbocyanine iodide (JC-1)","volume":"197","author":"Cossarizza","year":"1993","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1016\/j.freeradbiomed.2009.12.022","article-title":"Reactive oxygen species, cellular redox systems, and apoptosis","volume":"48","author":"Circu","year":"2010","journal-title":"Free Radic. Biol. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2977","DOI":"10.1016\/j.bbamcr.2016.09.012","article-title":"Activation of apoptosis signalling pathways by reactive oxygen species","volume":"1863","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"10822","DOI":"10.1002\/chem.201701045","article-title":"Tandem tetrahydroisoquinoline-4-carboxylic acid\/\u03b2-Alanine as a new construct able to induce a flexible turn","volume":"23","author":"Bucci","year":"2017","journal-title":"Chem. Eur. J."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/23\/5561\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:38:12Z","timestamp":1760179092000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/23\/5561"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,27]]},"references-count":49,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["molecules25235561"],"URL":"https:\/\/doi.org\/10.3390\/molecules25235561","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,27]]}}}