{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T02:04:36Z","timestamp":1791511476490,"version":"4.3.4"},"reference-count":23,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2019,11,11]],"date-time":"2019-11-11T00:00:00Z","timestamp":1573430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003549","name":"Hungarian Scientific Research Fund","doi-asserted-by":"publisher","award":["129037"],"award-info":[{"award-number":["129037"]}],"id":[{"id":"10.13039\/501100003549","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011019","name":"Nemzeti Kutat\u00e1si Fejleszt\u00e9si \u00e9s Innov\u00e1ci\u00f3s Hivatal","doi-asserted-by":"publisher","award":["16-1-2016-0036"],"award-info":[{"award-number":["16-1-2016-0036"]}],"id":[{"id":"10.13039\/501100011019","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>By means of copper(I)-and ruthenium(II)-catalyzed click reactions of quinine- and quinidine-derived alkynes with azide-substituted chalcones a systematic series of novel cinchona-chalcone hybrid compounds, containing 1,4-disubstituted- and 1,5-disubstituted 1,2,3-triazole linkers, were synthesized and evaluated for their cytotoxic activity on four human malignant cell lines (PANC-1, COLO-205, A2058 and EBC-1). In most cases, the cyclization reactions were accompanied by the transition-metal-catalyzed epimerization of the C9-stereogenic centre in the cinchona fragment. The results of the in vitro assays disclosed that all the prepared hybrids exhibit marked cytotoxicity in concentrations of low micromolar range, while the C9-epimerized model comprising quinidine- and (E)-1-(4-(3-oxo-3-(3,4,5-trimethoxyphenyl)prop-1-en-1-yl)phenyl) fragments, connected by 1,5-disubstituted 1,2,3-triazole linker, and can be regarded as the most potent lead of which activity is probably associated with a limited conformational space allowing for the adoption of a relatively rigid well-defined conformation identified by DFT modelling. The mechanism of action of this hybrid along with that of a model with markedly decreased activity were approached by comparative cell-cycle analyses in PANC-1 cells. These studies disclosed that the hybrid of enhanced antiproliferative activity exerts significantly more extensive inhibitory effects in subG1, S and G2\/M phases than does the less cytotoxic counterpart.<\/jats:p>","DOI":"10.3390\/molecules24224077","type":"journal-article","created":{"date-parts":[[2019,11,12]],"date-time":"2019-11-12T04:07:07Z","timestamp":1573531627000},"page":"4077","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Synthesis, Structure and In Vitro Cytotoxic Activity of Novel Cinchona\u2014Chalcone Hybrids with 1,4-Disubstituted- and 1,5-Disubstituted 1,2,3-Triazole Linkers"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4990-4281","authenticated-orcid":false,"given":"Tam\u00e1s","family":"Jernei","sequence":"first","affiliation":[{"name":"MTA-ELTE Research Group of Peptide Chemistry, P\u00e1zm\u00e1ny P. s\u00e9t\u00e1ny 1\/A, H-1117 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cintia","family":"Dur\u00f3","sequence":"additional","affiliation":[{"name":"Department of Inorganic Chemistry, E\u00f6tv\u00f6s Lor\u00e1nd University (ELTE), P\u00e1zm\u00e1ny P. s\u00e9t\u00e1ny 1\/A, H-1117 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Dembo","sequence":"additional","affiliation":[{"name":"Department of Inorganic Chemistry, E\u00f6tv\u00f6s Lor\u00e1nd University (ELTE), P\u00e1zm\u00e1ny P. s\u00e9t\u00e1ny 1\/A, H-1117 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eszter","family":"Lajk\u00f3","sequence":"additional","affiliation":[{"name":"Department of Genetics, Cell- and Immunobiology, Semmelweis University, Nagyv\u00e1rad t\u00e9r 4, H-1089 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ang\u00e9la","family":"Tak\u00e1cs","sequence":"additional","affiliation":[{"name":"Department of Genetics, Cell- and Immunobiology, Semmelweis University, Nagyv\u00e1rad t\u00e9r 4, H-1089 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9002-0296","authenticated-orcid":false,"given":"L\u00e1szl\u00f3","family":"K\u0151hidai","sequence":"additional","affiliation":[{"name":"Department of Genetics, Cell- and Immunobiology, Semmelweis University, Nagyv\u00e1rad t\u00e9r 4, H-1089 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7637-7133","authenticated-orcid":false,"given":"Gitta","family":"Schlosser","sequence":"additional","affiliation":[{"name":"MTA-ELTE Research Group of Peptide Chemistry, P\u00e1zm\u00e1ny P. s\u00e9t\u00e1ny 1\/A, H-1117 Budapest, Hungary"},{"name":"Department of Analytical Chemistry, E\u00f6tv\u00f6s Lor\u00e1nd University (ELTE), P\u00e1zm\u00e1ny P. s\u00e9t\u00e1ny 1\/A, H-1117 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antal","family":"Cs\u00e1mpai","sequence":"additional","affiliation":[{"name":"Department of Inorganic Chemistry, E\u00f6tv\u00f6s Lor\u00e1nd University (ELTE), P\u00e1zm\u00e1ny P. s\u00e9t\u00e1ny 1\/A, H-1117 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,11,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"90","DOI":"10.4103\/0973-7847.194047","article-title":"Anticancer Alkaloids from Trees: Development into Drugs","volume":"10","author":"Isah","year":"2016","journal-title":"Pharmacogn. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1778","DOI":"10.1111\/cbdd.13346","article-title":"Cytotoxic and trypanocidal activities of cinchona alkaloid derivatives","volume":"92","author":"Kacprzak","year":"2018","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1097\/00001813-199802000-00004","article-title":"A phase I\/II trial of paclitaxel for non-Hodgkin\u2019s lymphoma followed by paclitaxel plus quinine in drug-resistant disease","volume":"9","author":"Miller","year":"1998","journal-title":"Anti-Cancer Drugs"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1182\/blood.V77.2.348.348","article-title":"Synergistic inhibition by verapamil and quinine of P-glycoprotein- mediated multidrug resistance in a human myeloma cell line model","volume":"77","author":"Lehnert","year":"1991","journal-title":"Blood"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1007\/BF00685114","article-title":"Modulation of mitomycin C-induced multidrug resistance in vitro","volume":"27","author":"Dorr","year":"1991","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_6","first-page":"2316","article-title":"Acylated mono-, bis- and tris- Cinchona-Based Amines Containing Ferrocene or Organic Residues: Synthesis, Structure and in Vitro Antitumor Activity on Selected Human Cancer Cell Lines","volume":"17","author":"Drahos","year":"2010","journal-title":"Molecules"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1016\/j.bmcl.2015.12.059","article-title":"Synthesis, structure and in vitro cytostatic activity of ferrocene\u2014Cinchona hybrids","volume":"26","author":"Kocsis","year":"2015","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.ejmech.2015.05.004","article-title":"Anti-cancer chalcones: Structural and molecular target perspectives","volume":"98","author":"Mahapatra","year":"2015","journal-title":"Eur. J. Med. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"7228","DOI":"10.1021\/jm901278z","article-title":"Structure\u2212Activity Relationship Studies of Chalcone Leading to 3-Hydroxy-4,3\u2032,4\u2032,5\u2032-tetramethoxychalcone and Its Analogues as Potent Nuclear Factor \u03baB Inhibitors and Their Anticancer Activities","volume":"52","author":"Srinivasan","year":"2009","journal-title":"J. Med. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"363","DOI":"10.2174\/138945009787846416","article-title":"Chalcones Derivatives Acting as Cell Cycle Blockers: Potential Anti Cancer Drugs?","volume":"10","author":"Boumendjel","year":"2009","journal-title":"Curr. Drug Targets"},{"key":"ref_11","first-page":"80","article-title":"Bioactivity of chalcones","volume":"107","author":"Hijova","year":"2016","journal-title":"Bratisl. Med. J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1039\/C7MT00183E","article-title":"Ferrocene\u2013cinchona hybrids with triazolyl-chalcone linkers act as pro-oxidants and sensitize human cancer cell lines to paclitaxel","volume":"9","author":"Kocsis","year":"2017","journal-title":"Metallomics"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2596","DOI":"10.1002\/1521-3773(20020715)41:14<2596::AID-ANIE2596>3.0.CO;2-4","article-title":"A Stepwise Huisgen Cycloaddition Process: Copper(I)-Catalyzed Regioselective \u201cLigation\u201d of Azides and Terminal Alkynes","volume":"41","author":"Rostovtsev","year":"2002","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1002\/chir.10265","article-title":"Conformational spaces of Cinchona alkaloids","volume":"15","author":"Caner","year":"2003","journal-title":"Chirality"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5648","DOI":"10.1063\/1.464913","article-title":"Density-functional thermochemistry. III. The role of exact exchange","volume":"98","author":"Becke","year":"1993","journal-title":"J. Chem. Phys."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1103\/PhysRevB.37.785","article-title":"Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density","volume":"37","author":"Lee","year":"1988","journal-title":"Phys. Rev. B"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"11623","DOI":"10.1021\/j100096a001","article-title":"Ab Initio Calculation of Vibrational Absorption and Circular Dichroism Spectra Using Density Functional Force Fields","volume":"98","author":"Stephens","year":"1994","journal-title":"J. Phys. Chem."},{"key":"ref_18","unstructured":"Hehre, W.J., Radom, L., Schleyer, P.V.R., and Pople, J.A. (1986). Ab Initio Molecular Orbital Theory, Wiley."},{"key":"ref_19","unstructured":"Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Scalmani, G., Barone, V., Petersson, G.A., and Nakatsuji, H. (2016). Gaussian 09, Gaussian, Inc.. Revision A.02."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1002\/psc.2472","article-title":"Investigation on chemotactic drug targeting (chemotaxis and adhesion) inducer effect of GnRH-III derivatives in Tetrahymena and human leukemia cell line","volume":"19","author":"Pungor","year":"2013","journal-title":"J. Pept. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.dental.2009.08.007","article-title":"Real-time xCELLigence impedance analysis of the cytotoxicity of dental composite components on human gingival fibroblasts","volume":"26","author":"Urcan","year":"2010","journal-title":"Dent. Mater."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"B\u00e1r\u00e1ny, P., Ol\u00e1h, R.S., Kov\u00e1cs, I., Czuczi, T., Szab\u00f3, C.L., Tak\u00e1cs, A., Lajk\u00f3, E., L\u00e1ng, O., K\u0151hidai, L., and Schlosser, G. (2018). Ferrocene-Containing Impiridone (ONC201) Hybrids: Synthesis, DFT Modelling, In Vitro Evaluation, and Structure\u2013Activity Relationships. Molecules, 23.","DOI":"10.3390\/molecules23092248"},{"key":"ref_23","first-page":"2495","article-title":"Comparative cell biological study of in vitro antitumor and antimetastatic activity on melanoma cells of GnRH-III-containing conjugates modified with short-chain fatty acids","volume":"26","author":"Spring","year":"2018","journal-title":"Beilstein J. Org. Chem."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/22\/4077\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:33:35Z","timestamp":1760189615000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/22\/4077"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,11]]},"references-count":23,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2019,11]]}},"alternative-id":["molecules24224077"],"URL":"https:\/\/doi.org\/10.3390\/molecules24224077","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,11]]}}}