{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T11:52:53Z","timestamp":1781524373712,"version":"3.54.1"},"reference-count":28,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2019,11,23]],"date-time":"2019-11-23T00:00:00Z","timestamp":1574467200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Hypoxia is a common feature of neurodegenerative diseases, including Alzheimer\u2019s disease that may be responsible for disease pathogenesis and progression. Therefore, the hypoxia-inducible factor (HIF)1 system, responsible for hypoxic adaptation, is a potential therapeutic target to combat these diseases by activators of cytoprotective protein induction. We have selected a candidate molecule from our cytoprotective hydroxyquinoline library and developed a novel enantioselective synthesis for the production of its enantiomers. The use of quinidine or quinine as a catalyst enabled the preparation of enantiomer-pure products. We have utilized in vitro assays to evaluate cytoprotective activity, a fluorescence-activated cell sorting (FACS) based assay measuring mitochondrial membrane potential changes, and gene and protein expression analysis. Our data showed that the enantiomers of Q134 showed potent and similar activity in all tested assays. We have concluded that the enantiomers exert their cytoprotective activity via the HIF1 system through HIF1A protein stabilization.<\/jats:p>","DOI":"10.3390\/molecules24234269","type":"journal-article","created":{"date-parts":[[2019,11,25]],"date-time":"2019-11-25T03:10:00Z","timestamp":1574651400000},"page":"4269","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Enantioselective Synthesis of 8-Hydroxyquinoline Derivative, Q134 as a Hypoxic Adaptation Inducing Agent"],"prefix":"10.3390","volume":"24","author":[{"suffix":"Jr.","given":"L\u00e1szl\u00f3","family":"Hackler","sequence":"first","affiliation":[{"name":"Avidin Ltd., 6726 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e1ri\u00f3","family":"Gyuris","sequence":"additional","affiliation":[{"name":"Avidin Ltd., 6726 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orsolya","family":"Huzi\u00e1n","sequence":"additional","affiliation":[{"name":"Avicor Ltd., 6726 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R\u00f3bert","family":"Alf\u00f6ldi","sequence":"additional","affiliation":[{"name":"Avicor Ltd., 6726 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6998-5632","authenticated-orcid":false,"given":"G\u00e1bor J.","family":"Szebeni","sequence":"additional","affiliation":[{"name":"Avidin Ltd., 6726 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ram\u00f3na","family":"Mad\u00e1csi","sequence":"additional","affiliation":[{"name":"Avidin Ltd., 6726 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Levente","family":"Knapp","sequence":"additional","affiliation":[{"name":"Avicor Ltd., 6726 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0109-7097","authenticated-orcid":false,"given":"Iv\u00e1n","family":"Kanizsai","sequence":"additional","affiliation":[{"name":"Avidin Ltd., 6726 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L\u00e1szl\u00f3 G.","family":"Pusk\u00e1s","sequence":"additional","affiliation":[{"name":"Avidin Ltd., 6726 Szeged, Hungary"},{"name":"Aperus Pharma Co. Ltd., 6726 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,11,23]]},"reference":[{"key":"ref_1","first-page":"1","article-title":"Molecular mechanisms of neuropathological changes in Alzheimer\u2019s disease: A review","volume":"51","author":"Janout","year":"2013","journal-title":"Folia Neuropathol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1111\/ene.13439","article-title":"Alzheimer\u2019s disease","volume":"25","author":"Lane","year":"2018","journal-title":"Eur. J. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.brainresbull.2013.10.010","article-title":"Increase in Alzheimer\u2019s related markers preceeds memory disturbances: Studies in vasopressin-deficient Brattleboro rat","volume":"100","author":"Varga","year":"2014","journal-title":"Brain Res. Bull."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3555","DOI":"10.1007\/s00018-009-0141-0","article-title":"Contribution of hypoxia to Alzheimer\u2019s disease: Is HF1alpha a mediator of neurodegeneration?","volume":"66","author":"Ogunshola","year":"2009","journal-title":"Cell Mol. Life Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/j.expneurol.2009.07.033","article-title":"Pathological role of hypoxia in Alzheimer\u2019s disease","volume":"223","author":"Zhang","year":"2010","journal-title":"Exp. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1042\/bse0430153","article-title":"Hypoxia and Alzheimer\u2019s disease","volume":"43","author":"Peers","year":"2007","journal-title":"Essays Biochem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1007\/s004060170037","article-title":"Hypoxia and hypoxia-inducible factor modulated gene expression in brain: Involvement in neuroprotection and cell death","volume":"251","author":"Kietzmann","year":"2001","journal-title":"Eur. Arch. Psychiatry Clin. Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1111\/1440-1681.12717","article-title":"Hypoxia-inducible factors as neuroprotective agent in Alzheimer\u2019s disease","volume":"44","author":"Ashok","year":"2017","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3282","DOI":"10.1093\/brain\/aws269","article-title":"The novel proteasome inhibitor BSc2118 protects against cerebral ischaemia through HIF1A accumulation and enhanced angioneurogenesis","volume":"135","author":"Doeppner","year":"2012","journal-title":"Brain"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/j.chembiol.2010.03.008","article-title":"Utilization of an In Vivo Reporter for High Throughput Identification of Branched Small Molecule Regulators of Hypoxic Adaptation","volume":"17","author":"Smirnova","year":"2010","journal-title":"Chem. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5517","DOI":"10.1016\/j.bmcl.2006.08.040","article-title":"Structure-based design, synthesis, and SAR evaluation of a new series of 8-hydroxyquinolines as HF1alpha prolyl hydroxylase inhibitors","volume":"16","author":"Warshakoon","year":"2006","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e2214","DOI":"10.1038\/cddis.2016.107","article-title":"Inhibition of HIF-prolyl-4-hydroxylases prevents mitochondrial impairment and cell death in a model of neuronal oxytosis","volume":"7","author":"Neitemeier","year":"2016","journal-title":"Cell Death Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3119","DOI":"10.2174\/0929867043363848","article-title":"Recent advances in chemical genomics","volume":"11","author":"Darvas","year":"2004","journal-title":"Curr. Med. Chem."},{"key":"ref_14","first-page":"525","article-title":"A cell-microelectronic sensing technique for the screening of cytoprotective compounds","volume":"25","author":"Nagy","year":"2010","journal-title":"Int. J. Mol. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1817","DOI":"10.1253\/circj.CJ-12-1162","article-title":"Q50, an Iron-Chelating and zinc-complexing agent, improves cardiac function in rat models of ischemia\/reperfusion-induced myocardial injury","volume":"77","author":"Korkmaz","year":"2013","journal-title":"Circ. J."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Kanizsai, I., Mad\u00e1csi, R., Hackler, L., Gyuris, M., Szebeni, G., Huzi\u00e1n, O., and Puskas, L.G. (2018). Synthesis and Cytoprotective Characterization of 8-Hydroxyquinoline Betti Products. Molecules, 23.","DOI":"10.3390\/molecules23081934"},{"key":"ref_17","unstructured":"Puskas, L., Kanizsai, I., Pillot, T., Gyuris, M., Szabo, A., Takacs, F., and Hackler, L. (2017). Enantiomers of 8-Hydroxyquinoline Derivatives and the Synthesis Thereof. (Application 2017\/0197936 A1), U.S. Patent."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"6128","DOI":"10.1158\/1078-0432.CCR-08-3180","article-title":"Identification of a novel small molecule HF1alpha translation inhibitor","volume":"15","author":"Narita","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/S0022-2143(98)90091-9","article-title":"Hypoxia-inducible factor 1 and the molecular physiology of oxygen homeostasis","volume":"131","author":"Semenza","year":"1998","journal-title":"J. Lab. Clin. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1159\/000103385","article-title":"Characteristics of neural stem cells expanded in lowered oxygen and the potential role of hypoxia-inducible factor-1Alpha","volume":"15","author":"Zhang","year":"2006","journal-title":"Neurosignals"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.brainresrev.2009.09.006","article-title":"The role and regulation of hypoxia-inducible factor-1alpha expression in brain development and neonatal hypoxic-ischemic brain injury","volume":"62","author":"Fan","year":"2009","journal-title":"Brain Res. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1007\/s11172-019-2433-3","article-title":"Structural optimization of adaptaquin, a HIF prolyl hydroxylase inhibitor","volume":"68","author":"Poloznikov","year":"2019","journal-title":"Russ. Chem. Bull."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4273","DOI":"10.1021\/acs.joc.9b00242","article-title":"1,3-Dipolar Cycloaddition of Isatin-Derived Azomethine Ylides with 2-Azirines: Stereoselective Synthesis of 1,3-Diazaspiro[bicyclo[3.1.0]hexane]oxindoles","volume":"84","author":"Angyal","year":"2019","journal-title":"J. Org. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Hackler, L., \u00d3zsv\u00e1ri, B., Gyuris, M., Sipos, P., F\u00e1bi\u00e1n, G., Moln\u00e1r, E., Marton, A., Farag\u00f3, N., Mih\u00e1ly, J., and Nagy, L. (2016). The curcumin analog C-150, influencing NF-\u03baB, UPR and Akt\/Notch pathways has potent anticancer activity in vitro and in vivo. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0149832"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1186\/1476-511X-13-142","article-title":"Combination of unsaturated fatty acids and ionizing radiation on human glioma cells: Cellular, biochemical and gene expression analysis","volume":"13","author":"Antal","year":"2014","journal-title":"Lipids Health Dis."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Szebeni, G.J., Bal\u00e1zs, \u00c1., Madar\u00e1sz, I., P\u00f3cz, G., Ayaydin, F., Kanizsai, I., Fajka-Boja, R., Alf\u00f6ldi, R., Hackler, L., and Pusk\u00e1s, L.G. (2017). Achiral Mannich-Base Curcumin Analogs Induce Unfolded Protein Response and Mitochondrial Membrane Depolarization in PANC-1 Cells. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18102105"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"5245","DOI":"10.1158\/0008-5472.CAN-04-0496","article-title":"Normalization of real-time quantitative RT-PCR data: A model based variance estimation approach to identify genes suited for normalization\u2014Applied to bladder- and colon-cancer data-sets","volume":"64","author":"Andersen","year":"2004","journal-title":"Cancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e1700005","DOI":"10.1002\/ardp.201700005","article-title":"Mannich Curcuminoids as Potent Anticancer Agents","volume":"350","author":"Gyuris","year":"2017","journal-title":"Arch. Pharm."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/23\/4269\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:36:55Z","timestamp":1760189815000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/23\/4269"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,23]]},"references-count":28,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["molecules24234269"],"URL":"https:\/\/doi.org\/10.3390\/molecules24234269","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,23]]}}}