{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T12:57:10Z","timestamp":1790513830685,"version":"4.1.0"},"reference-count":50,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2022,8,8]],"date-time":"2022-08-08T00:00:00Z","timestamp":1659916800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Dr. Kleist Stiftung (Berlin)"},{"name":"The Stiftung David (K\u00f6ln)"},{"name":"The Blankenheimerdorf e.V. (Eifel)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Isatis tinctoria and its indigo dyes have already provided highly active anti-leukaemic lead compounds, with the focus mainly being on indirubin, whereas indigo itself is inactive. There are many more indigoids to find in this plant extract, for example, quingdainone, an indigoid derived from tryptanthrin. We present here a new synthesis of hitherto neglected substituted quingdainones, which is very necessary due to their poor solubility behaviour, and a structure-dependent anti-leukaemic activity study of a number of compounds. Substituted \u03b1-phenylaminoacrylic acid was synthesised by hydrogen sulfide extrusion from an analogue mercaptoacetic acid, available from the condensation of rhodanin and a substituted tryptanthrin. It is shown that just improving water solubility does not increase anti-leukaemic activity, since a quingdainone carboxylic acid is inactive compared to dihydroxyquingdainone. The most effective compound, dihydroxyquingdainone with an AC50 of 7.5 \u00b5mole, is further characterised, revealing its ability to overcome multidrug resistance in leukaemia cells (Nalm-6\/BeKa) with p-glycoprotein expression.<\/jats:p>","DOI":"10.3390\/molecules27155038","type":"journal-article","created":{"date-parts":[[2022,8,8]],"date-time":"2022-08-08T22:33:11Z","timestamp":1659997991000},"page":"5038","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Dihydroxyquingdainone Induces Apoptosis in Leukaemia and Lymphoma Cells via the Mitochondrial Pathway in a Bcl-2- and Caspase-3-Dependent Manner and Overcomes Resistance to Cytostatic Drugs In Vitro"],"prefix":"10.3390","volume":"27","author":[{"given":"Jennifer","family":"Baas","sequence":"first","affiliation":[{"name":"Department of Pediatric Hematology\/Oncology, Helios Clinic Schwerin, Wismarsche Stra\u00dfe 393-397, 19055 Schwerin, Germany"},{"name":"Department of Pediatric Hematology\/Oncology, Municipal Clinics of Cologne, Children\u2019s Hospital of the City Cologne, Amsterdamer Stra\u00dfe 59, 50735 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Bieringer","sequence":"additional","affiliation":[{"name":"Organic-Analytical Chemistry, Weihenstephan-Triesdorf University of Applied Sciences, 94315 Straubing, Germany"},{"name":"TUM Campus Straubing for Biotechnology and Sustainability, Technical University of Munich, 94315 Straubing, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corazon","family":"Frias","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology\/Oncology, Helios Clinic Schwerin, Wismarsche Stra\u00dfe 393-397, 19055 Schwerin, Germany"},{"name":"Department of Pediatric Hematology\/Oncology, Municipal Clinics of Cologne, Children\u2019s Hospital of the City Cologne, Amsterdamer Stra\u00dfe 59, 50735 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerico","family":"Frias","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology\/Oncology, Helios Clinic Schwerin, Wismarsche Stra\u00dfe 393-397, 19055 Schwerin, Germany"},{"name":"Department of Pediatric Hematology\/Oncology, Municipal Clinics of Cologne, Children\u2019s Hospital of the City Cologne, Amsterdamer Stra\u00dfe 59, 50735 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"Soehnchen","sequence":"additional","affiliation":[{"name":"Medical School Hamburg (MSH), University of Applied Sciences and Medical University, Am Kaiserkai 1, 20457 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8895-9416","authenticated-orcid":false,"given":"Corinna","family":"Urmann","sequence":"additional","affiliation":[{"name":"Organic-Analytical Chemistry, Weihenstephan-Triesdorf University of Applied Sciences, 94315 Straubing, Germany"},{"name":"TUM Campus Straubing for Biotechnology and Sustainability, Technical University of Munich, 94315 Straubing, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steffi","family":"Ritter","sequence":"additional","affiliation":[{"name":"Organic-Analytical Chemistry, Weihenstephan-Triesdorf University of Applied Sciences, 94315 Straubing, Germany"},{"name":"TUM Campus Straubing for Biotechnology and Sustainability, Technical University of Munich, 94315 Straubing, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herbert","family":"Riepl","sequence":"additional","affiliation":[{"name":"Organic-Analytical Chemistry, Weihenstephan-Triesdorf University of Applied Sciences, 94315 Straubing, Germany"},{"name":"TUM Campus Straubing for Biotechnology and Sustainability, Technical University of Munich, 94315 Straubing, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aram","family":"Prokop","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology\/Oncology, Helios Clinic Schwerin, Wismarsche Stra\u00dfe 393-397, 19055 Schwerin, Germany"},{"name":"Department of Pediatric Hematology\/Oncology, Municipal Clinics of Cologne, Children\u2019s Hospital of the City Cologne, Amsterdamer Stra\u00dfe 59, 50735 Cologne, Germany"},{"name":"Medical School Hamburg (MSH), University of Applied Sciences and Medical University, Am Kaiserkai 1, 20457 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1054\/bjoc.2000.1546","article-title":"Inhibition of cyclin-dependent kinase 1 (CDK 1) by indirubin derivatives in human tumor cells","volume":"84","author":"Marko","year":"2001","journal-title":"Br. J. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1038\/9035","article-title":"Indirubin, the active constituent of a Chinese antileukaemia medicine, inhibits cyclin-dependent kinases","volume":"1","author":"Hoessel","year":"1999","journal-title":"Nat. Cell Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3547","DOI":"10.1016\/0031-9422(89)80390-5","article-title":"The Identity of Candidine and Qingdainone","volume":"28","author":"Bergman","year":"1989","journal-title":"Phytochemistry"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Laatsch, H., and Ludwig-K\u00f6hn, H. (1986). Isolierung des indigoiden Pigmentes Candidin aus Urin und Hamofiltrat von Uramikern. Liebigs Ann. Chem., 1847\u20131853.","DOI":"10.1002\/jlac.198619861104"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1007\/BF00425335","article-title":"Synthese und Biosynthese substituierter Tryptanthrine","volume":"107","author":"Fiedler","year":"1976","journal-title":"Arch. Microbiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1021\/np800064w","article-title":"Isolation, Structure Elucidation, and Synthesis of Cytotoxic Tryptanthrin Analogues from Phaius mishmensis","volume":"71","author":"Jao","year":"2008","journal-title":"J. Nat. Prod."},{"key":"ref_7","unstructured":"Liu, D., and Yang, C. (2015). Application of Quingdainone in the Manufacture of an Antitumor Agent. (CN104910160AA)."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1039\/P19870000519","article-title":"Reduction and Stereochemical Studies through N.M.R. and X-Ray Techniques","volume":"1","author":"Bergman","year":"1987","journal-title":"J. Chem. Soc. Perkin. Trans."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"7711","DOI":"10.1021\/acs.joc.6b01346","article-title":"Thionation of Tryptanthrin, Rutaecarpine, and Related Molecules with a Reagent Prepared from P4S10 and Pyridine","volume":"81","author":"Kingi","year":"2016","journal-title":"J. Org. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1002\/hlca.201200042","article-title":"Improved Synthesis of Indirubin Derivatives by Sequential Build-Up of the Indoxyl Unit: First Preparation of Fluorescent Indirubins","volume":"95","author":"Riepl","year":"2012","journal-title":"Helv. Chim. Acta"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1002\/hlca.19230060149","article-title":"Uber die Verwendung des Rhodanins zu organischen Synthesen 111. Derivate des Oxindols","volume":"6","author":"Mahal","year":"1923","journal-title":"Helv. Chim. Acta"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1002\/mrc.4211","article-title":"Unambigous (Z)-geometry and complete 1H and 13C assignments of candidine","volume":"53","author":"Boiteau","year":"2015","journal-title":"Magn. Res. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4151","DOI":"10.1021\/ef800511v","article-title":"Reactions of Polyphosphoric Acid and Bitumen Model Compounds with Oxygenated Functional Groups: Where is the Phosphorylation?","volume":"22","author":"Masson","year":"2008","journal-title":"Energy Fuels"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3147","DOI":"10.1021\/jo00834a065","article-title":"Methyl Aryl Ether Cleavage in Benzazole","volume":"35","author":"Orlando","year":"1970","journal-title":"J. Org. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2517","DOI":"10.21769\/BioProtoc.2517","article-title":"Rapid Profiling Cell Cycle by Flow Cytometry Using Concurrent Staining of DNA and Mitotic Markers","volume":"7","author":"Shen","year":"2017","journal-title":"Bio-Protocol"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"12096","DOI":"10.1002\/chem.201200083","article-title":"Total Synthesis of Indole-derived Allocolchicine Analogs Exhibiting Strong Apoptosis-inducing Activity","volume":"18","author":"Sitnikov","year":"2012","journal-title":"Chem. Eur. J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4501","DOI":"10.1002\/ejoc.201200677","article-title":"Sythesis of Oxa-B-Ring Analogs of Colchicine through Rh-catalyzed Intramolecular (5 + 2) Cycloaddition","volume":"24","author":"Termath","year":"2012","journal-title":"Eur. J. Org. Chem."},{"key":"ref_18","first-page":"13017","article-title":"Nucleoside Analogues with a 1,3-Diene-Fe(CO)3 Substructure: Stereoselective Synthesis, Configurational Assignment, and Apoptosis-Inducing Activity","volume":"39","author":"Velcicky","year":"2013","journal-title":"Chemistry"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2158","DOI":"10.1039\/C5MD00320B","article-title":"Synthesis of indole-derived allocholchicine congeners exhibiting pronounced anti proliferative and apoptosis inducing properties","volume":"6","author":"Sitnikov","year":"2015","journal-title":"Med. Chem. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1039\/C7MD00269F","article-title":"Biscarbene gold(I) complexes: Structure-activity-relationships regarding antibacterial effects, cytotoxicity, TrxR inhibition and cellular bioavailability","volume":"8","author":"Schmidt","year":"2017","journal-title":"Med. Chem. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4798","DOI":"10.1038\/sj.onc.1209608","article-title":"Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy","volume":"25","author":"Fulda","year":"2006","journal-title":"Oncogene"},{"key":"ref_22","first-page":"3","article-title":"Apoptosis, oncosis, and necrosis. An overview of cell death","volume":"146","author":"Majno","year":"1995","journal-title":"Am. J. Pathol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4480","DOI":"10.1021\/bi00232a015","article-title":"J-aggregate formation of a carbocyanine as a quantitative fluorescent indicator of membrane potential","volume":"30","author":"Reers","year":"1991","journal-title":"Biochemistry"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/bj3260001","article-title":"Caspases: The executioners of apoptosis","volume":"326","author":"Cohen","year":"1997","journal-title":"Biochem. J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1038\/nrc3599","article-title":"Cancer drug resistance: An evolving paradigm","volume":"13","author":"Holohan","year":"2013","journal-title":"Nat. Rev. Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1159\/000086183","article-title":"Mechanisms of drug resistance in cancer chemotherapy","volume":"14","author":"Lugmani","year":"2005","journal-title":"Med. Princ. Pract."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1146\/annurev.pharmtox.39.1.361","article-title":"Biochemical, cellular, and pharmacological aspects of the multidrug transporter","volume":"39","author":"Ambudkar","year":"1999","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/S0928-0987(00)00114-7","article-title":"Multidrug resistance (MDR) in cancer. Mechanisms, reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anticancer drugs","volume":"11","author":"Krishna","year":"2000","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/S1040-8428(96)00223-5","article-title":"Everything you always wanted to know about cellular drug resistance in childhood acute lymphoblastic leukemia","volume":"25","author":"Pieters","year":"1997","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2591","DOI":"10.1021\/acsomega.1c04659","article-title":"B-nor-methylene Colchicinoid PT-100 Selectively Induces Apoptosis in Multidrug-Resistant Human Cancer Cells via an Intrinsic Pathway in a Caspase-Independent Manner","volume":"7","author":"Stein","year":"2022","journal-title":"ACS Omega"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.canlet.2009.02.026","article-title":"Selective cytostatic and cytotoxic anticancer effects of bisfunctional agents: A strategy for the design of DNA binding agents","volume":"281","author":"Spychala","year":"2009","journal-title":"Cancer Lett."},{"key":"ref_32","first-page":"4103","article-title":"Medicinal Plants: Their Use in Anticancer Treatment","volume":"6","author":"Greenwell","year":"2015","journal-title":"Int. J. Pharm. Sci. Res."},{"key":"ref_33","first-page":"81","article-title":"Taxol: A short history of a promising anticancer drug","volume":"10","author":"Bocca","year":"1998","journal-title":"Minerva Biotecnol"},{"key":"ref_34","first-page":"23","article-title":"Vincristine and Vinblastine: A Review","volume":"6","author":"Kumar","year":"2016","journal-title":"Int. J. Med. Pharm."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"15204","DOI":"10.1038\/s41598-020-71030-w","article-title":"Mechanisms of indigo naturalis on treating ulcerative colitis explored by GEO gene chips combined with network pharmacology and molecular docking","volume":"10","author":"Gu","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1515","DOI":"10.1055\/s-0032-1315261","article-title":"From Tyrian purple to kinase modulators: Naturally halogenated indirubins and synthetic analogues","volume":"78","author":"Vougogiannopoulou","year":"2012","journal-title":"Planta Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2879","DOI":"10.1016\/S0040-4020(01)96609-8","article-title":"The structure and properties of some indolic constituents in Couroupita guianensis Aubl","volume":"41","author":"Bergman","year":"1985","journal-title":"Tetrahedron"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1055\/s-1974-23353","article-title":"Synthesis of 2-anilino-3h-indol-3-one derivatives","volume":"7","author":"Grimshaw","year":"1974","journal-title":"Synthesis"},{"key":"ref_39","first-page":"48","article-title":"Synthesis and evaluation of the antiplasmodial activity of tryptanthrin derivatives","volume":"5","author":"Onambele","year":"2015","journal-title":"Int. J. Parasitol."},{"key":"ref_40","unstructured":"Prokop, A., Riepl, H., and Wieder, T. (2004). 8-Nitro-tryptanthrin and Other Tryptanthrine Derivatives Used for the Treatment of Diseases Caused by Highly Proliferating Cells. (WO2004087164A1)."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.leukres.2010.11.007","article-title":"[Fe(III)(salophene)Cl], a potent iron salophene complex overcomes multiple drug resistance in lymphoma and leukemia cells","volume":"35","author":"Lee","year":"2011","journal-title":"Leuk. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"8177","DOI":"10.1039\/c0dt00034e","article-title":"Discovery of a strongly apoptotic ruthenium complex through combinatorial coordination chemistry","volume":"39","author":"Mulcahy","year":"2010","journal-title":"Dalton Trans."},{"key":"ref_43","first-page":"251","article-title":"The DNA intercalators ethidium bromide and propidium iodide also bind to core histones","volume":"4","author":"Banerjee","year":"2014","journal-title":"FEBS"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1458","DOI":"10.1038\/nprot.2006.238","article-title":"Analysis of apoptosis by propidium iodide staining and flow cytometry","volume":"1","author":"Riccardi","year":"2006","journal-title":"Nat. Protoc."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1007\/978-1-62703-290-2_7","article-title":"Detection of necrosis by release of lactate dehydrogenase activity","volume":"979","author":"Chan","year":"2013","journal-title":"Methods Mol. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1007\/BF00955327","article-title":"Cellular death and necrosis: Chemical, physical and morphologic changes in rat liver","volume":"333","author":"Maino","year":"1960","journal-title":"Virchows Arch. Pathol. Anat. Physiol. Klin. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/BF01871776","article-title":"Membrane potential, anion and cation conductances in Ehrlich ascites tumor cell","volume":"111","author":"Lambert","year":"1989","journal-title":"J. Membr. Biol."},{"key":"ref_48","first-page":"2977","article-title":"Activation of apoptosis signalling pathways by reactive oxygen species","volume":"30","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Desai, M.A., and Merino, S.P. (2000). Application of Density Gradient Ultracentrifugation Using Zonal Rotors in the Large-Scale Purification of Biomolecules. Downstream Processing of Proteins, Humana Press.","DOI":"10.1007\/978-1-59259-027-8_6"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1093\/ajcp\/79.4.500","article-title":"The Leukocyte Composition of Peripheral Blood Buffy Coat","volume":"79","author":"Teetson","year":"1983","journal-title":"Am. J. Clin. Pathol."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/15\/5038\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:05:47Z","timestamp":1760141147000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/15\/5038"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,8]]},"references-count":50,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["molecules27155038"],"URL":"https:\/\/doi.org\/10.3390\/molecules27155038","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,8]]}}}