{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T22:13:10Z","timestamp":1789078390653,"version":"build-2803163510"},"reference-count":46,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,11]],"date-time":"2023-01-11T00:00:00Z","timestamp":1673395200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22007022"],"award-info":[{"award-number":["22007022"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["ZK {2021}034"],"award-info":[{"award-number":["ZK {2021}034"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["{2022}075"],"award-info":[{"award-number":["{2022}075"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["QjhKYZi {2021}041"],"award-info":[{"award-number":["QjhKYZi {2021}041"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Science and Technology Foundation of Guizhou Province","award":["22007022"],"award-info":[{"award-number":["22007022"]}]},{"name":"Science and Technology Foundation of Guizhou Province","award":["ZK {2021}034"],"award-info":[{"award-number":["ZK {2021}034"]}]},{"name":"Science and Technology Foundation of Guizhou Province","award":["{2022}075"],"award-info":[{"award-number":["{2022}075"]}]},{"name":"Science and Technology Foundation of Guizhou Province","award":["QjhKYZi {2021}041"],"award-info":[{"award-number":["QjhKYZi {2021}041"]}]},{"name":"Guizhou Education Department","award":["22007022"],"award-info":[{"award-number":["22007022"]}]},{"name":"Guizhou Education Department","award":["ZK {2021}034"],"award-info":[{"award-number":["ZK {2021}034"]}]},{"name":"Guizhou Education Department","award":["{2022}075"],"award-info":[{"award-number":["{2022}075"]}]},{"name":"Guizhou Education Department","award":["QjhKYZi {2021}041"],"award-info":[{"award-number":["QjhKYZi {2021}041"]}]},{"name":"Guizhou Provincial Department of Education","award":["22007022"],"award-info":[{"award-number":["22007022"]}]},{"name":"Guizhou Provincial Department of Education","award":["ZK {2021}034"],"award-info":[{"award-number":["ZK {2021}034"]}]},{"name":"Guizhou Provincial Department of Education","award":["{2022}075"],"award-info":[{"award-number":["{2022}075"]}]},{"name":"Guizhou Provincial Department of Education","award":["QjhKYZi {2021}041"],"award-info":[{"award-number":["QjhKYZi {2021}041"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In this study, a series of novel tryptanthrin derivatives were synthesized and their inhibitory activities against selected human cancer cell lines, namely, lung (A549), chronic myeloid leukemia (K562), prostate (PC3), and live (HepG2), were evaluated using a methyl thiazolyl tetrazolium colorimetric (MTT) assay. Among the tested compounds, compound C1 exhibited a promising inhibitory effect on the A549 cell line with an IC50 value of 0.55 \u00b1 0.33 \u00b5M. The observation of the cell morphological result showed that treatment with C1 could significantly inhibit the migration of A549 cells through the cell migration assay. Moreover, after treatment with C1, the A549 cells exhibited a typical apoptotic morphology and obvious autophagy. In addition, the detection of apoptosis and the mitochondrial membrane potential indicated that C1 induced A549 cell apoptosis via modulating the levels of Bcl2 family members and disrupted the mitochondrial membrane potential. Compound C1 also suppressed the expression of cyclin D1 and increased the expression of p21 in the A549 cells, inducing cell cycle arrest in the G2\/M phase in a dose dependent manner. The further mechanism study found that C1 markedly increased the transformation from LC3-I to LC3-II. Taken together, our results suggest that C1 is capable of inhibiting the proliferation of non-small cell lung cancer (NSCLC) cells, inducing cell apoptosis, and triggering autophagy.<\/jats:p>","DOI":"10.3390\/ijms24021450","type":"journal-article","created":{"date-parts":[[2023,1,12]],"date-time":"2023-01-12T01:32:26Z","timestamp":1673487146000},"page":"1450","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Discovery of Tryptanthrin and Its Derivatives and Its Activities against NSCLC In Vitro via Both Apoptosis and Autophagy Pathways"],"prefix":"10.3390","volume":"24","author":[{"given":"Yayu","family":"Zou","sequence":"first","affiliation":[{"name":"College of Pharmacy, Guizhou University, Guiyang 550025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanglong","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guiyang 550025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengpeng","family":"Li","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Guizhou University, Guiyang 550025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haitao","family":"Long","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Guizhou University, Guiyang 550025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danping","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Guizhou University, Guiyang 550025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhurui","family":"Li","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Guizhou University, Guiyang 550025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guiping","family":"Ouyang","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Guizhou University, Guiyang 550025, China"},{"name":"State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guiyang 550025, China"},{"name":"Guizhou Engineering Laboratory for Synthetic Drugs, Guizhou University, Guiyang 550025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjing","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Guizhou University, Guiyang 550025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Guizhou University, Guiyang 550025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9560-7627","authenticated-orcid":false,"given":"Zhenchao","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Guizhou University, Guiyang 550025, China"},{"name":"State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guiyang 550025, China"},{"name":"Guizhou Engineering Laboratory for Synthetic Drugs, Guizhou University, Guiyang 550025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1007\/s12272-013-0091-9","article-title":"Progress in the studies on tryptanthrin, an alkaloid of history","volume":"36","author":"Jahng","year":"2013","journal-title":"Arch. Pharm. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"245","DOI":"10.2478\/acph-2021-0020","article-title":"Tryptanthrin exerts anti-breast cancer effects both in vitro and in vivo through modulating the inflammatory tumor microenvironment","volume":"71","author":"Zeng","year":"2021","journal-title":"Acta Pharm."},{"key":"ref_3","first-page":"1335","article-title":"Design, synthesis and biomedical evaluation of mostotrin, a new water soluble tryptanthrin derivative","volume":"46","author":"Popov","year":"2020","journal-title":"Int. J. Mol. Med."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Latypova, D.K., Shmakov, S.V., Pechkovskaya, S.A., Filatov, A.S., Stepakov, A.V., Knyazev, N.A., and Boitsov, V.M. (2021). Identification of Spiro-Fused Pyrrolo[3,4-a]pyrrolizines and Tryptanthrines as Potential Antitumor Agents: Synthesis and In Vitro Evaluation. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222111997"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1007\/s12272-018-1020-8","article-title":"Anti-neuroinflammatory effects of tryptanthrin from Polygonum tinctorium Lour. in lipopolysaccharide-stimulated BV2 microglial cells","volume":"41","author":"Lee","year":"2018","journal-title":"Arch. Pharm. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1021\/np3007167","article-title":"Design, synthesis, and structure-activity relationship studies of tryptanthrins as antitubercular agents","volume":"76","author":"Hwang","year":"2013","journal-title":"J. Nat. Prod."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3558","DOI":"10.1021\/jm901847f","article-title":"Antimicrobial activity of tryptanthrins in Escherichia coli","volume":"53","author":"Bandekar","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/s005350170147","article-title":"Antibacterial action of tryptanthrin and kaempferol, isolated from the indigo plant (Polygonum tinctorium Lour.), against Helicobacter pylori-infected Mongolian gerbils.","volume":"36","author":"Kataoka","year":"2001","journal-title":"J. Gastroenterol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Tsai, Y.C., Lee, C.L., Yen, H.R., Chang, Y.S., Lin, Y.P., Huang, S.H., and Lin, C.W. (2020). Antiviral Action of Tryptanthrin Isolated from Strobilanthes cusia Leaf against Human Coronavirus NL63. Biomolecules, 10.","DOI":"10.3390\/biom10030366"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3831","DOI":"10.3390\/ijms12063831","article-title":"Proliferation-attenuating and apoptosis-inducing effects of tryptanthrin on human chronic myeloid leukemia K562 cell line in vitro","volume":"12","author":"Miao","year":"2011","journal-title":"Int. J. Mol. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.bbrc.2007.04.107","article-title":"Tryptanthrin inhibits MDR1 and reverses doxorubicin resistance in breast cancer cells","volume":"358","author":"Yu","year":"2007","journal-title":"Biocheml. Biophys. Res. Commun."},{"key":"ref_12","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_13","doi-asserted-by":"crossref","first-page":"15743","DOI":"10.1021\/acs.joc.0c02403","article-title":"Divergent Synthesis of Methylisatoid and Tryptanthrin Derivatives by Ph3P-I2-Mediated Reaction of Isatins with and without Alcohols","volume":"85","author":"Pattarawarapan","year":"2020","journal-title":"J. Org. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"106046","DOI":"10.1016\/j.bioorg.2022.106046","article-title":"Green synthesis and antibacterial evaluation of spiro fused tryptanthrin-thiopyrano[2,3-b]indole hybrids targeting drug-resistant S. aureus","volume":"128","author":"Kaul","year":"2022","journal-title":"Bioorg. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"143","DOI":"10.14723\/tmrsj.41.143","article-title":"Spectral Characteristics of Highly Fluorescent 2-(N,N-dimethylamino)tryptanthrin","volume":"41","author":"Kawakami","year":"2016","journal-title":"Trans. Mater. Res. Soc. Jpn."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"112504","DOI":"10.1016\/j.ejmech.2020.112504","article-title":"Targeting topoisomerase II with trypthantrin derivatives: Discovery of 7-((2-(dimethylamino)ethyl)amino)indolo[2,1-b]quinazoline-6,12-dione as an antiproliferative agent and to treat cancer","volume":"202","author":"Catanzaro","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4445","DOI":"10.1016\/j.tetlet.2007.04.057","article-title":"Ophiuroidine, the first indolo 2,1-b quinazoline alkaloid from the Caribbean brittle star Ophiocoma riisei","volume":"48","author":"Utkina","year":"2007","journal-title":"Tetrahedron Lett."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"9161","DOI":"10.1021\/acs.jmedchem.9b01079","article-title":"N-Benzyl\/Aryl Substituted Tryptanthrin as Dual Inhibitors of Indoleamine 2,3-Dioxygenase and Tryptophan 2,3-Dioxygenase","volume":"62","author":"Yang","year":"2019","journal-title":"J. Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/j.ejmech.2017.12.043","article-title":"Design, synthesis and QSAR study of novel isatin analogues inspired Michael acceptor as potential anticancer compounds","volume":"144","author":"Wang","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1016\/j.tetlet.2012.12.035","article-title":"Synthesis of Substituted Isatins","volume":"54","author":"Klein","year":"2013","journal-title":"Tetrahedron Lett."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"10147","DOI":"10.1038\/s41598-019-46657-z","article-title":"LC3-positive structures are prominent in autophagy-deficient cells","volume":"9","author":"Runwal","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e108863","DOI":"10.15252\/embj.2021108863","article-title":"Autophagy in major human diseases","volume":"40","author":"Klionsky","year":"2021","journal-title":"EMBO J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2282","DOI":"10.1080\/15548627.2020.1817286","article-title":"A new mechanism for autophagy regulation of anti-tumor immune responses","volume":"16","author":"Thorburn","year":"2020","journal-title":"Autophagy"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1543","DOI":"10.1080\/15548627.2020.1761659","article-title":"Using Reactome to build an autophagy mechanism knowledgebase","volume":"17","author":"Varusai","year":"2021","journal-title":"Autophagy"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/nrm3735","article-title":"Self-consumption: The interplay of autophagy and apoptosis","volume":"15","author":"Baehrecke","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"208","DOI":"10.3892\/or.2022.8423","article-title":"The role of interaction between autophagy and apoptosis in tumorigenesis","volume":"48","author":"Xi","year":"2022","journal-title":"Oncol. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2977","DOI":"10.1002\/jcp.25785","article-title":"Crosstalk of autophagy and apoptosis: Involvement of the dual role of autophagy under ER stress","volume":"232","author":"Song","year":"2017","journal-title":"J. Cell. Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.1056\/NEJMra2022774","article-title":"Autophagy in Human Diseases","volume":"383","author":"Mizushima","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1038\/s41580-018-0040-z","article-title":"Regulation of proteasome assembly and activity in health and disease","volume":"19","author":"Rousseau","year":"2018","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21654","article-title":"Cancer Statistics, 2021","volume":"71","author":"Siegel","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1038\/nature25183","article-title":"The biology and management of non-small cell lung cancer","volume":"553","author":"Herbst","year":"2018","journal-title":"Nature"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1016\/S0025-6196(11)60735-0","article-title":"Non-small cell lung cancer: Epidemiology, risk factors, treatment, and survivorship","volume":"83","author":"Molina","year":"2008","journal-title":"Mayo Clin. Proc."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.molcel.2010.09.023","article-title":"Autophagy and the integrated stress response","volume":"40","author":"Kroemer","year":"2010","journal-title":"Mol Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1186\/s13287-015-0245-4","article-title":"Autophagy promotes apoptosis of mesenchymal stem cells under inflammatory microenvironment","volume":"6","author":"Dang","year":"2015","journal-title":"Stem Cell Res. Ther."},{"key":"ref_35","first-page":"187","article-title":"Methyl jasmonate induces apoptosis and pro-apoptotic autophagy via the ROS pathway in human non-small cell lung cancer","volume":"6","author":"Zhang","year":"2016","journal-title":"Am. J. Cancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1038\/s41421-020-0141-7","article-title":"Lysosome biology in autophagy","volume":"6","author":"Yim","year":"2020","journal-title":"Cell Discov."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/onc.2015.99","article-title":"Emerging strategies to effectively target autophagy in cancer","volume":"35","author":"Rebecca","year":"2016","journal-title":"Oncogene"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1016\/j.cell.2013.11.019","article-title":"Autophagy-mediated tumor promotion","volume":"155","author":"Guo","year":"2013","journal-title":"Cell."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"83476","DOI":"10.18632\/oncotarget.13080","article-title":"Autophagy as an emerging therapy target for ovarian carcinoma","volume":"7","author":"Zhan","year":"2016","journal-title":"Oncotarget"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1913","DOI":"10.1101\/gad.287524.116","article-title":"Recent insights into the function of autophagy in cancer","volume":"30","author":"Amaravadi","year":"2016","journal-title":"Genes Dev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1038\/s41423-020-00630-3","article-title":"Necroptosis, pyroptosis and apoptosis: An intricate game of cell death","volume":"18","author":"Bertheloot","year":"2021","journal-title":"Cell Mol. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3449","DOI":"10.3892\/or.2017.5635","article-title":"SBI0206965, a novel inhibitor of Ulk1, suppresses non-small cell lung cancer cell growth by modulating both autophagy and apoptosis pathways","volume":"37","author":"Tang","year":"2017","journal-title":"Oncol. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1111\/j.1600-0854.2011.01305.x","article-title":"The role of EGF receptor ubiquitination in regulating its intracellular traffic","volume":"13","author":"Eden","year":"2012","journal-title":"Traffic"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1039\/C8MD00472B","article-title":"ADMET-score\u2014A comprehensive scoring function for evaluation of chemical drug-likeness","volume":"10","author":"Guan","year":"2019","journal-title":"Med. Chem. Commun."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1517\/17425255.3.5.641","article-title":"Maximising use of in vitro ADMET tools to predict in vivo bioavailability and safety","volume":"3","author":"Wang","year":"2007","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1038\/nrd4609","article-title":"An analysis of the attrition of drug candidates from four major pharmaceutical companies","volume":"14","author":"Waring","year":"2015","journal-title":"Nat. Rev. Drug Discov."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/2\/1450\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:03:22Z","timestamp":1760119402000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/2\/1450"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,11]]},"references-count":46,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["ijms24021450"],"URL":"https:\/\/doi.org\/10.3390\/ijms24021450","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,11]]}}}