{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T02:07:35Z","timestamp":1790042855940,"version":"4.0.1"},"reference-count":40,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2022,6,22]],"date-time":"2022-06-22T00:00:00Z","timestamp":1655856000000},"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":["21873075"],"award-info":[{"award-number":["21873075"]}],"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":["22073070"],"award-info":[{"award-number":["22073070"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Arsenicals have been widely used in the treatment of cancers such as leukemia and other tumors. However, their side effects limit their clinical application. Stiripentol, a second-line adjunctive treatment for epilepsy with a good safety profile, inhibits microsomal cytochrome-P450-family enzymes to extend the retention time of co-administration. Inspired by the metabolism of stiripentol, the 1,3-benzodioxole responsible for the inhibition and its metabolic derivatives were conjugated with arsenical precursors. The fabricated arsenicals were eliminated much slower in mice and maintained an efficient concentration in the blood for a longer time than that of the arsenical precursors. They also performed better in anti-proliferation by inhibiting the thioredoxin system to induce oxidative stress, and concomitantly to initiate apoptosis in vitro and in vivo. The fabricated arsenicals reversed the hemogram of tumor-bearing mice to normal and eliminated the tumor without causing damage to any organs, exhibiting a good design strategy and pre-clinical application for leukemia and other tumors.<\/jats:p>","DOI":"10.3390\/ijms23136930","type":"journal-article","created":{"date-parts":[[2022,6,22]],"date-time":"2022-06-22T21:31:06Z","timestamp":1655933466000},"page":"6930","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["1,3-Benzodioxole Derivatives Improve the Anti-Tumor Efficiency of Arsenicals"],"prefix":"10.3390","volume":"23","author":[{"given":"Xue-Min","family":"Shi","sequence":"first","affiliation":[{"name":"College of Chemistry and Molecular Science, Wuhan University, Wuhan 430072, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Yan","family":"She","sequence":"additional","affiliation":[{"name":"College of Chemistry and Molecular Science, Wuhan University, Wuhan 430072, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting-Ting","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Separation Membranes and Membrane Processes, School of Chemistry, Tiangong University, Tianjin 300387, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lian-Xun","family":"Gao","sequence":"additional","affiliation":[{"name":"College of Chemistry and Molecular Science, Wuhan University, Wuhan 430072, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4011-4857","authenticated-orcid":false,"given":"Yu-Jiao","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Separation Membranes and Membrane Processes, School of Chemistry, Tiangong University, Tianjin 300387, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Chemistry and Molecular Science, Wuhan University, Wuhan 430072, China"},{"name":"State Key Laboratory of Separation Membranes and Membrane Processes, School of Chemistry, Tiangong University, Tianjin 300387, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.freeradbiomed.2013.07.036","article-title":"The thioredoxin antioxidant system","volume":"66","author":"Lu","year":"2014","journal-title":"Free Radic. Biol. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1002\/prot.340110103","article-title":"Structural and functional relations among thioredoxins of different species","volume":"11","author":"Eklund","year":"1991","journal-title":"Proteins Struct. Funct. Bioinform."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1016\/j.tips.2017.06.001","article-title":"Targeting the Thioredoxin System for Cancer Therapy","volume":"38","author":"Zhang","year":"2017","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.mito.2019.04.010","article-title":"Overview of thioredoxin system and targeted therapies for acute leukemia","volume":"47","author":"Xie","year":"2019","journal-title":"Mitochondrion"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1186\/s12920-021-00930-1","article-title":"A pan-cancer study of selenoprotein genes as promising targets for cancer therapy","volume":"14","author":"Wu","year":"2021","journal-title":"BMC Med. Genom."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1768","DOI":"10.1002\/hep.30467","article-title":"Induction of Oxidative Stress Through Inhibition of Thioredoxin Reductase 1 Is an Effective Therapeutic Approach for Hepatocellular Carcinoma","volume":"69","author":"Lee","year":"2019","journal-title":"Hepatology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3593","DOI":"10.1002\/asia.201801136","article-title":"Small Molecules to Target the Selenoprotein Thioredoxin Reductase","volume":"13","author":"Zhang","year":"2018","journal-title":"Chem. Asian J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"5236","DOI":"10.1038\/s41388-021-01924-0","article-title":"Thioredoxin reductase is a major regulator of metabolism in leukemia cells","volume":"40","author":"Karunanithi","year":"2021","journal-title":"Oncogene"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1189\/jlb.0113006","article-title":"Novel roles of reactive oxygen species in the pathogenesis of acute myeloid leukemia","volume":"94","author":"Zhou","year":"2013","journal-title":"J. Leukoc. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5816","DOI":"10.1182\/blood-2011-01-326025","article-title":"Do reactive oxygen species play a role in myeloid leukemias?","volume":"117","author":"Hole","year":"2011","journal-title":"Blood"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1038\/ncb851","article-title":"Redox regulatory and anti-apoptotic functions of thioredoxin depend on S-nitrosylation at cysteine 69","volume":"4","author":"Haendeler","year":"2002","journal-title":"Nat. Cell Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1038\/nchembio720","article-title":"Thioredoxin catalyzes the S-nitrosation of the caspase-3 active site cysteine","volume":"1","author":"Mitchell","year":"2005","journal-title":"Nat. Chem. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1161\/01.RES.0000025101.04065.83","article-title":"Preventing apoptosis with thioredoxin","volume":"90","author":"Bishopric","year":"2002","journal-title":"Circ. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4450","DOI":"10.1158\/1078-0432.CCR-16-2426","article-title":"Jab1\/Csn5\u2013Thioredoxin Signaling in Relapsed Acute Monocytic Leukemia under Oxidative Stress","volume":"23","author":"Zhou","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"7309","DOI":"10.1021\/acs.jmedchem.8b01595","article-title":"Targeting the Thioredoxin System as a Strategy for Cancer Therapy","volume":"62","author":"Bian","year":"2019","journal-title":"J. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"7024","DOI":"10.1021\/jm050256l","article-title":"Synthesis of 5-Nitro-2-furancarbohydrazides and Their cis-Diamminedichloroplatinum Complexes as Bitopic and Irreversible Human Thioredoxin Reductase Inhibitors","volume":"48","author":"Millet","year":"2005","journal-title":"J. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1002\/med.21507","article-title":"Small molecule inhibitors of mammalian thioredoxin reductase as potential anticancer agents: An update","volume":"39","author":"Zhang","year":"2019","journal-title":"Med. Res. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5203","DOI":"10.1021\/jm500221p","article-title":"Dithiaarsanes Induce Oxidative Stress-Mediated Apoptosis in HL-60 Cells by Selectively Targeting Thioredoxin Reductase","volume":"57","author":"Liu","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.freeradbiomed.2019.11.013","article-title":"The novel thioredoxin reductase inhibitor A-Z2 triggers intrinsic apoptosis and shows efficacy in the treatment of acute myeloid leukemia","volume":"146","author":"Zhang","year":"2019","journal-title":"Free Radic. Biol. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.1016\/j.ejmech.2017.05.022","article-title":"Organic arsenicals target thioredoxin reductase followed by oxidative stress and mitochondrial dysfunction resulting in apoptosis","volume":"143","author":"Fan","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1080\/14737175.2020.1801423","article-title":"Therapeutic advances in Dravet syndrome: A targeted literature review","volume":"20","author":"Strzelczyk","year":"2020","journal-title":"Expert Rev. Neurother."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1007\/s10309-021-00399-z","article-title":"Dravet syndrome\u2014toward an optimal and disease-specific treatment","volume":"34","author":"Schoonjans","year":"2021","journal-title":"Z. Epileptol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.1111\/epi.16925","article-title":"Development of an antiseizure drug screening platform for Dravet syndrome at the NINDS contract site for the Epilepsy Therapy Screening Program","volume":"62","author":"Pernici","year":"2021","journal-title":"Epilepsia"},{"key":"ref_24","first-page":"154","article-title":"A novel antiepileptic drug","volume":"57","author":"Trojnar","year":"2004","journal-title":"Pharmacol. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"107832","DOI":"10.1016\/j.yebeh.2021.107832","article-title":"Drug-induced liver injury associated with antiseizure medications from the FDA Adverse Event Reporting System (FAERS)","volume":"117","author":"Kamitaki","year":"2021","journal-title":"Epilepsy Behav."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1517\/17425255.2016.1145657","article-title":"Pharmacological considerations in the use of stiripentol for the treatment of epilepsy","volume":"12","author":"Verrotti","year":"2016","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1016\/j.seizure.2021.06.020","article-title":"Comparative short-term efficacy and safety of add-on anti-seizure medications in Dravet syndrome: An indirect treatment comparison","volume":"91","author":"Devi","year":"2021","journal-title":"Seizure"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1111\/j.1528-1157.1983.tb04632.x","article-title":"Pharmacokinetic Profile of a New Anticonvulsant, Stiripentol, in the Rhesus Monkey","volume":"24","author":"Lin","year":"1983","journal-title":"Epilepsia"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Liu, Y.-J., Fan, X.-Y., Wang, A.-D., Xia, Y.-Z., Fu, W.-R., Liu, J.-Y., Jiang, F.-L., and Liu, Y. (2019). LDHA Suppression Altering Metabolism Inhibits Tumor Progress by an Organic Arsenical. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20246239"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2946","DOI":"10.1021\/acs.analchem.7b05429","article-title":"Far-Red Fluorescent Probe for Imaging of Vicinal Dithiol-Containing Proteins in Living Cells Based on a pKa Shift Mechanism","volume":"90","author":"Zhang","year":"2018","journal-title":"Anal. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1704","DOI":"10.1016\/j.cclet.2019.06.039","article-title":"Small molecule fluorescent probes of protein vicinal dithiols","volume":"30","author":"Hu","year":"2019","journal-title":"Chin. Chem. Lett."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4119","DOI":"10.1021\/acs.analchem.8b00066","article-title":"Sensitive and Selective Fluorescent Probe for Selenol in Living Cells Designed via a pKa Shift Strategy","volume":"90","author":"Zhang","year":"2018","journal-title":"Anal. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.ijbiomac.2020.09.096","article-title":"Thiol antioxidant thioredoxin reductase: A prospective biochemical crossroads between anticancer and antiparasitic treatments of the modern era","volume":"165","author":"Joardar","year":"2020","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4215","DOI":"10.1021\/jacs.5b01140","article-title":"Organic Arsenicals as Efficient and Highly Specific Linkers for Protein\/Peptide\u2013Polymer Conjugation","volume":"137","author":"Wilson","year":"2015","journal-title":"J. Am. Chem. Soc."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"14051","DOI":"10.1002\/anie.201608006","article-title":"p-Azidophenylarsenoxide: An Arsenical \u201cBait\u201d for the In Situ Capture and Identification of Cellular Arsenic-Binding Proteins","volume":"55","author":"Yan","year":"2016","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1080\/13543776.2021.1899160","article-title":"Thioredoxin reductase inhibitors: Updated patent review (2017-present)","volume":"31","author":"Chupakhin","year":"2021","journal-title":"Expert Opin. Ther. Patents"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2101032","DOI":"10.1002\/adhm.202101032","article-title":"Gold Nanoclusters as Nanoantibiotic Auranofin Analogues","volume":"11","author":"Ndugire","year":"2021","journal-title":"Adv. Healthc. Mater."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"188352","DOI":"10.1016\/j.bbcan.2020.188352","article-title":"Control of tumor angiogenesis and metastasis through modulation of cell redox state","volume":"1873","author":"Serrano","year":"2020","journal-title":"Biochim. Biophys. Acta Rev. Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.semcdb.2017.05.023","article-title":"ROS signalling in the biology of cancer","volume":"80","author":"Moloney","year":"2018","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2169","DOI":"10.1038\/leu.2016.227","article-title":"Rationale and efficacy of proteasome inhibitor combined with arsenic trioxide in the treatment of acute promyelocytic leukemia","volume":"30","author":"Ganesan","year":"2016","journal-title":"Leukemia"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/13\/6930\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:37:39Z","timestamp":1760139459000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/13\/6930"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,22]]},"references-count":40,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["ijms23136930"],"URL":"https:\/\/doi.org\/10.3390\/ijms23136930","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,22]]}}}