{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T12:45:22Z","timestamp":1778589922253,"version":"3.51.4"},"reference-count":31,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2021,9,29]],"date-time":"2021-09-29T00:00:00Z","timestamp":1632873600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP15K08047"],"award-info":[{"award-number":["JP15K08047"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP24659058"],"award-info":[{"award-number":["JP24659058"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP15K14992"],"award-info":[{"award-number":["JP15K14992"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP19K07005"],"award-info":[{"award-number":["JP19K07005"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Among organic\u2013inorganic hybrid molecules consisting of organic structure(s) and metal(s), only few studies are available on the cytotoxicity of nucleophilic molecules. In the present study, we investigated the cytotoxicity of a nucleophilic organotellurium compound, diphenyl ditelluride (DPDTe), using a cell culture system. DPDTe exhibited strong cytotoxicity against vascular endothelial cells and fibroblasts along with high intracellular accumulation but showed no cytotoxicity and had less accumulation in vascular smooth muscle cells and renal epithelial cells. The cytotoxicity of DPDTe decreased when intramolecular tellurium atoms were replaced with selenium or sulfur atoms. Electronic state analysis revealed that the electron density between tellurium atoms in DPDTe was much lower than those between selenium atoms of diphenyl diselenide and sulfur atoms of diphenyl disulfide. Moreover, diphenyl telluride did not accumulate and exhibit cytotoxicity. The cytotoxicity of DPDTe was also affected by substitution. p-Dimethoxy-DPDTe showed higher cytotoxicity, but p-dichloro-DPDTe and p-methyl-DPDTe showed lower cytotoxicity than that of DPDTe. The subcellular distribution of the compounds revealed that the compounds with stronger cytotoxicity showed higher accumulation rates in the mitochondria. Our findings suggest that the electronic state of tellurium atoms in DPDTe play an important role in accumulation and distribution of DPDTe in cultured cells. The present study supports the hypothesis that nucleophilic organometallic compounds, as well as electrophilic organometallic compounds, exhibit cytotoxicity by particular mechanisms.<\/jats:p>","DOI":"10.3390\/ijms221910520","type":"journal-article","created":{"date-parts":[[2021,9,29]],"date-time":"2021-09-29T08:27:44Z","timestamp":1632904064000},"page":"10520","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Effects of Substitution on Cytotoxicity of Diphenyl Ditelluride in Cultured Vascular Endothelial Cells"],"prefix":"10.3390","volume":"22","author":[{"given":"Takato","family":"Hara","sequence":"first","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi 274-8510, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takahiro","family":"Okazaki","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tamayo","family":"Hashiya","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyohei","family":"Nozawa","sequence":"additional","affiliation":[{"name":"Faculty of Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuji","family":"Yasuike","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya 464-8650, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jyoji","family":"Kurita","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Hokuriku University, Ho-3 Kanagawa-machi, Kanazawa 920-1181, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chika","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi 274-8510, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noriaki","family":"Hamada","sequence":"additional","affiliation":[{"name":"Faculty of Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7393-2656","authenticated-orcid":false,"given":"Toshiyuki","family":"Kaji","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,29]]},"reference":[{"key":"ref_1","first-page":"1322","article-title":"Regarding some new organometallic combinations of magnesium and their application to alcohol synthesis and hydrocarbides","volume":"130","author":"Grignard","year":"1900","journal-title":"CR Acad. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"SP81","DOI":"10.2131\/jts.41.SP81","article-title":"Toxicology of organic-inorganic hybrid molecules: Bio-organometallics and its toxicology","volume":"41","author":"Fujie","year":"2016","journal-title":"J. Toxicol. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"109","DOI":"10.2131\/fts.3.109","article-title":"Cytotoxicity of zinc, copper and rhodium complexes with 1, 10-phenanthroline or 2, 9-dimethyl-1, 10-phenanthroline in cultured vascular endothelial cells","volume":"3","author":"Hara","year":"2016","journal-title":"Fundam. Toxicol. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"845","DOI":"10.2131\/jts.44.845","article-title":"Intracellular accumulation-independent cytotoxicity of pentavalent organoantimony compounds in cultured vascular endothelial cells","volume":"44","author":"Hara","year":"2019","journal-title":"J. Toxicol. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"735","DOI":"10.2131\/jts.43.735","article-title":"Structure-activity relationship of [1,5]azastibocines in cytotoxicity to vascular endothelial cells","volume":"43","author":"Hara","year":"2018","journal-title":"J. Toxicol. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"553","DOI":"10.2131\/jts.42.553","article-title":"Copper diethyldithiocarbamate as an inhibitor of tissue plasminogen activator synthesis in cultured human coronary endothelial cells","volume":"42","author":"Fujie","year":"2017","journal-title":"J. Toxicol. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"217","DOI":"10.2131\/jts.41.217","article-title":"Zinc diethyldithiocarbamate as an inducer of metallothionein in cultured vascular endothelial cells","volume":"41","author":"Fujie","year":"2016","journal-title":"J. Toxicol. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"225","DOI":"10.2131\/jts.41.225","article-title":"Induction of metallothionein isoforms by copper diethyldithiocarbamate in cultured vascular endothelial cells","volume":"41","author":"Fujie","year":"2016","journal-title":"J. Toxicol. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Hara, T., Tatsuishi, H., Banno, T., Fujie, T., Yamamoto, C., Naka, H., and Kaji, T. (2018). Copper(II) bis(diethyldithiocarbamate) induces the expression of syndecan-4, a transmembrane heparan sulfate proteoglycan, via p38 MAPK activation in vascular endothelial cells. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19113302"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.tox.2017.09.013","article-title":"Methylmercury promotes prostacyclin release from cultured human brain microvascular endothelial cells via induction of cyclooxygenase-2 through activation of the EGFR-p38 MAPK pathway by inhibiting protein tyrosine phosphatase 1B activity","volume":"392","author":"Yoshida","year":"2017","journal-title":"Toxicology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1002\/jcc.540141112","article-title":"General atomic and molecular electronic structure system","volume":"14","author":"Schmidt","year":"1993","journal-title":"J. Comput. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"7529","DOI":"10.1021\/ja012545e","article-title":"Theoretical and electrochemical analysis of dissociative electron transfers proceeding through formation of loose radical anion species:\u2009 reduction of symmetrical and unsymmetrical disulfides","volume":"124","author":"Antonello","year":"2002","journal-title":"J. Am. Chem. Soc."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"113","DOI":"10.2131\/jts.44.113","article-title":"Bis(1,4-dihydro-2-methyl-1-phenyl-4-thioxo-3-pyridiolato)zinc(II) exhibits strong cytotoxicity and a high intracellular accumulation in cultured vascular endothelial cells","volume":"44","author":"Fujie","year":"2019","journal-title":"J. Toxicol. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"321","DOI":"10.2131\/jts.40.321","article-title":"The cytotoxicity of organobismuth compounds with certain molecular structures can be diminished by replacing the bismuth atom with an antimony atom in the molecules","volume":"40","author":"Kohri","year":"2015","journal-title":"J. Toxicol. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1248\/jhs.51.333","article-title":"An organobismuth compound that exhibits selective cytotoxicity to vascular endothelial cells in vitro","volume":"51","author":"Fujiwara","year":"2005","journal-title":"J. Health Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"7699","DOI":"10.3390\/molecules15117699","article-title":"Reduction of diphenyl diselenide and analogs by mammalian thioredoxin reductase is independent of their gluthathione peroxidase-like activity: A possible novel pathway for their antioxidant activity","volume":"15","author":"Wagner","year":"2010","journal-title":"Molecules"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.neulet.2011.07.050","article-title":"Diphenyl diselenide and analogs are substrates of cerebral rat thioredoxin reductase: A pathway for their neuroprotective effects","volume":"503","author":"Rocha","year":"2011","journal-title":"Neurosci. Lett."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.tiv.2012.10.011","article-title":"Mitochondrial electron transfer chain complexes inhibition by different organochalcogens","volume":"27","author":"Puntel","year":"2013","journal-title":"Toxicol. In Vitro"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1111\/bcpt.12315","article-title":"Diphenyl ditelluride-induced cell cycle arrest and apoptosis: A relation with topoisomerase I inhibition","volume":"116","author":"Jorge","year":"2015","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3288","DOI":"10.1021\/ol100558b","article-title":"An efficient one-pot synthesis of symmetrical diselenides or ditellurides from halides with CuO nanopowder\/Se0 or Te0\/Base","volume":"12","author":"Singh","year":"2010","journal-title":"Org. Lett."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2452","DOI":"10.1016\/j.tetlet.2013.02.084","article-title":"Catalyst free one-pot synthesis of symmetrical diaryl tellurides with Te0\/KOH","volume":"54","author":"Zhang","year":"2013","journal-title":"Tetarahedron Lett."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"795","DOI":"10.2131\/jts.45.795","article-title":"Cell density-dependent accumulation of low polarity gold nanocluster in cultured vascular endothelial cells","volume":"45","author":"Hara","year":"2020","journal-title":"J. Toxicol. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/S0021-9258(19)68051-8","article-title":"The fluorometric measurement of deoxyribonucleic acid in animal tissues with special reference to the central nervous system","volume":"233","author":"Kissane","year":"1958","journal-title":"J. Biol. Chem."},{"key":"ref_24","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_25","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1139\/v95-080","article-title":"1994 Polanyi Award Lecture Concept of active electrons in chemistry","volume":"73","author":"Huzinaga","year":"1995","journal-title":"Can. J. Chem."},{"key":"ref_26","first-page":"542","article-title":"Electronic wave functions\u2014I. A general method of calculation for the stationary states of any molecular system","volume":"200","author":"Boys","year":"1950","journal-title":"Proc. R. Soc. Lond. Ser. A. Math. Phys. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1063\/1.456153","article-title":"Gaussian basis sets for use in correlated molecular calculations. I. The atoms boron through neon and hydrogen","volume":"90","author":"Dunning","year":"1989","journal-title":"J. Chem. Phys."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"8084","DOI":"10.1063\/1.473816","article-title":"Model potentials for main group elements Li through Rn","volume":"106","author":"Sakai","year":"1997","journal-title":"J. Chem. Phys."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/s002140050274","article-title":"Contracted polarization functions for the atoms helium through neon","volume":"98","author":"Noro","year":"1997","journal-title":"Theor. Chem. Acc."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/S0166-1280(98)00175-4","article-title":"Contracted polarization functions for the atoms magnesium through argon","volume":"451","author":"Sekiya","year":"1998","journal-title":"J. Mol. Struct."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/S0166-1280(98)00161-4","article-title":"Relativistic dsp-model core potentials for main group elements in the fourth, fifth and sixth row and their applications","volume":"451","author":"Miyoshi","year":"1998","journal-title":"J. Mol. Struct."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/19\/10520\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:07:18Z","timestamp":1760166438000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/19\/10520"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,29]]},"references-count":31,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["ijms221910520"],"URL":"https:\/\/doi.org\/10.3390\/ijms221910520","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,29]]}}}