{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T11:37:20Z","timestamp":1778326640725,"version":"3.51.4"},"reference-count":48,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2021,5,13]],"date-time":"2021-05-13T00:00:00Z","timestamp":1620864000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF\u20102016R1D1A1B04930774"],"award-info":[{"award-number":["NRF\u20102016R1D1A1B04930774"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF\u20102019R1A6A3A01091754"],"award-info":[{"award-number":["NRF\u20102019R1A6A3A01091754"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF\u20102019R1C1C1003558"],"award-info":[{"award-number":["NRF\u20102019R1C1C1003558"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF\u20102021M3A9C4000960"],"award-info":[{"award-number":["NRF\u20102021M3A9C4000960"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Pineal Research"],"published-print":{"date-parts":[[2021,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Hypoxia\u2010inducible factor\u20101 (HIF\u20101) plays an important role in cellular responses to hypoxia, including the transcriptional activation of several genes involved in tumor angiogenesis. Melatonin, also known as N\u2010acetyl\u20105\u2010methopxytryptamine, is produced naturally by the pineal gland and has anti\u2010angiogenic effects in cancer through its ability to modulate HIF\u20101\u03b1 activity. However, the use of melatonin as a therapeutic is limited by its low oral bioavailability and short half\u2010life. Here, we synthesized melatonin\u2010like molecules with enhanced HIF\u20101\u03b1 targeting activity and less toxicity and investigated their effects on tumor growth and angiogenesis, as well as the underlying molecular mechanisms. Among melatonin derivatives, <jats:italic>N<\/jats:italic>\u2010butyryl\u20105\u2010methoxytryptamine (NB\u20105\u2010MT) showed the most potent HIF\u20101\u03b1 targeting activity. This molecule was able to (a) reduce the expression of HIF\u20101\u03b1 at the protein level, (b) reduce the transcription of HIF\u20101\u03b1 target genes, (c) reduce reactive oxygen species (ROS) generation, (d) decrease angiogenesis in vitro and in vivo, and (e) suppress tumor size and metastasis. In addition, NB\u20105\u2010MT showed improved anti\u2010angiogenic activity compared with melatonin due to its enhanced cellular uptake. NB\u20105\u2010MT is thus a promising lead for the future development of anticancer compounds with HIF\u20101\u03b1 targeting activity. Given that HIF\u20101\u03b1 is overexpressed in the majority of human cancers, the melatonin derivative NB\u20105\u2010MT could represent a novel potent therapeutic agent for cancer.<\/jats:p>","DOI":"10.1111\/jpi.12739","type":"journal-article","created":{"date-parts":[[2021,5,6]],"date-time":"2021-05-06T18:41:59Z","timestamp":1620326519000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Enhanced anti\u2010angiogenic activity of novel melatonin\u2010like agents"],"prefix":"10.1111","volume":"71","author":[{"given":"Su Jung","family":"Hwang","sequence":"first","affiliation":[{"name":"School of Pharmacy Sungkyunkwan University Suwon Gyeonggi\u2010do Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yeonghun","family":"Jung","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research Inje University Gimhae Gyungnam Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ye\u2010Seul","family":"Song","sequence":"additional","affiliation":[{"name":"School of Pharmacy Sungkyunkwan University Suwon Gyeonggi\u2010do Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suryeon","family":"Park","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research Inje University Gimhae Gyungnam Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6844-2241","authenticated-orcid":false,"given":"Yohan","family":"Park","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research Inje University Gimhae Gyungnam Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4826-7954","authenticated-orcid":false,"given":"Hyo\u2010Jong","family":"Lee","sequence":"additional","affiliation":[{"name":"School of Pharmacy Sungkyunkwan University Suwon Gyeonggi\u2010do Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,5,13]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.2174\/1566524018666181109121849"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-007-7082-2"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1080\/07357907.2016.1245317"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13402-014-0216-2"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/pros.20808"},{"issue":"3","key":"e_1_2_9_7_1","first-page":"425","article-title":"STAT3 and hypoxia induced proteins\u2010\u2010HIF\u20101alpha, EPO and EPOR in relation with Bax and Bcl\u2010xL in nodal metastases of ductal breast cancers","volume":"47","author":"Wincewicz A","year":"2009","journal-title":"Folia Histochem Cytobiol"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1535-6108(02)00044-2"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.4155\/fso.15.84"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-012513-104720"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/jpi.12525"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.2174\/156802608784936719"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.10-154450"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0891-5849(98)00168-3"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/0-306-46814-X_47"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1054-3589(08)60981-3"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1155\/2017\/1835195"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-008-8601-5"},{"key":"e_1_2_9_19_1","first-page":"373","article-title":"Melatonin and cancer","volume":"7","author":"Zamfir CAA","year":"2014","journal-title":"J Med Life"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.29036"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12935-019-0853-7"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2016.02.004"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-079X.2012.01030.x"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells8070681"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpb.2016.11.003"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11940-003-0013-0"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1097\/00002826-200111000-00004"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-079X.2008.00581.x"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1111\/jpi.12210"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-079X.2005.00309.x"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/jps.2600830220"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2015.05.007"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/emm.2004.1"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.est.6b01472"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.3109\/714041018"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(95)91382-3"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-3223(93)90007-Z"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00540-010-0891-8"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpedsurg.2003.10.003"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-079X.2007.00545.x"},{"issue":"12","key":"e_1_2_9_41_1","first-page":"2458","article-title":"The melatonin antagonist luzindole protects retinal photoreceptors from light damage in the rat","volume":"39","author":"Sugawara T","year":"1998","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1177\/00912700022009422"},{"issue":"4","key":"e_1_2_9_43_1","first-page":"169","article-title":"Pharmacokinetics of alternative administration routes of melatonin: a systematic review","volume":"66","author":"Zetner D","year":"2016","journal-title":"Drug Res"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2017.10.025"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199704033361418"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-08-0944"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.02.013"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.3390\/clockssleep1040034"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2015.3199"}],"container-title":["Journal of Pineal Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jpi.12739","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/jpi.12739","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jpi.12739","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,23]],"date-time":"2023-08-23T19:30:02Z","timestamp":1692819002000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jpi.12739"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,13]]},"references-count":48,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,8]]}},"alternative-id":["10.1111\/jpi.12739"],"URL":"https:\/\/doi.org\/10.1111\/jpi.12739","archive":["Portico"],"relation":{},"ISSN":["0742-3098","1600-079X"],"issn-type":[{"value":"0742-3098","type":"print"},{"value":"1600-079X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,13]]},"assertion":[{"value":"2019-12-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-04-23","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-05-13","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e12739"}}