{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T03:03:13Z","timestamp":1760151793248,"version":"build-2065373602"},"reference-count":30,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2022,11,29]],"date-time":"2022-11-29T00:00:00Z","timestamp":1669680000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong Province","doi-asserted-by":"publisher","award":["ZR2022QH186","202013051070","2021-0013","2021-009"],"award-info":[{"award-number":["ZR2022QH186","202013051070","2021-0013","2021-009"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Medical Science and Technology Development Project of Shandong Province","award":["ZR2022QH186","202013051070","2021-0013","2021-009"],"award-info":[{"award-number":["ZR2022QH186","202013051070","2021-0013","2021-009"]}]},{"name":"Strengthening Foundation Plan for Young Teachers of School of Pharmacy","award":["ZR2022QH186","202013051070","2021-0013","2021-009"],"award-info":[{"award-number":["ZR2022QH186","202013051070","2021-0013","2021-009"]}]},{"name":"Strengthening Foundation Plan for Young Teachers of School of Pharmacy","award":["ZR2022QH186","202013051070","2021-0013","2021-009"],"award-info":[{"award-number":["ZR2022QH186","202013051070","2021-0013","2021-009"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Aminopeptidase N (APN) was closely associated with cancer invasion, metastasis, and angiogenesis. Therefore, APN inhibitors have attracted more and more attention of scientists as antitumor agents. In the current study, we designed, synthesized, and evaluated one new series of pyrazoline-based hydroxamate derivatives as APN inhibitors. Moreover, the structure\u2013activity relationships of those were discussed in detail. 2,6-Dichloro substituted compound 14o with R1 = CH3, showed the best capacity for inhibiting APN with an IC50 value of 0.0062 \u00b1 0.0004 \u03bcM, which was three orders of magnitude better than that of the positive control bestatin. Compound 14o possessed both potent anti-proliferative activities against tumor cells and potent anti-angiogenic activity. At the same concentration of 50 \u03bcM, compound 14o exhibited much better capacity for inhibiting the micro-vessel growth relative to bestatin in the rat thoracic aorta ring model. Additionally, the putative interactions of 14o with the active site of APN are also discussed. The hydroxamate moiety chelated the zinc ion and formed four hydrogen bonds with His297, Glu298 and His301. Meanwhile, the terminal phenyl group and another phenyl group of 14o interacted with S2\u2032 and S1 pockets via hydrophobic effects, respectively.<\/jats:p>","DOI":"10.3390\/molecules27238339","type":"journal-article","created":{"date-parts":[[2022,11,30]],"date-time":"2022-11-30T07:38:50Z","timestamp":1669793930000},"page":"8339","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Development of Hydroxamate Derivatives Containing a Pyrazoline Moiety as APN Inhibitors to Overcome Angiogenesis"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8732-677X","authenticated-orcid":false,"given":"Yangyang","family":"Liu","sequence":"first","affiliation":[{"name":"School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3265-5442","authenticated-orcid":false,"given":"Dongsheng","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chenghua","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui","family":"Fang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qingsitong","family":"Shen","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhixian","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiangying","family":"Cao","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1002\/1521-1878(200103)23:3<251::AID-BIES1035>3.0.CO;2-O","article-title":"Ectopeptidases in pathophysiology","volume":"23","author":"Antczak","year":"2001","journal-title":"Bioessays"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/j.molmed.2008.06.003","article-title":"The moonlighting enzyme CD13: Old and new functions to target","volume":"14","year":"2008","journal-title":"Trends. 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