Development of Hydroxamate Derivatives Containing a Pyrazoline Moiety as APN Inhibitors to Overcome Angiogenesis
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 hydro...
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MDPI AG
2022-11-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/27/23/8339 |
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| author | Yangyang Liu Dongsheng Zhao Chenghua Zhang Hui Fang Qingsitong Shen Zhixian Wang Jiangying Cao |
| author_facet | Yangyang Liu Dongsheng Zhao Chenghua Zhang Hui Fang Qingsitong Shen Zhixian Wang Jiangying Cao |
| author_sort | Yangyang Liu |
| collection | DOAJ |
| description | 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–activity relationships of those were discussed in detail. 2,6-Dichloro substituted compound <b>14o</b> with R<sub>1</sub> = CH<sub>3</sub>, showed the best capacity for inhibiting APN with an IC<sub>50</sub> value of 0.0062 ± 0.0004 μM, which was three orders of magnitude better than that of the positive control bestatin. Compound <b>14o</b> possessed both potent anti-proliferative activities against tumor cells and potent anti-angiogenic activity. At the same concentration of 50 μM, compound <b>14o</b> 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 <b>14o</b> with the active site of APN are also discussed. The hydroxamate moiety chelated the zinc ion and formed four hydrogen bonds with His<sup>297</sup>, Glu<sup>298</sup> and His<sup>301</sup>. Meanwhile, the terminal phenyl group and another phenyl group of <b>14o</b> interacted with S<sub>2</sub>′ and S<sub>1</sub> pockets via hydrophobic effects, respectively. |
| first_indexed | 2024-03-09T17:39:18Z |
| format | Article |
| id | doaj.art-09ee9f8060414f33a1eae2542b2be5db |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T17:39:18Z |
| publishDate | 2022-11-01 |
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| series | Molecules |
| spelling | doaj.art-09ee9f8060414f33a1eae2542b2be5db2023-11-24T11:40:37ZengMDPI AGMolecules1420-30492022-11-012723833910.3390/molecules27238339Development of Hydroxamate Derivatives Containing a Pyrazoline Moiety as APN Inhibitors to Overcome AngiogenesisYangyang Liu0Dongsheng Zhao1Chenghua Zhang2Hui Fang3Qingsitong Shen4Zhixian Wang5Jiangying Cao6School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, ChinaSchool of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, ChinaSchool of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, ChinaSchool of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, ChinaSchool of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, ChinaSchool of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, ChinaSchool of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, ChinaAminopeptidase 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–activity relationships of those were discussed in detail. 2,6-Dichloro substituted compound <b>14o</b> with R<sub>1</sub> = CH<sub>3</sub>, showed the best capacity for inhibiting APN with an IC<sub>50</sub> value of 0.0062 ± 0.0004 μM, which was three orders of magnitude better than that of the positive control bestatin. Compound <b>14o</b> possessed both potent anti-proliferative activities against tumor cells and potent anti-angiogenic activity. At the same concentration of 50 μM, compound <b>14o</b> 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 <b>14o</b> with the active site of APN are also discussed. The hydroxamate moiety chelated the zinc ion and formed four hydrogen bonds with His<sup>297</sup>, Glu<sup>298</sup> and His<sup>301</sup>. Meanwhile, the terminal phenyl group and another phenyl group of <b>14o</b> interacted with S<sub>2</sub>′ and S<sub>1</sub> pockets via hydrophobic effects, respectively.https://www.mdpi.com/1420-3049/27/23/8339aminopeptidase NCD13inhibitorsantitumor agentsanti-angiogenesis |
| spellingShingle | Yangyang Liu Dongsheng Zhao Chenghua Zhang Hui Fang Qingsitong Shen Zhixian Wang Jiangying Cao Development of Hydroxamate Derivatives Containing a Pyrazoline Moiety as APN Inhibitors to Overcome Angiogenesis Molecules aminopeptidase N CD13 inhibitors antitumor agents anti-angiogenesis |
| title | Development of Hydroxamate Derivatives Containing a Pyrazoline Moiety as APN Inhibitors to Overcome Angiogenesis |
| title_full | Development of Hydroxamate Derivatives Containing a Pyrazoline Moiety as APN Inhibitors to Overcome Angiogenesis |
| title_fullStr | Development of Hydroxamate Derivatives Containing a Pyrazoline Moiety as APN Inhibitors to Overcome Angiogenesis |
| title_full_unstemmed | Development of Hydroxamate Derivatives Containing a Pyrazoline Moiety as APN Inhibitors to Overcome Angiogenesis |
| title_short | Development of Hydroxamate Derivatives Containing a Pyrazoline Moiety as APN Inhibitors to Overcome Angiogenesis |
| title_sort | development of hydroxamate derivatives containing a pyrazoline moiety as apn inhibitors to overcome angiogenesis |
| topic | aminopeptidase N CD13 inhibitors antitumor agents anti-angiogenesis |
| url | https://www.mdpi.com/1420-3049/27/23/8339 |
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