Melatonin Analogues Potently Inhibit MAO-B and Protect PC12 Cells against Oxidative Stress
Monoamine oxidase B (MAO-B) metabolizes dopamine and plays an important role in oxidative stress by altering the redox state of neuronal and glial cells. MAO-B inhibitors are a promising therapeutical approach for Parkinson’s disease (PD). Herein, 24 melatonin analogues (<b>3a</b>–<b&...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-10-01
|
| Series: | Antioxidants |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2076-3921/10/10/1604 |
| _version_ | 1827680291561406464 |
|---|---|
| author | Ahmed Elkamhawy Jiyu Woo Noha A. Gouda Jushin Kim Hossam Nada Eun Joo Roh Ki Duk Park Jungsook Cho Kyeong Lee |
| author_facet | Ahmed Elkamhawy Jiyu Woo Noha A. Gouda Jushin Kim Hossam Nada Eun Joo Roh Ki Duk Park Jungsook Cho Kyeong Lee |
| author_sort | Ahmed Elkamhawy |
| collection | DOAJ |
| description | Monoamine oxidase B (MAO-B) metabolizes dopamine and plays an important role in oxidative stress by altering the redox state of neuronal and glial cells. MAO-B inhibitors are a promising therapeutical approach for Parkinson’s disease (PD). Herein, 24 melatonin analogues (<b>3a</b>–<b>x</b>) were synthesized as novel MAO-B inhibitors with the potential to counteract oxidative stress in neuronal PC12 cells. Structure elucidation, characterization, and purity of the synthesized compounds were performed using <sup>1</sup>H-NMR, <sup>13</sup>C-NMR, HRMS, and HPLC. At 10 µM, 12 compounds showed >50% MAO-B inhibition. Among them, compounds <b>3n</b>, <b>3r</b>, and <b>3u</b>–<b>w</b> showed >70% inhibition of MAO-B and IC<sub>50</sub> values of 1.41, 0.91, 1.20, 0.66, and 2.41 µM, respectively. When compared with the modest selectivity index of rasagiline (<b>II</b>, a well-known MAO-B inhibitor, SI > 50), compounds <b>3n, 3r, 3u</b>, and <b>3v</b> demonstrated better selectivity indices (SI > 71, 109, 83, and 151, respectively). Furthermore, compounds <b>3n</b> and <b>3r</b> exhibited safe neurotoxicity profiles in PC12 cells and reversed 6-OHDA- and rotenone-induced neuronal oxidative stress. Both compounds significantly up-regulated the expression of the anti-oxidant enzyme, heme oxygenase (HO)-1. Treatment with Zn(II)-protoporphyrin IX (ZnPP), a selective HO-1 inhibitor, abolished the neuroprotective effects of the tested compounds, suggesting a critical role of HO-1 up-regulation. Both compounds increased the nuclear translocation of Nrf2, which is a key regulator of the antioxidative response. Taken together, these data show that compounds <b>3n</b> and <b>3r</b> could be further exploited for their multi-targeted role in oxidative stress-related PD therapy. |
| first_indexed | 2024-03-10T06:45:39Z |
| format | Article |
| id | doaj.art-c630a0a8ffc644af9223996627ec7133 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-10T06:45:39Z |
| publishDate | 2021-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-c630a0a8ffc644af9223996627ec71332023-11-22T17:16:36ZengMDPI AGAntioxidants2076-39212021-10-011010160410.3390/antiox10101604Melatonin Analogues Potently Inhibit MAO-B and Protect PC12 Cells against Oxidative StressAhmed Elkamhawy0Jiyu Woo1Noha A. Gouda2Jushin Kim3Hossam Nada4Eun Joo Roh5Ki Duk Park6Jungsook Cho7Kyeong Lee8College of Pharmacy, Dongguk University-Seoul, Goyang 10326, KoreaCollege of Pharmacy, Dongguk University-Seoul, Goyang 10326, KoreaCollege of Pharmacy, Dongguk University-Seoul, Goyang 10326, KoreaConvergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology (KIST), Seoul 02792, KoreaCollege of Pharmacy, Dongguk University-Seoul, Goyang 10326, KoreaChemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, KoreaConvergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology (KIST), Seoul 02792, KoreaCollege of Pharmacy, Dongguk University-Seoul, Goyang 10326, KoreaCollege of Pharmacy, Dongguk University-Seoul, Goyang 10326, KoreaMonoamine oxidase B (MAO-B) metabolizes dopamine and plays an important role in oxidative stress by altering the redox state of neuronal and glial cells. MAO-B inhibitors are a promising therapeutical approach for Parkinson’s disease (PD). Herein, 24 melatonin analogues (<b>3a</b>–<b>x</b>) were synthesized as novel MAO-B inhibitors with the potential to counteract oxidative stress in neuronal PC12 cells. Structure elucidation, characterization, and purity of the synthesized compounds were performed using <sup>1</sup>H-NMR, <sup>13</sup>C-NMR, HRMS, and HPLC. At 10 µM, 12 compounds showed >50% MAO-B inhibition. Among them, compounds <b>3n</b>, <b>3r</b>, and <b>3u</b>–<b>w</b> showed >70% inhibition of MAO-B and IC<sub>50</sub> values of 1.41, 0.91, 1.20, 0.66, and 2.41 µM, respectively. When compared with the modest selectivity index of rasagiline (<b>II</b>, a well-known MAO-B inhibitor, SI > 50), compounds <b>3n, 3r, 3u</b>, and <b>3v</b> demonstrated better selectivity indices (SI > 71, 109, 83, and 151, respectively). Furthermore, compounds <b>3n</b> and <b>3r</b> exhibited safe neurotoxicity profiles in PC12 cells and reversed 6-OHDA- and rotenone-induced neuronal oxidative stress. Both compounds significantly up-regulated the expression of the anti-oxidant enzyme, heme oxygenase (HO)-1. Treatment with Zn(II)-protoporphyrin IX (ZnPP), a selective HO-1 inhibitor, abolished the neuroprotective effects of the tested compounds, suggesting a critical role of HO-1 up-regulation. Both compounds increased the nuclear translocation of Nrf2, which is a key regulator of the antioxidative response. Taken together, these data show that compounds <b>3n</b> and <b>3r</b> could be further exploited for their multi-targeted role in oxidative stress-related PD therapy.https://www.mdpi.com/2076-3921/10/10/1604bioactive moleculesoxidative stressneurodegenerationbrain healthParkinson’s diseaseMAO-B |
| spellingShingle | Ahmed Elkamhawy Jiyu Woo Noha A. Gouda Jushin Kim Hossam Nada Eun Joo Roh Ki Duk Park Jungsook Cho Kyeong Lee Melatonin Analogues Potently Inhibit MAO-B and Protect PC12 Cells against Oxidative Stress Antioxidants bioactive molecules oxidative stress neurodegeneration brain health Parkinson’s disease MAO-B |
| title | Melatonin Analogues Potently Inhibit MAO-B and Protect PC12 Cells against Oxidative Stress |
| title_full | Melatonin Analogues Potently Inhibit MAO-B and Protect PC12 Cells against Oxidative Stress |
| title_fullStr | Melatonin Analogues Potently Inhibit MAO-B and Protect PC12 Cells against Oxidative Stress |
| title_full_unstemmed | Melatonin Analogues Potently Inhibit MAO-B and Protect PC12 Cells against Oxidative Stress |
| title_short | Melatonin Analogues Potently Inhibit MAO-B and Protect PC12 Cells against Oxidative Stress |
| title_sort | melatonin analogues potently inhibit mao b and protect pc12 cells against oxidative stress |
| topic | bioactive molecules oxidative stress neurodegeneration brain health Parkinson’s disease MAO-B |
| url | https://www.mdpi.com/2076-3921/10/10/1604 |
| work_keys_str_mv | AT ahmedelkamhawy melatoninanaloguespotentlyinhibitmaobandprotectpc12cellsagainstoxidativestress AT jiyuwoo melatoninanaloguespotentlyinhibitmaobandprotectpc12cellsagainstoxidativestress AT nohaagouda melatoninanaloguespotentlyinhibitmaobandprotectpc12cellsagainstoxidativestress AT jushinkim melatoninanaloguespotentlyinhibitmaobandprotectpc12cellsagainstoxidativestress AT hossamnada melatoninanaloguespotentlyinhibitmaobandprotectpc12cellsagainstoxidativestress AT eunjooroh melatoninanaloguespotentlyinhibitmaobandprotectpc12cellsagainstoxidativestress AT kidukpark melatoninanaloguespotentlyinhibitmaobandprotectpc12cellsagainstoxidativestress AT jungsookcho melatoninanaloguespotentlyinhibitmaobandprotectpc12cellsagainstoxidativestress AT kyeonglee melatoninanaloguespotentlyinhibitmaobandprotectpc12cellsagainstoxidativestress |