Design and synthesis of 3,4-seco-lupane triterpene derivatives to resist myocardial ischemia-reperfusion injury by inhibiting oxidative stress-mediated mitochondrial dysfunction via the PI3K/AKT/HIF-1α axis
In this study, 86 new seco-lupane triterpenoid derivatives were designed, synthesized, and characterized, and their protective activities against ischemia-reperfusion injury were investigated in vitro and in vivo. Structure–activity relationship studies revealed that most target compounds could prot...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-11-01
|
| Series: | Biomedicine & Pharmacotherapy |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332223012507 |
| _version_ | 1797660611274866688 |
|---|---|
| author | Hongbo Teng Di Wu Luo Lu Chunyu Gao Haohao Wang Yan Zhao Liyan Wang |
| author_facet | Hongbo Teng Di Wu Luo Lu Chunyu Gao Haohao Wang Yan Zhao Liyan Wang |
| author_sort | Hongbo Teng |
| collection | DOAJ |
| description | In this study, 86 new seco-lupane triterpenoid derivatives were designed, synthesized, and characterized, and their protective activities against ischemia-reperfusion injury were investigated in vitro and in vivo. Structure–activity relationship studies revealed that most target compounds could protect cardiomyocytes against hypoxia/reoxygenation-induced injury in vitro, with compound 85 being the most active and exhibiting more potent protective activity than clinical first-line drugs. Furthermore, all thiophene derivatives exhibited stronger protective activity than furan, pyridine, and pyrazine derivatives, and the protective activity gradually increased with the extension of the alkyl chain and changed in the substituent. The data from the in-vitro and in-vivo experiments revealed that compound 85 protected mitochondria from damage by inhibiting excessive production of oxidative stressors, such as intracellular ROS, which in turn inhibited the apoptosis and necrotize of cardiomyocytes and reduced infarct size, thereby protecting normal cardiac function. It was associated with enhanced activation of the PI3K/AKT-mediated HIF-1α signaling pathway. Therefore, compound 85 acts as an oxidative stress inhibitor, blocks ROS production, protects mitochondria and cells from myocardial ischemia/reperfusion (MI/R) injury, and represents an effective new drug for treating MI/R injury. |
| first_indexed | 2024-03-11T18:32:23Z |
| format | Article |
| id | doaj.art-e68b4b1c43bc44219f6285ae4601a3e9 |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-03-11T18:32:23Z |
| publishDate | 2023-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-e68b4b1c43bc44219f6285ae4601a3e92023-10-13T11:02:40ZengElsevierBiomedicine & Pharmacotherapy0753-33222023-11-01167115452Design and synthesis of 3,4-seco-lupane triterpene derivatives to resist myocardial ischemia-reperfusion injury by inhibiting oxidative stress-mediated mitochondrial dysfunction via the PI3K/AKT/HIF-1α axisHongbo Teng0Di Wu1Luo Lu2Chunyu Gao3Haohao Wang4Yan Zhao5Liyan Wang6College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, Jilin, ChinaDepartment of Breast Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, ChinaDrug Evaluation Center of Jilin Province, Changchun, Jilin, ChinaCollege of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, Jilin, ChinaCollege of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, Jilin, ChinaCollege of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, Jilin, China; Corresponding authors.College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, Jilin, China; Corresponding authors.In this study, 86 new seco-lupane triterpenoid derivatives were designed, synthesized, and characterized, and their protective activities against ischemia-reperfusion injury were investigated in vitro and in vivo. Structure–activity relationship studies revealed that most target compounds could protect cardiomyocytes against hypoxia/reoxygenation-induced injury in vitro, with compound 85 being the most active and exhibiting more potent protective activity than clinical first-line drugs. Furthermore, all thiophene derivatives exhibited stronger protective activity than furan, pyridine, and pyrazine derivatives, and the protective activity gradually increased with the extension of the alkyl chain and changed in the substituent. The data from the in-vitro and in-vivo experiments revealed that compound 85 protected mitochondria from damage by inhibiting excessive production of oxidative stressors, such as intracellular ROS, which in turn inhibited the apoptosis and necrotize of cardiomyocytes and reduced infarct size, thereby protecting normal cardiac function. It was associated with enhanced activation of the PI3K/AKT-mediated HIF-1α signaling pathway. Therefore, compound 85 acts as an oxidative stress inhibitor, blocks ROS production, protects mitochondria and cells from myocardial ischemia/reperfusion (MI/R) injury, and represents an effective new drug for treating MI/R injury.http://www.sciencedirect.com/science/article/pii/S07533322230125073,4-seco-lupane triterpene derivativesMyocardial ischemia-reperfusion injuryMitochondrial dysfunctionOxidative stress blockerPI3K/AKT/HIF-1α |
| spellingShingle | Hongbo Teng Di Wu Luo Lu Chunyu Gao Haohao Wang Yan Zhao Liyan Wang Design and synthesis of 3,4-seco-lupane triterpene derivatives to resist myocardial ischemia-reperfusion injury by inhibiting oxidative stress-mediated mitochondrial dysfunction via the PI3K/AKT/HIF-1α axis Biomedicine & Pharmacotherapy 3,4-seco-lupane triterpene derivatives Myocardial ischemia-reperfusion injury Mitochondrial dysfunction Oxidative stress blocker PI3K/AKT/HIF-1α |
| title | Design and synthesis of 3,4-seco-lupane triterpene derivatives to resist myocardial ischemia-reperfusion injury by inhibiting oxidative stress-mediated mitochondrial dysfunction via the PI3K/AKT/HIF-1α axis |
| title_full | Design and synthesis of 3,4-seco-lupane triterpene derivatives to resist myocardial ischemia-reperfusion injury by inhibiting oxidative stress-mediated mitochondrial dysfunction via the PI3K/AKT/HIF-1α axis |
| title_fullStr | Design and synthesis of 3,4-seco-lupane triterpene derivatives to resist myocardial ischemia-reperfusion injury by inhibiting oxidative stress-mediated mitochondrial dysfunction via the PI3K/AKT/HIF-1α axis |
| title_full_unstemmed | Design and synthesis of 3,4-seco-lupane triterpene derivatives to resist myocardial ischemia-reperfusion injury by inhibiting oxidative stress-mediated mitochondrial dysfunction via the PI3K/AKT/HIF-1α axis |
| title_short | Design and synthesis of 3,4-seco-lupane triterpene derivatives to resist myocardial ischemia-reperfusion injury by inhibiting oxidative stress-mediated mitochondrial dysfunction via the PI3K/AKT/HIF-1α axis |
| title_sort | design and synthesis of 3 4 seco lupane triterpene derivatives to resist myocardial ischemia reperfusion injury by inhibiting oxidative stress mediated mitochondrial dysfunction via the pi3k akt hif 1α axis |
| topic | 3,4-seco-lupane triterpene derivatives Myocardial ischemia-reperfusion injury Mitochondrial dysfunction Oxidative stress blocker PI3K/AKT/HIF-1α |
| url | http://www.sciencedirect.com/science/article/pii/S0753332223012507 |
| work_keys_str_mv | AT hongboteng designandsynthesisof34secolupanetriterpenederivativestoresistmyocardialischemiareperfusioninjurybyinhibitingoxidativestressmediatedmitochondrialdysfunctionviathepi3kakthif1aaxis AT diwu designandsynthesisof34secolupanetriterpenederivativestoresistmyocardialischemiareperfusioninjurybyinhibitingoxidativestressmediatedmitochondrialdysfunctionviathepi3kakthif1aaxis AT luolu designandsynthesisof34secolupanetriterpenederivativestoresistmyocardialischemiareperfusioninjurybyinhibitingoxidativestressmediatedmitochondrialdysfunctionviathepi3kakthif1aaxis AT chunyugao designandsynthesisof34secolupanetriterpenederivativestoresistmyocardialischemiareperfusioninjurybyinhibitingoxidativestressmediatedmitochondrialdysfunctionviathepi3kakthif1aaxis AT haohaowang designandsynthesisof34secolupanetriterpenederivativestoresistmyocardialischemiareperfusioninjurybyinhibitingoxidativestressmediatedmitochondrialdysfunctionviathepi3kakthif1aaxis AT yanzhao designandsynthesisof34secolupanetriterpenederivativestoresistmyocardialischemiareperfusioninjurybyinhibitingoxidativestressmediatedmitochondrialdysfunctionviathepi3kakthif1aaxis AT liyanwang designandsynthesisof34secolupanetriterpenederivativestoresistmyocardialischemiareperfusioninjurybyinhibitingoxidativestressmediatedmitochondrialdysfunctionviathepi3kakthif1aaxis |