Synthesis and evaluation of 5, 6-dihydro-8H-isoquinolino[1, 2-b]quinazolin-8-one derivatives as novel non-lipogenic ABCA1 up-regulators with inhibitory effects on macrophage-derived foam cell formation
Increasing the expression of ATP-binding cassette transporter A1 (ABCA1) can lower cellular cholesterol levels and prevent foam cell formation. In this study, a series of 5, 6-dihydro-8H-isoquinolino[1, 2-b]quinazolin-8-one derivatives were synthesised and assessed for their ability to up-regulate A...
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| Language: | English |
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Taylor & Francis Group
2025-12-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/14756366.2025.2470310 |
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| author | Changhuan Yang Lin Chen Yanmei Jiang Demeng Sun Yun Hu |
| author_facet | Changhuan Yang Lin Chen Yanmei Jiang Demeng Sun Yun Hu |
| author_sort | Changhuan Yang |
| collection | DOAJ |
| description | Increasing the expression of ATP-binding cassette transporter A1 (ABCA1) can lower cellular cholesterol levels and prevent foam cell formation. In this study, a series of 5, 6-dihydro-8H-isoquinolino[1, 2-b]quinazolin-8-one derivatives were synthesised and assessed for their ability to up-regulate ABCA1 expression. The structure-activity relationship was explored and summarised. Among the 28 derivatives, compound 3 exhibited the most potent activity in activating the ABCA1 promoter (2.50-fold), significantly up-regulating both ABCA1 mRNA and protein levels in RAW264.7 macrophage cells. Mechanism studies revealed that compound 3 acted by targeting the LXR-involved pathway. In a foam cell model, compound 3 reduced ox-LDL-induced lipid accumulation and thereby inhibited foam cell formation. Moreover, compared to the LXR agonist T0901317, compound 3 led to minimal accumulation of unwanted lipids and triglycerides in HepG2 cells. With little cytotoxicity towards all the tested cell lines, compound 3 holds promise as a novel potential anti-atherogenic agent for further exploration. |
| format | Article |
| id | doaj-art-4fa76e2a94884c38bd3abbb8ae3dd4f5 |
| institution | OA Journals |
| issn | 1475-6366 1475-6374 |
| language | English |
| publishDate | 2025-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj-art-4fa76e2a94884c38bd3abbb8ae3dd4f52025-08-20T02:30:15ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742025-12-0140110.1080/14756366.2025.2470310Synthesis and evaluation of 5, 6-dihydro-8H-isoquinolino[1, 2-b]quinazolin-8-one derivatives as novel non-lipogenic ABCA1 up-regulators with inhibitory effects on macrophage-derived foam cell formationChanghuan Yang0Lin Chen1Yanmei Jiang2Demeng Sun3Yun Hu4School of Bioengineering, Zunyi Medical University, Zhuhai, ChinaSchool of Bioengineering, Zunyi Medical University, Zhuhai, ChinaSchool of Bioengineering, Zunyi Medical University, Zhuhai, ChinaSchool of Bioengineering, Zunyi Medical University, Zhuhai, ChinaSchool of Bioengineering, Zunyi Medical University, Zhuhai, ChinaIncreasing the expression of ATP-binding cassette transporter A1 (ABCA1) can lower cellular cholesterol levels and prevent foam cell formation. In this study, a series of 5, 6-dihydro-8H-isoquinolino[1, 2-b]quinazolin-8-one derivatives were synthesised and assessed for their ability to up-regulate ABCA1 expression. The structure-activity relationship was explored and summarised. Among the 28 derivatives, compound 3 exhibited the most potent activity in activating the ABCA1 promoter (2.50-fold), significantly up-regulating both ABCA1 mRNA and protein levels in RAW264.7 macrophage cells. Mechanism studies revealed that compound 3 acted by targeting the LXR-involved pathway. In a foam cell model, compound 3 reduced ox-LDL-induced lipid accumulation and thereby inhibited foam cell formation. Moreover, compared to the LXR agonist T0901317, compound 3 led to minimal accumulation of unwanted lipids and triglycerides in HepG2 cells. With little cytotoxicity towards all the tested cell lines, compound 3 holds promise as a novel potential anti-atherogenic agent for further exploration.https://www.tandfonline.com/doi/10.1080/14756366.2025.2470310ABCA1macrophage foam cellatherosclerosisquinazolinone |
| spellingShingle | Changhuan Yang Lin Chen Yanmei Jiang Demeng Sun Yun Hu Synthesis and evaluation of 5, 6-dihydro-8H-isoquinolino[1, 2-b]quinazolin-8-one derivatives as novel non-lipogenic ABCA1 up-regulators with inhibitory effects on macrophage-derived foam cell formation Journal of Enzyme Inhibition and Medicinal Chemistry ABCA1 macrophage foam cell atherosclerosis quinazolinone |
| title | Synthesis and evaluation of 5, 6-dihydro-8H-isoquinolino[1, 2-b]quinazolin-8-one derivatives as novel non-lipogenic ABCA1 up-regulators with inhibitory effects on macrophage-derived foam cell formation |
| title_full | Synthesis and evaluation of 5, 6-dihydro-8H-isoquinolino[1, 2-b]quinazolin-8-one derivatives as novel non-lipogenic ABCA1 up-regulators with inhibitory effects on macrophage-derived foam cell formation |
| title_fullStr | Synthesis and evaluation of 5, 6-dihydro-8H-isoquinolino[1, 2-b]quinazolin-8-one derivatives as novel non-lipogenic ABCA1 up-regulators with inhibitory effects on macrophage-derived foam cell formation |
| title_full_unstemmed | Synthesis and evaluation of 5, 6-dihydro-8H-isoquinolino[1, 2-b]quinazolin-8-one derivatives as novel non-lipogenic ABCA1 up-regulators with inhibitory effects on macrophage-derived foam cell formation |
| title_short | Synthesis and evaluation of 5, 6-dihydro-8H-isoquinolino[1, 2-b]quinazolin-8-one derivatives as novel non-lipogenic ABCA1 up-regulators with inhibitory effects on macrophage-derived foam cell formation |
| title_sort | synthesis and evaluation of 5 6 dihydro 8h isoquinolino 1 2 b quinazolin 8 one derivatives as novel non lipogenic abca1 up regulators with inhibitory effects on macrophage derived foam cell formation |
| topic | ABCA1 macrophage foam cell atherosclerosis quinazolinone |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2025.2470310 |
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