Identification of Nitric Oxide Donating Dasatinib Derivatives with Intraocular Pressure Lowering and Senolytic Activities
Based on two major risk factors of glaucoma, elevated intraocular pressure (IOP) and senescence, two new series of nitric oxide (NO) donating dasatinib derivatives <b>1a</b>-<b>f</b>, <b>2a</b>-<b>f</b> were designed, synthesized, and biologically evaluated. The results demonstrated that the most active compound <b>2e</b> effectively released NO and increased the concentration of 3',5'-cyclic guanosine monophosphate in human trabecular meshwork cells, as well as maintained senolytic activity. Topical administration of <b>2e</b> in chronic ocular hypertension (COHT) glaucoma mice not only significantly eliminated senescent cells in retina but also exhibited potent retinal ganglion cells (RGCs) surviving, IOP lowering, and visual function protection activities, which were superior to those of dasatinib. Compared with younger adult mice, aged COHT mice resulted in more severe RGCs loss, while <b>2e</b> demonstrated a greater capacity to improve RGCs survival. Our findings show that dual IOP lowering and senolytic functions could be a promising therapeutic strategy for glaucoma, particularly in older patients.
Authors
- Cunrui Li (ORCID: https://orcid.org/0009-0003-5523-7478)
- Yuhua Lai
- Zhangjian Huang (ORCID: https://orcid.org/0000-0001-6409-8535)
- Keling Wu
- Hua Zuo (ORCID: https://orcid.org/0000-0002-8461-8988)
- Ling Zhao (ORCID: https://orcid.org/0000-0002-6644-2886)
- Jianbing Wu (ORCID: https://orcid.org/0000-0003-2725-9859)
- Minglei Zhao (ORCID: https://orcid.org/0000-0001-5832-6060)
- Jingyi Luo (ORCID: https://orcid.org/0000-0002-8408-3880)
- Jiaming Zhang (ORCID: https://orcid.org/0000-0002-1929-5481)
- Haohan Yang
- Zhongshu Pan
- Huiying Song
- Zirong Zhang
Institutions
- Xinjiang Medical University (CN)
- Sun Yat-sen University (CN)
- China Pharmaceutical University (CN)
- Key Laboratory of Guangdong Province (CN)
- Drug Discovery Laboratory (Norway) (NO)
- State Key Laboratory of Natural Medicine
- Zhongshan Ophthalmic Center, Sun Yat-sen University
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-04-14
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00269
- Citations
- 1
- Primary Topic
- Glaucoma and retinal disorders
- Type
- article
- Field-Weighted Citation Impact
- 1.71
Funders
- Natural Science Foundation of Xinjiang Province
- National Natural Science Foundation of China
- Sun Yat-sen University
- Science and Technology Department of Xinjiang Uyghur Autonomous Region
- State Key Laboratory of Ophthalmology
- National Key Research and Development Program of China
- Science and Technology Planning Project of Guangdong Province