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Development of a metabolically stable topoisomerase I poison as anticancer agent.
- Source :
-
European Journal of Medicinal Chemistry . Sep2020, Vol. 202, pN.PAG-N.PAG. 1p. - Publication Year :
- 2020
-
Abstract
- We have recently reported a new chemotype of a potent topoisomerase I poison with compound 1 as a potential anticancer chemotherapeutic agent. During further optimization, it has been observed that compound 1 suffers from high intrinsic clearance in human liver microsomes. To overcome the metabolic instability of compound 1 , we report design and synthesis of metabolically stable Top1 poison 3. Newly identified Top1 poison 3 exhibits t 1/2 of 69.1 min in human liver microsomes in comparison to compound 1 with t 1/2 of 9.9 min. Molecular dynamic study of the newly optimized Top1 poison 3 was performed to get the insight into the stability of the binding pose in the active site. Compound 3 was able to trap DNA-Top1 cleavage complex and found to be less cytotoxic in non-cancerous cell line as compared to compound 1. Image 1 • Strategic development of potent Top1 poison with enhanced metabolic stability. • Validation of compound 3 as Top1 poison by ex vivo plasmid DNA cleavage assay. • Molecular Dynamic simulations of compound 3 in the active site. • Lead compound 3 found to be less cytotoxic in non-cancerous cell line. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 02235234
- Volume :
- 202
- Database :
- Academic Search Index
- Journal :
- European Journal of Medicinal Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 145071082
- Full Text :
- https://doi.org/10.1016/j.ejmech.2020.112551