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The Design, Structure–Activity, and kinetic studies of 3-Benzyl-5-oxa-1,2,3,4-Tetrahydro-2H-chromeno-(3,4-c)pyridin-8-yl sulfamates as Steroid sulfatase inhibitors.
- Source :
-
Bioorganic Chemistry . Dec2022, Vol. 129, pN.PAG-N.PAG. 1p. - Publication Year :
- 2022
-
Abstract
- [Display omitted] • Synthesis of 32 tricyclic sulfamates as STS irreversible inhibitors. • SAR studies revealed that adjacent halogen-bearing phenyl gave the best inhibition. • 19 m , 19v , and 19w , had K I of 0.02 to 0.11 nM against STS. • Cellular potency is significant correlated with covalent kinetics (k inact/ K I). Steroid sulfatase inhibitors block the local production of estrogenic steroids and are attractive agents for the treatment of estrogen-dependent cancers. Inspiration of coumarin-based inhibitors, we synthesized thirty-two 5-oxa-1,2,3,4-tetrahydro-2H-chromeno-(3,4-c)pyridin-8-yl sulfamates , focusing on the substitution derivatives on the adjacent phenyl ring and evaluated their abilities to block STS from human placenta and MCF-7 cells. SAR analysis revealed that the incorporation of chlorine at either meta and/or para position of the adjacent phenyl ring of the tricyclic skeleton enhanced STS inhibition. Di-substitutions at the adjacent phenyl ring were superior to mono and tri-substitutions. Further kinetic analysis of these compounds revealed that chloride-bearing compounds, such as 19 m , 19v , and 19w , had K I of 0.02 to 0.11 nM and k inact / K I ratios of 8.8–17.5 nM-1min-1, a parameter indicated for the efficiency of irreversible inhibition. We also used the docking model to illustrate the difference in STS inhibitory potency of compounds. Finally, the safety and anti-cancer activity of selected compounds 19 m , 19v , and 19w were also studied, showing the results of low cytotoxicity on NHDF cell line and being more potent than irosustat on ZR-75–1 cell, which was a hormone-dependent cancer cell line with high STS expression. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00452068
- Volume :
- 129
- Database :
- Academic Search Index
- Journal :
- Bioorganic Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 160030876
- Full Text :
- https://doi.org/10.1016/j.bioorg.2022.106148