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- Chang, Chiao-Nien, et al.
(författare)
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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
- 2022
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Ingår i: Bioorganic chemistry. - : Elsevier BV. - 0045-2068.
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Tidskriftsartikel (refereegranskat)abstract
- 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 19m, 19v, and 19w, had KI of 0.02 to 0.11 nM and kinact/KI 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 19m, 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.
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| 2. |
- Lin, Tzung-Sheng, et al.
(författare)
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Sulfation pattern of chondroitin sulfate in human osteoarthritis cartilages reveals a lower level of chondroitin-4-sulfate
- 2020
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Ingår i: Carbohydrate Polymers. - : Elsevier. - 0144-8617 .- 1879-1344. ; 229
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Tidskriftsartikel (refereegranskat)abstract
- Chondroitin sulfates (CS) account for more than 80% of glycosaminoglycans of articular cartilage, which imparts its physiological functions. We quantified the absolute concentration of the CS components of the full thickness cartilages from the knees of patients with terminal-phase osteoarthritis. Osteochondrol biopsies were removed from the medial femoral condyle and lateral femoral condyle of sixty female patients receiving total knee arthroplasty, aged from 58 to 83 years old. We found that total CS concentrations and chondroitin-4-sulfate disaccharide were significantly lowered in osteoarthritic samples. Microstructure analysis indicated that while chondroitin-0-sulfate was equally distributed across different zones of the osteoarthritic cartilages, chondroitin-4-sulfate is significantly less in the deep zones. Down-regulation of sulfotransferases, the enzymes responsible for CS sulfation in the lesion site of cartilage were observed. Our study suggested chondroitin-4-sulfate down-regulation may be a diagnostic marker for degraded osteoarthritis cartilage, with potential implications in cartilage regeneration.
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