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• W2028085462 abstract "Abstract 17β‐Hydroxysteroid dehydrogenase type 1 (17β‐HSD1), an oxidoreductase which has a preferential reductive activity using NADPH as cofactor, converts estrone to estradiol and is expressed in many steroidogenic tissues including breast and in malignant breast cells. As estradiol stimulates the growth and development of hormone‐dependent breast cancer, inhibition of the final step of its synthesis is an attractive target for the treatment of this disease. The parallel synthesis of novel focused libraries of 16‐substituted estrone derivatives and modified E‐ring pyrazole steroids as new potent 17β‐HSD1 inhibitors is described. Substituted 3‐O‐sulfamoylated estrone derivatives were used as templates and were immobilised on 2‐chlorotrityl chloride resin to give resin‐bound scaffolds with a multi‐detachable linker. Novel focused libraries of 16‐substituted estrone derivatives and new modified E‐ring steroids were assembled from these immobilised templates using solid‐phase organic synthesis and solution‐phase methodologies. Among the derivatives synthesised, the most potent 17β‐HSD1 inhibitors were 25 and 26 with IC 50 values in T‐47D human breast cancer cells of 27 and 165 n m, respectively. Parallel synthesis resulting in a library of C5′‐linked amides from the pyrazole E‐ring led to the identification of 62 with an IC 50 value of 700 n M . These potent inhibitors of 17β‐HSD1 have a 2‐ethyl substituent which will decrease their estrogenic potential. Several novel 17β‐HSD1 inhibitors emerged from these libraries and these provide direction for further template exploration in this area. A new efficient diastereoselective synthesis of 25 has also been developed to facilitate supply for in vivo evaluation, and an X‐ray crystal structure of this inhibitor is presented." @default.
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• W2028085462 date "2006-03-29" @default.
• W2028085462 modified "2023-10-10" @default.
• W2028085462 title "Focused Libraries of 16-Substituted Estrone Derivatives and Modified E-Ring Steroids: Inhibitors of 17ß-Hydroxysteroid Dehydrogenase Type 1" @default.
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• W2028085462 doi "https://doi.org/10.1002/cmdc.200500087" @default.
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