کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
9892185 | 1541104 | 2005 | 8 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
A letrozole-based dual aromatase-sulphatase inhibitor with in vivo activity
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کلمات کلیدی
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شیمی
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چکیده انگلیسی
The role of aromatase inhibitors in the treatment of hormone-dependent breast cancer is well established. However, it is now recognised that steroid sulphatase (STS) inhibitors represent a new form of endocrine therapy. To explore the potential advantage of dual inhibition by a single agent, we recently developed a series of dual aromatase-sulphatase inhibitors (DASIs) based on the aromatase inhibitor YM511. We report here a new structural class of DASI obtained by obtained introducing the pharmacophore for STS inhibition, i.e. a phenol sulphamate ester into another established aromatase inhibitor letrozole. Hence, the bis-sulphamate 9 was synthesised which exhibited IC50 values of 3044 nM for aromatase and >10 μM for STS in JEG-3 cells. However, at a single oral dose of 10 mg/kg, 9 inhibited aromatase and rat liver STS by 60% and 88%, respectively, 24 h after administration. A proposed metabolite of 9, carbinol 10, was synthesised. Despite also showing weak STS inhibition in JEG-3 cells, 10 inhibited rat liver STS activity to the same extent as 9 at a single oral dose of 10 mg/kg. Thus, the concept of a letrozole-based DASI has been validated and could be further developed and modified for therapeutic exploitation.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: The Journal of Steroid Biochemistry and Molecular Biology - Volume 94, Issues 1â3, February 2005, Pages 123-130
Journal: The Journal of Steroid Biochemistry and Molecular Biology - Volume 94, Issues 1â3, February 2005, Pages 123-130
نویسندگان
Paul M. Wood, L.W. Lawrence Woo, Anna Humphreys, Surinder K. Chander, Atul Purohit, Michael J. Reed, Barry V.L. Potter,