کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1372710 981879 2009 7 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Syntheses of aminoalcohol-derived macrocycles leading to a small-molecule binder to and inhibitor of Sonic Hedgehog
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آلی
پیش نمایش صفحه اول مقاله
Syntheses of aminoalcohol-derived macrocycles leading to a small-molecule binder to and inhibitor of Sonic Hedgehog
چکیده انگلیسی

We report the synthesis and biological activity of a library of aminoalcohol-derived macrocycles from which robotnikinin (17), a binder to and inhibitor of Sonic Hedgehog, was derived. Using an asymmetric alkylation to set a key stereocenter and an RCM reaction to close the macrocycle, we were able to synthesize compounds for testing. High-throughput screening via small-molecule microarray (SMM) technology led to the discovery of a compound capable of binding ShhN. Follow-up chemistry led to a library of macrocycles with enhanced biological activity relative to the original hit compounds. Differences in ring size and stereochemistry, leading to alterations in the mode of binding, may account for differences in the degree of biological activity. These compounds are the first ones reported that inhibit Shh signaling at the ShhN level.

We report the synthesis and biological activity of a library of aminoalcohol-derived macrocycles from which robotnikinin (17), a binder and inhibitor of Sonic Hedgehog, was derived.Figure optionsDownload as PowerPoint slide

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 19, Issue 22, 15 November 2009, Pages 6319–6325
نویسندگان
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