Scientific Publications

Syntheses of aminoalcohol-derived macrocycles leading to a small-molecule binder to and inhibitor of Sonic Hedgehog.

Publication TypeJournal Article
AuthorsPeng, LF, Stanton BZ, Maloof N., Wang X., and Schreiber SL
AbstractWe report the synthesis and biological activity of a library of aminoalcohol-derived macrocycles from which robotnikinin, 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.
Year of Publication2009
JournalBioorganic & medicinal chemistry letters
Volume19
Issue22
Pages6319-25
Date Published (YYYY/MM/DD)2009/11/15
ISSN Number0960-894X
DOI10.1016/j.bmcl.2009.09.089
PubMedhttp://www.ncbi.nlm.nih.gov/pubmed/19819139?dopt=Abstract